ORCID Profile
0000-0001-8554-1823
Current Organisations
Hong Kong University of Science and Technology
,
Charles Sturt University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 12-1974
Publisher: Wiley
Date: 30-11-2009
Abstract: In line with the enhancement of antimalarial activities of the current clinical artemisinins against parasites cultured under CO, the artemisinins are unaffected in vitro by carboxyhemoglobin (CO-Hb-Fe(II)) or CO-heme-Fe(II), but are competitively decomposed by Hb-Fe(II) or heme-Fe(II). In the latter case, the heme studies are greatly facilitated by solubilization of the heme in aqueous medium by use of arginine. None of the Hb species has an appreciable effect on artemisone, or on other aminoartemisinins, and antimalarial activities are either less affected or remain essentially unchanged against parasites cultured under standard microaerophilic conditions or under CO. The findings not only indicate that artemisinins do not require Hb-Fe(II) or heme-Fe(II) for promotion of antimalarial activity, but are also important in relation to the therapy of severe/complicated or cerebral malaria.
Publisher: Oxford University Press (OUP)
Date: 19-07-2019
DOI: 10.1093/JAC/DKZ290
Abstract: Drug resistance exists to all current and investigational antimalarial drug classes. Consequently, we have set out to develop chemically and mechanistically discrete antimalarials. Here we report on the development of thiosemicarbazone (TSC) antimalarials, with TSC3 as the most advanced lead. Thiosemicarbazones were generated through simple condensation reactions of thiosemicarbazides and ketones. TSC3 was selected and tested for in vitro antimalarial activities against MDR Plasmodium falciparum lines using the [3H]hypoxanthine growth assay, in vitro cytotoxicity against mammalian cell lines using the alamarBlue fluorescence cell viability assay, in vivo potency in the mouse–Plasmodium berghei model and blood exposure in mice measured by LC-MS for pharmacokinetic analysis. TSC3 showed potent in vitro activity against atovaquone-, dihydroartemisinin-, chloroquine- and mefloquine-resistant P. falciparum lines (EC50 nM). The selectivity index (EC50 cells/EC50Pf W2 line) of TSC3 was in two of three mammalian cell lines. In P. berghei-infected mice, TSC3 showed potent activity in the Peters 4 day suppression test (ED50 1.2 mg/kg/day) and was as potent as artesunate and chloroquine in the curative modified Thompson test. A single oral dose of TSC3 at 16 mg/kg in healthy mice achieved a mean maximum blood concentration of 1883 ng/mL at 1 h after dosing and an elimination half-life of 48.7 h in groups of five mice. TSC3 shows promise as a persistent, potent and orally effective antimalarial. This, coupled with the extremely low cost of synthesis, suggests that the further development of antimalarial thiosemicarbazones is clearly warranted.
Publisher: Elsevier BV
Date: 1986
Publisher: American Psychological Association (APA)
Date: 06-2012
DOI: 10.1037/A0025831
Publisher: Elsevier BV
Date: 08-2017
Publisher: Royal Society of Chemistry (RSC)
Date: 1974
DOI: 10.1039/C39740000511
Publisher: Elsevier BV
Date: 08-1999
Publisher: Wiley
Date: 12-1974
Publisher: Springer Science and Business Media LLC
Date: 02-10-2018
DOI: 10.1038/S42004-018-0062-7
Abstract: The quinolone decoquinate is coadministered with feed for treatment of parasites which cause coccidiosis in poultry. However, from a drug-development perspective, the biological activity is often not adequately exploited due to poor physicochemical properties. Here we convert decoquinate into N -alkyl quinolone amides that, in contrast to decoquinate, are active against the tuberculosis bacterium with MIC 90 values ranging from 1.4 to 3.64 µM, and quinoline O -carbamates active against apicomplexan parasites that cause malaria, toxoplasmosis, and neosporosis with IC 50 values of 0.32–1.5 nM for the best derivative. Uniquely for the TB-active amides, disruption of cell wall homoeostasis is identified as one target. With IC 50 values against fetal lung fibroblast cells of 40 to μM, the derivatives are selective for the pathogens. Structures of the most active derivatives are determined by NMR spectroscopy and X-ray crystallography. Analogues lacking the decyl side chain of decoquinate are inactive.
Publisher: American Psychological Association (APA)
Date: 2013
DOI: 10.1037/A0032366
Publisher: Wiley
Date: 11-07-2011
Abstract: Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB) they also oxidize dihydroflavins such as the reduced conjugates RFH₂ of riboflavin (RF), and FADH₂ of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH₂, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin-mediated oxidation of RFH₂ generated from N-benzyl-1,4-dihydronicotinamide (BNAH)-RF, or FADH₂ generated from NADPH or NADPH-Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor-acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ-MB and CQ-artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP-CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ-resistance transporter (PfCRT).
Publisher: Wiley
Date: 07-06-2016
Abstract: We sought to establish if methylene homologues of artemisone are biologically more active and more stable than artemisone. The analogy is drawn with the conversion of natural O- and N-glycosides into more stable C-glycosides that may possess enhanced biological activities and stabilities. Dihydroartemisinin was converted into 10β-cyano-10-deoxyartemisinin that was hydrolyzed to the α-primary amide. Reduction of the β-cyanide and the α-amide provided the respective methylamine epimers that upon treatment with inyl sulfone gave the β- and α-methylene homologues, respectively, of artemisone. Surprisingly, the compounds were less active in vitro than artemisone against P. falciparum and displayed no appreciable activity against A549, HCT116, and MCF7 tumor cell lines. This loss in activity may be rationalized in terms of one model for the mechanism of action of artemisinins, namely the cofactor model, wherein the presence of a leaving group at C10 assists in driving hydride transfer from reduced flavin cofactors to the peroxide during perturbation of intracellular redox homeostasis by artemisinins. It is noted that the carba analogue of artemether is less active in vitro than the O-glycoside parent toward P. falciparum, although extrapolation of such activity differences to other artemisinins at this stage is not possible. However, literature data coupled with the leaving group rationale suggest that artemisinins bearing an amino group attached directly to C10 are optimal compounds.
Publisher: Royal Society of Chemistry (RSC)
Date: 1988
DOI: 10.1039/C39880000137
Publisher: CSIRO Publishing
Date: 1982
DOI: 10.1071/CH9820517
Abstract: Tributyldiiodophosphorane and diiodotriphenylphosphorane, prepared in situ from the corresponding phosphine and iodine, are generally able to convert primary and secondary alcohols into iodides at room temperature in diethyl ether or benzene containing two equivalents of hexamethylphosphoric triamide. Tertiary alcohols, as gauged by the lack of reactivity of t-butyl alcohol, are, however, inert to these iodinating agents. 6-Hydroxyhexanoic acid yields a mixture of 6-iodohexanoic acid and 7-heptanolide. The first reagent also promotes facile condensation of secondary and tertiary alcohols with carboxylic acids to form hindered esters in good yields. The phosphorane derived from tris-(dimethy1amino)phosphine and iodine, while less effective as an iodinating agent, rapidly converts 6-hydroxyhexanoic acid into 6-iodo-N,N-dimethylhexanamide, and hexanoic and benzoic acids into the corresponding N,N-dimethylamides in excellent yields at room temperature. Treatment of 3β- tosyloxycholest-5-ene with lithium iodide yields 3β-iodocholest-5-ene, and not 3α-iodocholest-5-ene, as previously reported.
Publisher: American Society for Microbiology
Date: 16-07-2021
DOI: 10.1128/AAC.00990-21
Abstract: As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug, and a third drug with different mode of action. Thus, here we briefly review efficacy data on artemisone, artemiside, other amino-artemisinins, and 11-aza-artemisinin and conduct absorption, distribution, and metabolism and excretion (ADME) profiling in vitro and pharmacokinetic (PK) profiling in vivo via intravenous (i.v.) and oral (p.o.) administration to mice.
Publisher: Public Library of Science (PLoS)
Date: 31-12-2013
Publisher: CSIRO Publishing
Date: 1980
DOI: 10.1071/CH9802653
Abstract: 1,3-Diphenylisobenzofuran is converted into o-dibenzoylbenzene (40-70%) by oxygen, either in dichloromethane at -78° in the presence of 1-2 equiv. of a variety of Lewis acids, or on silica gel at 20°, in the dark. Tetraphenylfuran is converted into (Z)-dibenzoylstilbene (55-65%) under the former conditions in the presence of 0.05 equiv. of I2 or SnI4 under irradiation from a tungsten l . The conversions, which correspond to a mono-oxygenation process, do not involve as intermediates the furan endoperoxides, which were independently generated from the furans by use of singlet oxygen. 2,5-Dimethylfuran and p-menthofuran do not react with oxygen in the presence of Lewis acids under the foregoing conditions. Tetraphenylcyclopentadiene is converted by oxygen into the corresponding endoperoxide (70-85%) in the presence of 0.05 equiv. of I2 and SnI4 or 0.1 equiv. of Ph3C+BF4- in dichloromethane at -78° under irradiation.
Publisher: Royal Society of Chemistry (RSC)
Date: 1990
DOI: 10.1039/C39900000448
Publisher: Wiley
Date: 14-12-2022
DOI: 10.1111/CBDD.14187
Abstract: The development of inhibitors that target the papain‐like protease (PLpro) has the potential to counteract the spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the agent causing coronavirus disease 2019 (COVID‐19). Based on a consideration of its several downstream effects, interfering with PLpro would both revert immune suppression exerted by the virus and inhibit viral replication. By following a repurposing strategy, the current study evaluates the potential of antimalarial drugs as PLpro inhibitors, and thereby the possibility of their use for treatment of SARS‐CoV‐2 infection. Computational tools were employed for structural analysis, molecular docking, and molecular dynamics simulations to screen antimalarial drugs against PLpro, and in silico data were validated by in vitro experiments. Virtual screening highlighted amodiaquine and methylene blue as the best candidates, and these findings were complemented by the in vitro results that indicated amodiaquine as a μM PLpro deubiquitinase inhibitor. The results of this study demonstrate that the computational workflow adopted here can correctly identify active compounds. Thus, the highlighted antimalarial drugs represent a starting point for the development of new PLpro inhibitors through structural optimization.
Publisher: Royal Society of Chemistry (RSC)
Date: 1990
DOI: 10.1039/C39900000449
Publisher: Elsevier BV
Date: 1985
Publisher: Springer Science and Business Media LLC
Date: 24-05-2023
DOI: 10.1007/S43450-023-00407-5
Abstract: Schistosomiasis, a neglected tropical disease, affects millions of lives and accounts for thousands of deaths each year. The Schistosoma parasites depend on two hosts during their lifecycle: snails as intermediate hosts and human beings as definitive hosts. Therefore, to control and ultimately eliminate schistosomiasis relies on the reduction of snail populations as well as the prevention and treatment of schistosomiasis infections. Praziquantel is the primary drug for prevention and treatment, and although it is considered safe and efficacious, concerns exist regarding emerging drug resistance due to mass drug administration. For this reason, novel antischistosomal drugs are in need and the genus Artemisia might be a promising source. Notably, Artemisia species not only have been evaluated for their antischistosomal effects against Schistosoma parasites, but also for their molluscicidal effects against the snail vectors. Extracts of Artemisia afra seem to be the most active, with IC 50 values comparable with the positive control, praziquantel. The antimalarial drug artemisinin, obtained from A. annua , and its semisynthetic derivatives artemether, artesunate, and artemisone have also been evaluated against both schistosomes and snail vectors. Artemether and artesunate have been found to be notably active against the adult and juvenile stages of schistosomes, whereas artemisone was shown to be effective in treating hosts harboring juvenile schistosomes. Artemisinin on the other hand in combination with praziquantel presents as a good lead combination in curing schistosomiasis. Graphical Abstract
Publisher: American Society for Microbiology
Date: 31-10-2021
DOI: 10.1128/SPECTRUM.00434-21
Abstract: This study addresses the development of novel therapeutic compounds for the eventual treatment of drug-resistant tuberculosis. Tuberculosis continues to progress, with cases of Mycobacterium tuberculosis ( M. tuberculosis ) resistance to first-line medications increasing.
Publisher: Royal Society of Chemistry (RSC)
Date: 1987
DOI: 10.1039/C39870000092
Publisher: MDPI AG
Date: 20-04-2023
DOI: 10.3390/PHARMACEUTICS15041293
Abstract: Self-emulsification is considered a formulation technique that has proven capacity to improve oral drug delivery of poorly soluble drugs by advancing both solubility and bioavailability. The capacity of these formulations to produce emulsions after moderate agitation and dilution by means of water phase addition provides a simplified method to improve delivery of lipophilic drugs, where prolonged drug dissolution in the aqueous environment of the gastro-intestinal (GI) tract is known as the rate-limiting step rendering decreased drug absorption. Additionally, spontaneous emulsification has been reported as an innovative topical drug delivery system that enables successful crossing of mucus membranes as well as skin. The ease of formulation generated by the spontaneous emulsification technique itself is intriguing due to the simplified production procedure and unlimited upscaling possibilities. However, spontaneous emulsification depends solely on selecting excipients that complement each other in order to create a vehicle aimed at optimizing drug delivery. If excipients are not compatible or unable to spontaneously transpire into emulsions once exposed to mild agitation, no self-emulsification will be achieved. Therefore, the generalized view of excipients as inert bystanders facilitating delivery of an active compound cannot be accepted when selecting excipients needed to produce self-emulsifying drug delivery systems (SEDDSs). Hence, this review describes the excipients needed to generate dermal SEDDSs as well as self-double-emulsifying drug delivery systems (SDEDDSs) how to consider combinations that complement the incorporated drug(s) and an overview of using natural excipients as thickening agents and skin penetration enhancers.
Publisher: Wiley
Date: 2002
DOI: 10.1002/1099-0690(20021)2002:1<113::AID-EJOC113>3.0.CO;2-N
Publisher: American Society for Microbiology
Date: 08-2014
DOI: 10.1128/AAC.01553-13
Abstract: The decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. Artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications of Plasmodium falciparum resistance to artemisinins. Consequently, drug combinations are recommended for prevention of the induction of resistance. The research here demonstrates the effects of novel combinations of the new artemisinin derivative, artemisone, a recently described 10-alkylamino artemisinin derivative with improved antimalarial activity and reduced neurotoxicity. We here investigate its ability to kill P. falciparum in a high-throughput in vitro assay and to protect mice against lethal cerebral malaria caused by Plasmodium berghei ANKA when used alone or in combination with established antimalarial drugs. Artemisone effects against P. falciparum in vitro were synergistic with halofantrine and mefloquine, and additive with 25 other drugs, including chloroquine and doxycycline. The concentrations of artemisone combinations that were toxic against THP-1 cells in vitro were much higher than their effective antimalarial concentration. Artemisone, mefloquine, chloroquine, or piperaquine given in idually mostly protected mice against cerebral malaria caused by P. berghei ANKA but did not prevent parasite recrudescence. Combinations of artemisone with any of the other three drugs did completely cure most mice of malaria. The combination of artemisone and chloroquine decreased the ratio of proinflammatory (gamma interferon, tumor necrosis factor) to anti-inflammatory (interleukin 10 [IL-10], IL-4) cytokines in the plasma of P. berghei -infected mice. Thus, artemisone in combinations with other antimalarial drugs might have a dual action, both killing parasites and limiting the potentially deleterious host inflammatory response.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2010
Abstract: Artemisinins are the newest class of drug approved for malaria treatment. Due to their unique mechanism of action, rapid effect on Plasmodium, and high efficacy in vivo, artemisinins have become essential components of malaria treatment. Administration of artemisinin derivatives in combination with other anti-plasmodials has become the first-line treatment for uncomplicated falciparum malaria. However, their efficiency in cases of cerebral malaria (CM) remains to be determined. The efficacy of several artemisinin derivatives for treatment of experimental CM was evaluated in ICR or C57BL/6 mice infected by Plasmodium berghei ANKA. Both mouse strains serve as murine models for CM. Artemisone was the most efficient drug tested, and could prevent death even when administered at relatively late stages of cerebral pathogenesis. No parasite resistance to artemisone was detected in recrudescence. Co-administration of artemisone together with chloroquine was more effective than monotherapy with either drug, and led to complete cure. Artemiside was even more effective than artemisone, but this substance has yet to be submitted to preclinical toxicological evaluation. Altogether, the results support the use of artemisone for combined therapy of CM.
Publisher: MDPI AG
Date: 03-12-2021
DOI: 10.3390/PHARMACEUTICS13122066
Abstract: Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1 DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual
Publisher: American Society for Microbiology
Date: 03-2002
DOI: 10.1128/AAC.46.3.821-827.2002
Abstract: We recently described a screening system designed to detect neurotoxicity of artemisinin derivatives based on primary neuronal brain stem cell cultures (G. Schmuck and R. K. Haynes, Neurotoxicity Res. 2:37-49, 2000). Here, we probe possible mechanisms of this brain stem-specific neurodegeneration, in which artemisinin-sensitive neuronal brain stem cell cultures are compared with nonsensitive cultures (cortical neurons, astrocytes). Effects on the cytoskeleton of brain stem cell cultures, but not that of cortical cell cultures, were visible after 7 days. However, after a recovery period of 7 days, this effect also became visible in cortical cells and more severe in brain stem cell cultures. Neurodegeneration appears to be induced by effects on intracellular targets such as the cytoskeleton, modulation of the energy status by mitochondrial or metabolic defects, oxidative stress or excitotoxic events. Artemisinin reduces intracellular ATP levels and the potential of the inner mitochondrial membrane below the cytotoxic concentration range in all three cell cultures, with these effects being most dominant in the brain stem cultures. Surprisingly, there were substantial effects on cortical neurons after 7 days and on astrocytes after 1 day. Artemisinin additionally induces oxidative stress, as observed as an increase of reactive oxygen species and of lipid peroxidation in both neuronal cell types. Interestingly, an induction of expression of AOE was only seen in astrocytes. Here, manganese superoxide dismutase (MnSOD) expression was increased more than 3-fold and catalase expression was increased more than 1.5-fold. In brain stem neurons, MnSOD expression was dose dependently decreased. Copper-zinc superoxide dismutase and glutathione peroxidase, two other antioxidant enzymes that were investigated, did not show any changes in their mRNA expression in all three cell types after exposure to artemisinin.
Publisher: Elsevier BV
Date: 06-1999
Publisher: Elsevier BV
Date: 2001
Publisher: Elsevier BV
Date: 03-2001
DOI: 10.1016/S1471-4922(00)01838-9
Abstract: Artemisinin-type compounds are used for the treatment of uncomplicated and severe forms of malaria. They reduce parasitaemia more rapidly than any other antimalarial compound known, and are effective against multidrug-resistant parasites. However, uncertainties remain as to how they act on the parasite and cause toxicity. In this review, we summarize current ideas.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2023
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.IJPHARM.2011.05.003
Abstract: Artemisinins have low aqueous solubility that results in poor and erratic absorption upon oral administration. The poor solubility and erratic absorption usually translate to low bioavailability. Artemisinin-based monotherapy and combination therapies are essential for the management and treatment of uncomplicated as well as cerebral malaria. Artemisone and artemiside are novel artemisinin derivatives that have very good antimalarial activities. Pheroid™ technology is a patented drug delivery system which has the ability to entrap, transport and deliver pharmacologically active compounds. Pharmacokinetic models were constructed for artemisone and artemiside in Pheroid™ vesicle formulations. The compounds were administered at a dose of 50.0mg/kg bodyweight to C57 BL/6 mice via an oral gavage tube and blood s les were collected by means of tail-bleeding. Drug concentrations in the s les were determined using an LC/MS/MS method. There was 4.57 times more artemisone in the blood when the drug was entrapped in Pheroid™ vesicles in comparison to the drug only formulation (p < 0.0001). The absorption of artemiside was not dramatically enhanced by the Pheroid™ delivery system.
Publisher: American Society for Microbiology
Date: 10-2009
DOI: 10.1128/AAC.00502-09
Abstract: Immunocompromised patients are at risk of developing toxoplasmosis, and although chemotherapy is available, standard treatments are often complicated by severe side effects. Artemisinin is a new highly potent antimalarial drug that has activity against Toxoplasma gondii in vitro. However, artemisinin derivatives have previously been ineffective in vivo using a rat model of toxoplasmosis. In the present study, the efficacy of several new artemisinin derivates was investigated for treatment of mice infected with the parasite Toxoplasma gondii . Artemiside and artemisone displayed better inhibition than either artemisinin or artesunate against the parasite in vitro. Artemiside and artemisone treatment controlled parasite replication in vivo, and mice survived the acute infection. In a murine model of reactivated toxoplasmosis, both drugs increased survival, although artemiside was more effective. These results indicate that these newer derivatives of artemisinin may have potential for treatment of toxoplasmosis.
Publisher: Wiley
Date: 09-2000
DOI: 10.1002/1099-0690(200009)2000:18<3205::AID-EJOC3205>3.0.CO;2-D
Publisher: Springer Science and Business Media LLC
Date: 07-08-2018
DOI: 10.1007/S11095-018-2471-9
Abstract: The aim of this study was to formulate nano-emulsions comprising natural oils and the active pharmaceutical ingredients (APIs) clofazimine (CLF), artemisone (ATM) and decoquinate (DQ) in order to determine effectiveness of the nano-emulsions for topical delivery of the APIs. The APIs alone do not possess suitable physicochemical properties for topical drug delivery. Nano-emulsions were formulated with olive and safflower oils encapsulating the APIs. Skin diffusion and tape stripping studies were performed. By using the lactate dehydrogenase (LDH) assay, in vitro toxicity studies were carried out on immortalized human keratinocytes (HaCaT) cell line to determine cytotoxicities due to the APIs and the nano-emulsions incorporating the APIs. The nano-emulsions were effective in delivering the APIs within the stratum corneum-epidermis and the epidermis-dermis, were non-cytotoxic towards HaCaT cell lines (p < 0.05) and inhibited Mycobacterium tuberculosis in vitro. Natural oil nano-emulsions successfully deliver CLF, ATM and DQ and in principle could be used as supplementary topical treatment of cutaneous tuberculosis (CTB). Graphical Abstract ᅟ.
Publisher: Walter de Gruyter GmbH
Date: 1993
Publisher: American Chemical Society (ACS)
Date: 16-07-2004
DOI: 10.1021/IC049744U
Abstract: Interaction of PdCl(2)(MeCN)(2) with 2 equiv of (S(P))-(t)BuPhP(O)H (1H) followed by treatment with Et(3)N gave [Pd((1)(2)H)](2)(micro-Cl)(2) (2). Reaction of 2 with Na[S(2)CNEt(2)] or K[N(PPh(2)S)(2)] afforded Pd[(1)(2)H](S(2)CNEt(2)) (3) or Pd[(1)(2)H)[N(PPh(2)S)(2)] (4), respectively. Treatment of 3 with V(O)(acac)(2) (acac = acetylacetonate) and CuSO(4) in the presence of Et(3)N afforded bimetallic complexes V(O)[Pd(1)(2)(S(2)CNEt(2))](2) (5) or Cu[Pd(1)(2)(S(2)CNEt(2))](2) (6), respectively. X-ray crystallography established the S(P) configuration for the phosphinous acid ligands in 3 and 6, indicating that 1H binds to Pd(II) with retention of configuration at phosphorus. The geometry around Cu in 6 is approximately square planar with the average Cu-O distance of 1.915(3) A. Treatment of 2 with HBF(4) gave the BF(2)-capped compound [Pd((1)(2)BF(2))](2)(micro-Cl)(2) (7). The solid-state structure of 7 containing a PdP(2)O(2)B metallacycle has been determined. Chloride abstraction of 7 with AgBF(4) in acetone/water afforded the aqua compound [Pd((1)(2)BF(2))(H(2)O)(2)][BF(4)] (8) that reacted with [NH(4)](2)[WS(4)] to give [Pd((1)(2)BF(2))(2)](2)[micro-WS(4)] (9). The average Pd-S and W-S distances in 9 are 2.385(3) and 2.189(3) A, respectively. Treatment of [(eta(6)-p-cymene)RuCl(2)](2) with 1H afforded the phosphinous acid adduct (eta(6)-p-cymene)RuCl(2)(1H) (10). Reduction of [CpRuCl(2)](x)() (Cp = eta(5)-C(5)Me(5)) with Zn followed by treatment with 1H resulted in the formation of the Zn(II) phosphinate complex [(CpRu(eta(6)-C(6)H(5)))(t)BuPO(2))](2)(ZnCl(2))(2) (11) that contains a Zn(2)O(4)P(2) eight-membered ring.
Publisher: Wiley
Date: 22-03-2005
Publisher: Springer Science and Business Media LLC
Date: 02-2012
DOI: 10.1038/NSMB0212-264
Publisher: CSIRO Publishing
Date: 1981
DOI: 10.1071/CH9812465
Abstract: The title anion in tetrahydrofuran containing one equivalent of hexamethylphosphoric triamide at - 78� undergoes a rapid conjugate addition reaction with cyclopent-2-en-1-one. The sole product obtained, in 73% yield, is (E)-3-[3-(phenylsulfinyl)prop-2-enyl]cyclopentan-1-one.
Publisher: Royal Society of Chemistry (RSC)
Date: 1995
DOI: 10.1039/C39950002479
Publisher: Elsevier BV
Date: 04-1998
Publisher: Wiley
Date: 16-03-1988
Publisher: American Chemical Society (ACS)
Date: 09-1981
DOI: 10.1021/JO00332A005
Publisher: Royal Society of Chemistry (RSC)
Date: 1991
DOI: 10.1039/C39910000058
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2002
DOI: 10.1097/00001756-200212200-00001
Abstract: Psychophysical experiments identified effects of galvanic vestibular stimulation (GVS) on the perception of whole-body angular rotation. Subjects lay supine on a platform that could rotate about a vertical axis through the vestibular axis so that linear movements were excluded. Movements were applied sufficiently above perception threshold to enable a reliable report of direction and movement size. In some trials, binaural GVS was applied concurrently at 1-2 mA. When GVS that was incongruent with the movement was applied, subjects reported lesser spin, on average cancelling the movement perception. When the GVS and movement were congruent, subjects reported greater spin. We conclude that GVS produces a vestibular signal of rotation, probably though an effect on semicircular canals.
Publisher: Elsevier BV
Date: 1984
Publisher: Frontiers Media SA
Date: 19-05-2020
Publisher: Wiley
Date: 06-04-2005
Abstract: An economical phase-transfer method is used to prepare 10-arylaminoartemisinins from DHA and arylamines, and artemether, arteether, and artelinate from the corresponding alcohols. In vivo sc screens against Plasmodium berghei and P. yoelii in mice reveal that the p-fluorophenylamino derivative 5 g is some 13 and 70 times, respectively, more active than artesunate this reflects the very high sc activity of 10-alkylaminoartemisinins. However, through the po route, the compounds are less active than the alkylaminoartemisinins, but still approximately equipotent with artesunate.
Publisher: American Society for Microbiology
Date: 02-2011
DOI: 10.1128/AAC.01216-10
Abstract: Artemisone is one of the most promising artemisinin derivatives in clinical trials. Previous studies with radiolabeled artemisinin and dihydroartemisinin have measured uptake in Plasmodium falciparum -infected erythrocytes. Uptake is much greater in infected than in uninfected erythrocytes, but the relative contributions of transport, binding, and metabolism to this process still await definition. In this study, we characterized mechanisms by which [ 14 C]artemisone is taken up into uninfected and P. falciparum -infected human erythrocytes in vitro . Radiolabeled artemisone rapidly enters uninfected erythrocytes without much exceeding extracellular concentrations. Unlabeled artemisone does not compete in this process. Radiolabeled artemisone is concentrated greatly by a time- and temperature-dependent mechanism in infected erythrocytes. This uptake is abrogated by unlabeled artemisone. In addition, the uptake of artemisone into three subcellular fractions, and its distribution into these fractions, is examined as a function of parasite maturation. These data are relevant to an understanding of the mechanisms of action of this important class of drugs.
Publisher: American Chemical Society (ACS)
Date: 07-1991
DOI: 10.1021/JO00015A035
Publisher: Bentham Science Publishers Ltd.
Date: 16-08-2018
DOI: 10.2174/1567201815666180518125113
Abstract: Malaria continues to be a major health concern and affects more than 200 million people a year. Drugs currently used for treatment of malaria are increasingly rendered ineffectual by the ongoing emergence of parasite resistance. For any new drugs, however, knowledge of their membrane permeability is an essential pre-requisite for eventual use. Treatment failure and emergence of resistance can occur as a result of reduced availability of the drug at the desired site of action. Cellbased permeability assays such as Caco-2 cell monolayers serve as a model for predicting drug absorption and efflux, and provide an estimate of drug bioavailability. Here we have studied the bi-directional transport of new anti-malarial compounds, artemisone and artemiside, as well as reference compounds, namely the known anti-malarial drug artemether, and caffeine and atenolol. The Caco-2 cell monolayer model was used to assess the membrane permeation properties of these compounds, and to identify if they are subject to P-gp associated efflux, in the presence and absence of verapamil. The effect of piperine on the transport of the compounds that were identified to be P-gp substrates was also assessed. S les withdrawn from the acceptor chambers at pre-determined time intervals were analysed by means of high-performance liquid chromatography (HPLC). Transport results in terms of the absorptive direction revealed that artemisone and artemether had low absorption rates relative to the reference compounds. It was further demonstrated that artemisone is slightly effluxed, and although both artemether and artemiside were susceptible to P-gp mediated efflux, it appears that other efflux proteins may also be involved. The low permeability of anti-malarial drugs must be borne in mind during development of effective dosage regimens of new drugs.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.ACTATROPICA.2014.08.008
Abstract: Malaria remains one of the world's most common infectious diseases, being responsible for more deaths than any other communicable disease except tuberculosis. There is strong evidence that tumour necrosis factor α and interleukin-1β are important contributors to the systemic disease caused by the infection with Plasmodium falciparum. Circulating levels of TNFα are increased after infection, as a consequence of stimulation of monocyte-macrophages by infected red blood cells or parasite products, as shown in vitro for the malaria pigment haemozoin. TNFα in turn enhances the synthesis of metalloproteinase-9 in monocytes and macrophages. Metalloproteinase-9 acts on the extracellular matrix but also on non-traditional substrates, including precursors of inflammatory cytokines, which are proteolytically activated and contribute to the lification of the inflammatory response. The aim of the present work was to establish whether artemisinin and its derivatives artemisone, artesunate and dihydroartemisinin possess immuno-modulatory properties. In particular, it is necessary to evaluate their effects on mRNA levels and secretion of MMP-9 by the human monocytic cell line (THP-1 cells) stimulated by hemozoin or TNFα. 5μM of each derivative, although not artemisinin itself, induced significantly inhibited TNFα production. Artesunate, artemisone and DHA antagonized haemozoin-induced MMP-9 secretion by 25%, 24% and 50%, respectively. mRNA levels were also depressed by 14%, 20% and 27%, respectively, thus reflecting in part the effect observed on protein production. The derivatives significantly inhibited both TNFα-induced MMP-9 secretion and mRNA levels to a greater extent than haemozoin itself. Both haemozoin and TNFα increased NF-κB driven transcription by 11 and 7.7 fold, respectively. Artesunate, artemisone and DHA inhibited haemozoin-induced NF-κB driven transcription by 28%, 34%, and 49%, respectively. Similarly the derivatives, but not artemisinin, prevented TNFα-induced NF-κB driven transcription by 47-51%. The study indicates that artemisinins may attenuate the inflammatory potential of monocytes in vivo. Thus, in addition to direct anti-parasitic activities, the beneficial clinical effects of artemisinins for the treatment of malaria include the apparent ability to attenuate the inflammatory response, thus limiting the risk of progression to the more severe form of the disease, including the onset of cerebral malaria.
Publisher: MDPI AG
Date: 16-09-2021
DOI: 10.20944/PREPRINTS202109.0296.V1
Abstract: The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacte-rial and parasitic infections, most notably coccidiosis in poultry and in ruminants. We have in-vestigated the effects of treatment of Toxoplasma gondii in infected human foreskin fibroblasts (HFF) with DCQ. It induced distinct alterations in the parasite mitochondrion within 24h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC50) of 1.1 nM and the high selec-tivity index of & , the efficacy of oral treatment of pregnant mice experimentally infected with T. gondii oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than T. gondii infection alone, and did not prevent vertical transmission. Thus, three quinoline-O-carbamate derivatives of DCQ antici-pated to have better physicochemical properties than DCQ were assessed in vitro. One such com-pound RMB060 displayed an exceedingly low IC50 of 0.07 nM when applied concomitantly with infection of host cells and had no impact on HFF viability at 10 & micro M. As was the case for DCQ, RMB060 treatment resulted in alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6h after commencement of treatment. After 48h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features remi-niscent of bradyzoites. Exposure of infected cultures to 300 nM RMB060 for 52 days did not re-sult in complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. Treatment of mice infected with T. gondii oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.
Publisher: CSIRO Publishing
Date: 1984
DOI: 10.1071/CH9841571
Abstract: The preparation of t-butyl 2-(phenylthiomethyl)propenoate, t-butyl and methyl 3-(phenylthio)-2-(phenylthiomethyl)propenoate, the corresponding carboxylic acids, and 3-(phenylthio)-2-(phenyl- sulfinylmethyl)propenoate from 3-bromo-2-(bromomethyl)propionic acid is described.
Publisher: American Chemical Society (ACS)
Date: 08-11-2020
DOI: 10.1021/JO048395I
Abstract: A new chiral tertiary aminonaphthol ligand 3b served as a highly efficient ligand for the asymmetric catalytic phenyl transfer to aromatic aldehydes and a variety of chiral diarylmethanols was prepared in high ee values (ee up to 99%) and chemical yields. The straightforward syntheses of both 3b and its enantiomer provide an excellent opportunity for large-scale applications.
Publisher: CSIRO Publishing
Date: 1978
DOI: 10.1071/CH9781737
Abstract: 1,1-Diphenylethylene, 1,1-di-p-tolylethylene, 1,1-di-p-anisylethylene and 1,1-di(p-t-butylphenyl)-ethylene are converted in high yields (80- 90%) into the corresponding 3,3,6,6-tetraaryl-1,2-dioxans in the presence of oxygen and catalytic amounts of antimony(v) chloride in dichloromethane at -40° to -78° under irradiation from a tungsten l .
Publisher: Royal Society of Chemistry (RSC)
Date: 1975
DOI: 10.1039/P19750002065
Publisher: International Union of Crystallography (IUCr)
Date: 24-05-2018
DOI: 10.1107/S2053229618006320
Abstract: The stoichiometry, X-ray structures and stability of four pharmaceutical cocrystals previously identified from liquid-assisted grinding (LAG) of 11-azaartemisinin (11-Aza systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.0 4,13 .0 8,13 ]hexadecan-10-one) with trans -cinnamic (Cin), maleic (Mal) and fumaric (Fum) acids are herein reported. trans -Cinnamic acid, a mono acid, forms 1:1 cocrystal 11-Aza:Cin ( 1 , C 15 H 23 NO 4 ·C 9 H 8 O 2 ). Maleic acid forms both 1:1 cocrystal 11-Aza:Mal ( 2 , C 15 H 23 NO 4 ·C 4 H 4 O 4 ), in which one COOH group is involved in self-catenation, and 2:1 cocrystal 11-Aza 2 :Mal ( 3 , 2C 15 H 23 NO 4 ·C 4 H 4 O 4 ). Its isomer, fumaric acid, only affords 2:1 cocrystal 11-Aza 2 :Fum ( 4 ). All cocrystal formation appears driven by acid–lactam R 2 2 (8) heterosynthons with short O—H...O=C hydrogen bonds [O...O = 2.56 (2) Å], augmented by weaker C=O...H—N contacts. Despite a better packing efficiency, cocrystal 3 is metastable with respect to 2 , probably due to a higher conformational energy for the maleic acid molecule in its structure. In each case, the microcrystalline powders from LAG were useful in providing seeding for the single-crystal growth.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.NANO.2015.07.010
Abstract: Artemisone is a 10-amino-artemisinin derivative that is markedly superior in vitro and in vivo to current artemisinins against malaria and also possesses antitumor activity. In seeking to capitalise on the last property, we have examined the encapsulation of artemisone in nano-vesicular niosomes and solid lipid nanoparticles, and have evaluated efficacies of the free and encapsulated artemisone against human melanoma A-375 cells and effects on human keratinocytes (HaCaT). Artemisone is successfully encapsulated into the nano-vesicles with encapsulation efficiencies of 67±6% and 79±5%, and with average particle sizes being 211±10nm and 295±18nm respectively. The formulations displayed highly selective cytotoxicity towards the melanoma cells with negligible toxicity towards the normal skin cells. The artemisone-loaded nano-vesicles almost completely inhibited the melanoma cells compared to the free drug. The results overall suggest a potentially more useful therapeutic strategy that needs to be evaluated for the treatment of melanoma and other cancers. Apart from being an effective anti-malarial drug, a surprising action of artemisone also has antitumor activity. Nonetheless, its low water solubility and bioavailability has limited its clinical use. In this article, the authors enacapsulated artemisone in nano- vesicles and solid lipid nano-particles (SLNs). In-vitro studies confirmed the selective cytotoxicity towards melanoma cells. Further in-vivo and pre-clinical studies are awaited.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.BMCL.2017.12.057
Abstract: Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC
Publisher: Elsevier BV
Date: 05-2006
Publisher: Wiley
Date: 19-05-2003
Publisher: Wiley
Date: 30-10-2012
Abstract: Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox-active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Ascorbic acid-methylene blue (MB), N-benzyl-1,4-dihydronicotinamide (BNAH)-MB, BNAH-lumiflavine, BNAH-riboflavin (RF), and NADPH-FAD-E. coli flavin reductase (Fre) systems at pH 7.4 generate leucomethylene blue (LMB) and reduced flavins that are rapidly oxidized in situ by artemisinins. These oxidations are inhibited by the 4-aminoquinolines piperaquine (PPQ), chloroquine (CQ), and others. In contrast, the arylmethanols lumefantrine, mefloquine (MFQ), and quinine (QN) have little or no effect. Inhibition correlates with the antagonism exerted by 4-aminoquinolines on the antimalarial activities of MB, RF, and artemisinins. Lack of inhibition correlates with the additivity/synergism between the arylmethanols and artemisinins. We propose association via π complex formation between the 4-aminoquinolines and LMB or the dihydroflavins this hinders hydride transfer from the reduced conjugates to the artemisinins. The arylmethanols have a decreased tendency to form π complexes, and so exert no effect. The parallel between chemical reactivity and antagonism or additivity/synergism draws attention to the mechanism of action of all drugs described herein. CQ and QN inhibit the formation of hemozoin in the parasite digestive vacuole (DV). The buildup of heme-Fe(III) results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme-Fe(III) complexes of CQ and QN that form in the DV are proposed to diffuse across the DV membrane. At the higher pH of the cytosol, the complexes decompose to liberate heme-Fe(III) . The quinoline or arylmethanol reenters the DV, and so transfers more heme-Fe(III) out of the DV. In this way, the 4-aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme-Fe(III) and thence free Fe(III) concentrations in the cytosol. The iron species enter into redox cycles through reduction of Fe(III) to Fe(II) largely mediated by reduced flavin cofactors and likely also by NAD(P)H-Fre. Generation of ROS through oxidation of Fe(II) by oxygen will also result. The cytotoxicities of artemisinins are thereby reinforced by the iron. Other aspects of drug action are emphasized. In the cytosol or DV, association by π complex formation between pairs of lipophilic drugs must adversely influence the pharmacokinetics of each drug. This explains the antagonism between PPQ and MFQ, for ex le. The basis for the antimalarial activity of RF mirrors that of MB, wherein it participates in redox cycling that involves flavoenzymes or Fre, resulting in attrition of NAD(P)H. The generation of ROS by artemisinins and ensuing Fenton chemistry accommodate the ability of artemisinins to induce membrane damage and to affect the parasite SERCA PfATP6 Ca(2+) transporter. Thus, the effect exerted by artemisinins is more likely a downstream event involving ROS that will also be modulated by mutations in PfATP6. Such mutations attenuate, but cannot abrogate, antimalarial activities of artemisinins. Overall, parasite resistance to artemisinins arises through enhancement of antioxidant defense mechanisms.
Publisher: Elsevier BV
Date: 1996
Publisher: Elsevier BV
Date: 02-2023
Publisher: Frontiers Media SA
Date: 10-01-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 1975
DOI: 10.1039/P19750002055
Publisher: American Chemical Society (ACS)
Date: 09-1991
DOI: 10.1021/JO00020A018
Publisher: Elsevier BV
Date: 10-1997
DOI: 10.1016/S0885-3924(97)00181-4
Abstract: The aim of this study was to investigate the flow performance of the mechanical Springfusor 30 short model and the electronic Graseby MS16A. Flow rate was measured gravimetrically in a temperature-controlled cabinet. There was no statistically significant difference between the Graseby and Springfusor syringe drivers in the flow rate error at 25 degrees C. The percentage of flow rates within +/-20% accuracy during a 35-min periods at 25 degrees C was significantly less with the Graseby, being 91.9% compared with 100% for the Springfusor. Only 58.2% of flow rates with the Graseby were within the manufacturer claimed accuracy of +/-5%. The flow rate of the Springfusor was affected by temperature at 30 degrees C the mean flow rate was 10.8% greater than at 25 degrees C. These results indicate that the Springfusor 30 had less flow rate variation than the Graseby MS16A. However, this would not be expected to cause noticeable clinical effects when used for opioid infusion in palliative care.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.TOX.2007.08.084
Abstract: Artemisinin derivatives are highly effective and well-tolerated antimalarial drugs that now form the basis of antimalarial combination therapies recommended by the World Health Organization. Although not yet reported to be a problem in clinical use, neurotoxicity and embryotoxicity are displayed by the compound class in in vitro and in vivo experimental models, in particular by dihydroartemisinin, the main metabolite of all current clinical artemisinins. Embryotoxicity appears to be connected with defective angiogenesis and vasculogenesis in certain stages of embryo development. This may prevent the use of artemisinin derivatives in malaria during pregnancy, when both mother and fetus are at high risk of death. Artemisone is a novel 10-alkylamino derivative which is not metabolised to dihydroartemisinin. It was selected as a clinical drug candidate on the basis of its high efficacy against Plasmodium falciparum in vitro and its lack of detectable neurotoxicity in both in vitro and in vivo screens. Here we describe the results of a comparative study of the anti-angiogenic properties of both artemisone and dihydroartemisinin in different model systems. We evaluated the proliferation of human endothelial cells and their migration on a fibronectin matrix, the sprouting of new vessels from rat aorta sections grown in collagen and the production of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF) and interleukin-8 (CXCL-8). The data show that artemisone is significantly less anti-angiogenic than dihydroartemisinin in all the experimental models, suggesting that it will be safer to use than the current clinical artemisinins during pregnancy.
Publisher: American Chemical Society (ACS)
Date: 07-1997
DOI: 10.1021/JO970337S
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.ANTIVIRAL.2019.104639
Abstract: We have recently shown that the artemisinin derivative artemisone, which was screened against malaria in human clinical studies, is a potent inhibitor of human cytomegalovirus (HCMV). Here we evaluated the antiviral effect of artemisone when employed in 2-drug combinations with approved and experimental anti-HCMV agents. Using the Chou-Talalay method, we found that in-vitro combination of artemisone with cidofovir, brincidofovir, or with the HCMV UL97 inhibitor maribavir resulted in antiviral synergism and the combination of artemisone with ganciclovir or with the viral terminase inhibitors letermovir and BDCRB resulted in moderate synergism. Importantly, the combination of artemisone with maribavir demonstrated synergistic antiviral activity ex-vivo, in a clinically-relevant multicellular model of human placental tissues maintained in organ culture. Our findings provide the basis for the use of artemisone in synergistically acting drug combinations, to enhance viral control and reduce antiviral drug toxicities.
Publisher: American Chemical Society (ACS)
Date: 11-12-2019
Publisher: Oxford University Press (OUP)
Date: 02-2005
Abstract: Artemisinins were discovered to be highly effective antimalarial drugs shortly after the isolation of the parent artemisinin in 1971 in China. These compounds combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance. Artemisinin containing regimens meet the urgent need to find effective treatments for multidrug resistant malaria and have recently been advocated for widespread deployment. Comparative trials of artesunate and quinine for severe malaria are in progress to see if the persistently high mortality of this condition can be reduced.
Publisher: Bentham Science Publishers Ltd.
Date: 28-10-2015
DOI: 10.2174/0929867322666150729115752
Abstract: The current treatment regimens for uncomplicated malaria comprise an artemisinin in combination with another drug (ACT). However, the recent emergence of resistance to ACTs in South East Asia dramatically emphasizes the need for new artemisinins. The current artemisinins have been in use since the late 1970s and have relatively poor thermal, chemical and metabolic stabilities - all are metabolized or hydrolyzed in vivo to dihydroartemisinin (DHA) that itself undergoes facile decomposition in vivo. The current artemisinins possess neurotoxicity as demonstrated in animal models, an issue that mandates increased vigilance in view of trends to use of protracted treatment regimens involving sequential administration of different ACTs against the resistant disease. As artemisinins induce the most rapid reduction in parasitaemia of any drug, common sense dictates that any new artemisinin derivative, selected on the bases of more robust chemical and thermal stability, metabolic stability with respect to the generation of DHA in vivo, and relatively benign neurotoxicity should be used in any new ACT whose components are rationally chosen in order to counter resistant malaria and inhibit transmission. 11-Azaartemisinin and its N-substituted derivatives attract because of overall ease of preparation from artemisinin. Some derivatives also possess notable thermal stabilities and although metabolic pathways of the derivatives are as yet unknown, none can provide DHA. The azaartemisinins synthesized over the past 20 years are critically discussed on the basis of their synthetic accessibility and biological activities with the view to assessing suitability to serve as new artemisinin derivatives for treatment of malaria.
Publisher: Oxford University Press (OUP)
Date: 18-04-2013
Abstract: The mechanism of action of artemisinins against malaria is unclear, despite their widespread use in combination therapies and the emergence of resistance. Here, we report expression of PfATP6 (a SERCA pump) in yeast and demonstrate its inhibition by artemisinins. Mutations in PfATP6 identified in field isolates (such as S769N) and in laboratory clones (such as L263E) decrease susceptibility to artemisinins, whereas they increase susceptibility to unrelated inhibitors such as cyclopiazonic acid. As predicted from the yeast model, Plasmodium falciparum with the L263E mutation is also more susceptible to cyclopiazonic acid. An inability to knockout parasite SERCA pumps provides genetic evidence that they are essential in asexual stages of development. Thaperoxides are a new class of potent antimalarial designed to act by inhibiting PfATP6. Results in yeast confirm this inhibition. The identification of inhibitors effective against mutated PfATP6 suggests ways in which artemisinin resistance may be overcome.
Publisher: American Society for Microbiology
Date: 12-2014
DOI: 10.1128/AAC.02707-14
Abstract: The in vitro antimalarial activities of artemisone and artemisone entrapped in Pheroid vesicles were compared, as was their ability to induce dormancy in Plasmodium falciparum . There was no increase in the activity of artemisone entrapped in Pheroid vesicles against multidrug-resistant P. falciparum lines. Artemisone induced the formation of dormant ring stages similar to dihydroartemisinin. Thus, the Pheroid delivery system neither improved the activity of artemisone nor prevented the induction of dormant rings.
Publisher: Bentham Science Publishers Ltd.
Date: 07-01-2019
DOI: 10.2174/1573406414666180525132204
Abstract: The emergence of resistance to the artemisinins which are the current mainstays for antimalarial chemotheraphy has created an environment where the development of new drugs acting in a mechanistally discrete manner is a priority. The goal of this work was to synthesize ane evaluate bis-thiosemicarbazones as potential antimalarial agents. /P P Methods: Fifteen compounds were generated using two condensation protocols and evaluated in vitro against the NF54 (CQ sensitive) strain of Plasmodium falciparum. A preliminary assessment of the potential for human toxicity was conducted in vitro against the MRC5 human lung fibroblast line. The activity of the bis-thiosemicarbazones was highly dependent on the nature of the arene at the core of the structure. The inclusion of a non-coordinating benzene core resulted in inactive compounds, while the inclusion of a pyridyl core resulted in compounds of moderate or potent antimalarial activity (4 compounds showing IC50 250 nM). Bis-thiosemicarbazones containing a central pyridyl core display potent antimalarial activity in vitro. Sequestration and activation of ferric iron appears to play a significant role in this activity. Ongoing studies are aimed at further development of this series as potential antimalarials.
Publisher: Royal Society of Chemistry (RSC)
Date: 1972
DOI: 10.1039/P19720000408
Publisher: CSIRO Publishing
Date: 1980
DOI: 10.1071/CH9801537
Abstract: A series of reagents for the conversion of enones into dienones via allylpalladium compounds has been studied and mild conditions for dienone preparation are recommended.
Publisher: Wiley
Date: 06-12-2017
Abstract: Neosporosis caused by the apicomplexan parasite Neospora caninum is an economically important disease that induces abortion in dairy and beef cattle. There are no vaccines or drugs available on the market for control or treatment of the disease in bovines. The peroxide artemisinin and its derivatives used clinically for treatment of malaria are active against N. caninum and other apicomplexan parasites. We have now evaluated the activities of the readily accessible and chemically robust 11-azaartemisinin 5 and selected N-sulfonyl derivatives prepared as described in the accompanying paper against N. caninum tachyzoites grown in infected human foreskin fibroblasts. Azaartemisinin elicited an IC
Publisher: Georg Thieme Verlag KG
Date: 12-1993
Publisher: MDPI AG
Date: 15-06-2022
DOI: 10.3390/ANTIBIOTICS11060806
Abstract: Although chemotherapeutic treatment regimens are currently available, and considerable effort has been lavished on the development of new drugs for the treatment of tuberculosis (TB), the disease remains deeply intractable and widespread. This is due not only to the nature of the life cycle and extraordinarily disseminated habitat of the causative pathogen, principally Mycobacterium tuberculosis (Mtb), in humans and the multi-drug resistance of Mtb to current drugs, but especially also to the difficulty of enabling universal treatment of in iduals, immunocompromised or otherwise, in widely differing socio-economic environments. For the purpose of globally eliminating TB by 2035, the World Health Organization (WHO) introduced the “End-TB” initiative by employing interventions focusing on high impact, integrated and patient-centered approaches, such as in idualized therapy. However, the extraordinary shortfall in stipulated aims, for ex le in actual treatment and in TB preventative treatments during the period 2018–2022, latterly and greatly exacerbated by the COVID-19 pandemic, means that even greater pressure is now placed on enhancing our scientific understanding of the disease, repurposing or repositioning old drugs and developing new drugs as well as evolving innovative treatment methods. In the specific context of multidrug resistant Mtb, it is furthermore noted that the incidence of extra-pulmonary TB (EPTB) has significantly increased. This review focusses on the potential of utilizing self-double-emulsifying drug delivery systems (SDEDDSs) as topical drug delivery systems for the dermal route of administration to aid in treatment of cutaneous TB (CTB) and other mycobacterial infections as a prelude to evaluating related systems for more effective treatment of CTB and other mycobacterial infections at large. As a starting point, we consider here the possibility of adapting the highly lipophilic riminophenazine clofazimine, with its potential for treatment of multi-drug resistant TB, for this purpose. Additionally, recently reported synergism achieved by adding clofazimine to first-line TB regimens signifies the need to consider clofazimine. Thus, the biological effects and pharmacology of clofazimine are reviewed. The potential of plant-based oils acting as emulsifiers, skin penetration enhancers as well as these materials behaving as anti-microbial components for transporting the incorporated drug are also discussed.
Publisher: Frontiers Media SA
Date: 19-08-2022
DOI: 10.3389/FPHAR.2022.957690
Abstract: The emergence of Plasmodium falciparum ( Pf ) parasite strains tolerant of the artemisinin component and resistant to the other drug component in artemisinin combination therapies (ACTs) used for treatment now markedly complicates malaria control. Thus, development of new combination therapies are urgently required. For the non-artemisinin component, the quinolone ester decoquinate (DQ) that possesses potent activities against blood stage Pf and acts on a distinct target, namely the Pf cytochrome bc 1 complex, was first considered. However, DQ has poor drug properties including high lipophilicity and exceedingly poor aqueous solubility (0.06 μg/ml), rendering it difficult to administer. Thus, DQ was chemically modified to provide the secondary amide derivative RMB005 and the quinoline O -carbamate derivatives RMB059 and RMB060. The last possesses sub-nanomolar activities against multidrug resistant blood stages of Pf , and P. berghei sporozoite liver stages. Here we present the results of ADME analyses in vitro and pharmacokinetic analyses using C57BL/6 mice. The amide RMB005 had a maximum mean whole blood concentration of 0.49 ± 0.02 µM following oral administration however, the area under the curve (AUC), elimination half-life (t 1/2 ) and bioavailability (BA) were not significantly better than those of DQ. Surprisingly, the quinoline O -carbamates which can be recrystallized without decomposition were rapidly converted into DQ in human plasma and blood s les. The maximum concentrations of DQ reached after oral administration of RMB059 and RMB060 were 0.23 ± 0.05 and 0.11 ± 0.01 µM, the DQ elimination half-lives were 4.79 ± 1.66 and 4.66 ± 1.16 h, and the DQ clearance were 19.40 ± 3.14 and 21.50 ± 3.38 respectively. Under these assay conditions, the BA of DQ could not be calculated Overall although RMB059 and -060 are labile in physiological medium with respect to the DQ parent, the potential to apply these as prodrugs is apparent from the current data coupled with their ease of preparation.
Publisher: American Chemical Society (ACS)
Date: 07-1995
DOI: 10.1021/JO00120A007
Publisher: American Chemical Society (ACS)
Date: 04-1989
DOI: 10.1021/JO00269A040
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.IJANTIMICAG.2016.03.018
Abstract: The in vitro activity of the new artemisinin derivative artemisone as well as other molecules of the same class against Helicobacter pylori and their effects when combined with standard antibiotics were evaluated. Since H. pylori can be internalised into gastric epithelial cells, the effects of artemisinin, dihydroartemisinin and artemisone against intracellular H. pylori were also investigated. Bacteriostatic [minimum inhibitory concentration (MIC)] and bactericidal [minimum bactericidal concentration (MBC)] activities were assessed against 24 clinical strains of H. pylori with different antibiotics susceptibilities. Artemisone showed MIC50 and MIC90 values of 0.25 mg/L and 0.5 mg/L, respectively, and an MBC50 value of 0.5 mg/L. Artemisone was synergistic with amoxicillin in 60% of strains, with clarithromycin in 40% and with metronidazole in 20%. There was no interaction between artemisone and omeprazole or bismuth citrate. Against intracellular H. pylori, only dihydroartemisinin at 2× MIC caused a 1 log10 CFU decrease after 18 h and 24 h of incubation. This is the first demonstration in vitro of the activity of artemisinin derivatives against intracellular H. pylori and indicates that artemisone has the potential to be efficacious for the treatment of H. pylori infection, especially in combination with antibiotics.
Publisher: Wiley
Date: 26-09-2007
Abstract: Artesunate drug substance, for which a rectal capsule formulation is under development for the treatment of severe malaria, when heated at 100 degrees C for 39 h gives beta-artesunate, artesunate dimers, 9,10-anhydrodihydroartemisinin (glycal), a DHA beta-formate ester, and smaller amounts of other products that arise via intermediate formation of dihydroartemisinin (DHA) and subsequent thermal degradation. Solid DHA at 100 degrees C provides an epimeric mixture of a known peroxyhemiacetal, arising via ring opening to a hydroperoxide and re-closure, smaller amounts of a 3:1 mixture of epimers of a known tricarbonyl compound, and a single epimer of a new dicarbonyl compound. The latter arises via homolysis of the peroxide and an ensuing cascade of alpha-cleavage reactions which leads to loss of formic acid incorporating the C10 carbonyl group of DHA exposed by this 'unzipping' cascade. The tricarbonyl compound that arises via peroxide homolysis and extrusion of formic acid from a penultimate hydroxyformate ester incorporating C12 of the original DHA, is epimeric at the exocyclic 1''-aldehyde, and not in the cyclohexanone moiety. It is converted into the dicarbonyl compound by peroxide-induced deformylation. The dicarbonyl compound is not formed during anhydrous ferrous bromide mediated decomposition of DHA at room temperature, which provides the 1''-R epimer of the tricarbonyl compound as the dominant product this equilibrates at room temperature to the 3:1 mixture of epimers of the tricarbonyl compound obtained from thermolysis. Each of artesunate and DHA decomposes readily under aqueous acidic conditions to provide significant amounts of the peroxyhemiacetal, which, like DHA, decomposes to the inert end product 2-deoxyartemisinin under acidic or basic conditions. DHA and the peroxyhemiacetal are the principal degradants in aged rectal capsule formulations of artesunate. TGA analysis and thermal degradation of DHA reveals a thermal lability which would pose a problem not only in relation to ICH stability testing guidelines, but in the use of DHA in fixed formulations currently under development. This thermolability coupled with the poor physicochemical properties and relative oral bioavailability of DHA suggests that it is inferior to artesunate in application as an antimalarial drug.
Publisher: Elsevier BV
Date: 1996
Publisher: American Chemical Society (ACS)
Date: 07-1998
DOI: 10.1021/JO984003U
Publisher: Wiley
Date: 26-09-2007
Abstract: As the clinically used artemisinins do not withstand the thermal stress testing required to evaluate shelf life for storage in tropical countries where malaria is prevalent, there is a need to develop thermally more robust artemisinin derivatives. Herein we describe the attachment of electron-withdrawing arene- and alkanesulfonyl and -carbonyl groups to the nitrogen atom of the readily accessible Ziffer 11-azaartemisinin to provide the corresponding N-sulfonyl- and -carbonylazaartemisinins. Two acylurea analogues were also prepared by treatment of the 11-azaartemisinin with arylisocyanates. Several of the N-sulfonylazaartemisinins have melting points above 200 degrees C and possess substantially greater thermal stabilities than the artemisinins in current clinical use, with the antimalarial activities of several of the arylsulfonyl derivatives being similar to that of artesunate against the drug-sensitive 3D7 clone of the NF54 isolate and the multidrug-resistant K1 strain of P. falciparum. The compounds possess relatively low cytotoxicities. The carbonyl derivatives are less crystalline than the N-sulfonyl derivatives, but are generally more active as antimalarials. The N-nitroarylcarbonyl and arylurea derivatives possess sub-ng ml(-1) activities. Although several of the azaartemisinins possess log P values below 3.5, the compounds have poor aqueous solubility (<1 mg L(-1) at pH 7). The greatly enhanced thermal stability of our artemisinins suggests that strategic incorporation of electron-withdrawing polar groups into both new artemisinin derivatives and totally synthetic trioxanes or trioxolanes may assist in the generation of practical new antimalarial drugs which will be stable to storage conditions in the field, while retaining favorable physicochemical properties.
Publisher: American Chemical Society (ACS)
Date: 06-1994
DOI: 10.1021/JO00090A003
Publisher: Frontiers Media SA
Date: 02-09-2022
DOI: 10.3389/FPHAR.2022.988748
Abstract: Artemisinin, isolated from the traditional Chinese medicinal plant qīng hāo 青蒿 ( Artemisia annua ) and its derivatives are used for treatment of malaria. With treatment failures now being recorded for the derivatives and companion drugs used in artemisinin combination therapies new drug combinations are urgently required. The amino-artemisinins artemiside and artemisone display optimal efficacies in vitro against asexual and sexual blood stages of the malaria parasite Plasmodium falciparum and are active against tumour cell lines. In continuing the evolution of combinations of the amino-artemisinins with new drugs, we examine the triterpenoid quinone methide celastrol isolated from the traditional Chinese medicinal plant léi gōng téng 雷公藤 ( Tripterygium wilfordii ). This compound is redox active, and has attracted considerable attention because of potent biological activities against manifold targets. We report that celastrol displays good IC 50 activities ranging from 0.50–0.82 µM against drug-sensitive and resistant asexual blood stage Pf , and 1.16 and 0.28 µM respectively against immature and late stage Pf NF54 gametocytes. The combinations of celastrol with each of artemisone and methylene blue against asexual blood stage Pf are additive. Given that celastrol displays promising antitumour properties, we examined its activities alone and in combinations with amino-artemisinins against human liver HepG2 and other cell lines. IC 50 values of the amino-artemisinins and celastrol against HepG2 cancer cells ranged from 0.55–0.94 µM. Whereas the amino-artemisinins displayed notable selectivities (SI & 171) with respect to normal human hepatocytes, in contrast, celastrol displayed no selectivity (SI & 1). The combinations of celastrol with artemiside or artemisone against HepG2 cells are synergistic. Given the promise of celastrol, judiciously designed formulations or structural modifications are recommended for mitigating its toxicity.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.TOX.2012.05.024
Abstract: Artemisinin derivatives such as dihydroartemisinin (DHA) induce significant depletion of early embryonic erythroblasts in animal models. We have reported previously that DHA specifically targets pro-erythroblasts and basophilic erythroblasts, when human CD34+ stem cells are differentiated toward the erythroid lineage, indicating that a window of susceptibility to artemisinins may exist also in human developmental erythropoiesis during pregnancy. To better investigate the toxicity of artemisinin derivatives, the structure-activity relationship was evaluated against the K562 leukaemia cell line, used as a model for differentiating early human erythroblasts. All artemisinins derivatives, except deoxyartemisinin, inhibited both spontaneous and induced erythroid differentiation, confirming that the peroxide bridge is responsible for the erythro-toxicity. On the contrary, cell growth was markedly reduced by DHA, artemisone and artesunate but not by artemisinin, 10-deoxoartemisinin or deoxy-artemisinin. The substituent at position C-10 is responsible only for the anti-proliferative effect, since 10-deoxoartemisinin did not reduce cell growth but arrested the differentiation of K562 cells. In particular, the results showed that DHA resulted the most potent and rapidly acting compound of the drug family, causing (i) the decreased expression of GpA surface receptors and the down regulation the γ-globin gene (ii) the alteration of S phase of cell cycle and (iii) the induction of programmed cell death of early erythroblasts in a dose dependent manner within 24h. In conclusion, these findings confirm that the active metabolite DHA is responsible for the erythro-toxicity of most of artemisinins used in therapy. Thus, as long as no further clinical data are available, current WHO recommendations of avoiding malaria treatment with artemisinins during the first trimester of pregnancy remain valid.
Publisher: Elsevier BV
Date: 09-2003
Publisher: Elsevier BV
Date: 12-2014
Publisher: Wiley
Date: 23-12-2010
Abstract: Flavin adenine dinucleotide (FAD) is reduced by NADPH-E. coli flavin reductase (Fre) to FADH(2) in aqueous buffer at pH 7.4 under argon. Under the same conditions, FADH(2) in turn cleanly reduces the antimalarial drug methylene blue (MB) to leucomethylene blue. The latter is rapidly re-oxidized by artemisinins, thus supporting the proposal that MB exerts its antimalarial activity, and synergizes the antimalarial action of artemisinins, by interfering with redox cycling involving NADPH reduction of flavin cofactors in parasite flavin disulfide reductases. Direct treatment of the FADH(2) generated from NADPH-Fre-FAD by artemisinins and antimalaria-active tetraoxane and trioxolane structural analogues under physiological conditions at pH 7.4 results in rapid reduction of the artemisinins, and efficient conversion of the peroxide structural analogues into ketone products. Comparison of the relative rates of FADH(2) oxidation indicate optimal activity for the trioxolane. Therefore, the rate of intraparastic redox perturbation will be greatest for the trioxolane, and this may be significant in relation to its enhanced in vitro antimalarial activities. (1)H NMR spectroscopic studies using the BNAH-riboflavin (RF) model system indicate that the tetraoxane is capable of using both peroxide units in oxidizing the RFH(2) generated in situ. Use of the NADPH-Fre-FAD catalytic system in the presence of artemisinin or tetraoxane confirms that the latter, in contrast to artemisinin, consumes two reducing equivalents of NADPH. None of the processes described herein requires the presence of ferrous iron. Ferric iron, given its propensity to oxidize reduced flavin cofactors, may play a role in enhancing oxidative stress within the malaria parasite, without requiring interaction with artemisinins or peroxide analogues. The NADPH-Fre-FAD system serves as a convenient mimic of flavin disulfide reductases that maintain redox homeostasis in the malaria parasite.
Publisher: MDPI AG
Date: 13-03-2023
DOI: 10.3390/PATHOGENS12030447
Abstract: The effects of decoquinate (DCQ) and three O-quinoline-carbamate-derivatives were investigated using human foreskin fibroblasts (HFF) infected with Neospora caninum tachyzoites. These compounds exhibited half-maximal proliferation inhibition (IC50s) from 1.7 (RMB060) to 60 nM (RMB055). Conversely, when applied at 5 (DCQ, RMB054) or 10µM (RMB055, RMB060), HFF viability was not affected. Treatments of infected cell cultures at 0.5µM altered the ultrastructure of the parasite mitochondrion and cytoplasm within 24 h, most pronounced for RMB060, and DCQ, RMB054 and RMB060 did not impair the viability of splenocytes from naïve mice. Long-term treatments of N. caninum-infected HFF monolayers with 0.5µM of each compound showed that only exposure to RMB060 over a period of six consecutive days had a parasiticidal effect, while the other compounds were not able to kill all tachyzoites in vitro. Thus, DCQ and RMB060 were comparatively assessed in the pregnant neosporosis mouse model. The oral application of these compounds suspended in corn oil at 10 mg/kg/day for 5 d resulted in a decreased fertility rate and litter size in the DCQ group, whereas reproductive parameters were not altered by RMB060 treatment. However, both compounds failed to protect mice from cerebral infection and did not prevent vertical transmission up mortality. Thus, despite the promising in vitro efficacy and safety characteristics of DCQ and DCQ-derivatives, proof of concept for activity against neosporosis could not be demonstrated in the murine model.
Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/CH9891785
Abstract: The reactions of lithiated 1-(t-butylsulfinyl)prop-2-ene, 1-(t-butylsulfinyl)-3-methylbut-2-ene, 1-(t-butylsulfinyl)but-2-ene, 1-(phenylsulfinyl)but-2-ene and 2-methyl-1-(phenylsu1finyl)prop- 2-ene with methyl vinyl ketone, mesityl oxide and crotonaldehyde give largely carbonyl addition products arising from reaction through C1 or C3 of the allyl system. In the case of methyl crotonate, conjugate addition through C3 is observed. The initially formed diastereomers of the C1 adducts, allylic sulfoxides, are configurationally unstable. Only the lithiated 1-(t-butylsulfinyl)-3-methylbut-2-ene undergoes conjugate addition with methyl vinyl ketone to give an (E)-vinyl sulfoxide whose formation may involve the trans-decalyl transition state characteristic of the reactions of lithiated allylic sulfoxides with cyclic enones.
Publisher: Elsevier BV
Date: 09-2018
Publisher: American Society for Microbiology
Date: 2012
DOI: 10.1128/AAC.05006-11
Abstract: This research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both in Plasmodium falciparum culture and in vivo in a murine malaria model depicting cerebral malaria (CM). In vitro high-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, in idual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with in idual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM.
Publisher: Elsevier BV
Date: 06-1995
Publisher: American Chemical Society (ACS)
Date: 07-1985
DOI: 10.1021/JA00301A053
Publisher: Elsevier BV
Date: 08-2022
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.VETPAR.2011.12.020
Abstract: Neosporosis caused by Neospora caninum has global economic, clinical, and epidemiological impacts, mainly in the cattle industry. Currently, there is no useful drug for treatment of neosporosis. This publication is the first to describe the significant benefits that artemisone has on Neospora infections both in vitro and in vivo. Artemisone is a new semi-synthetic 10-alkylamino artemisinin that is superior to other artemisinin derivatives in terms of its significantly higher antimalarial activity, its tolerance in vivo, lack of detectable neurotoxic potential, improved in vivo pharmacokinetics and metabolic stability. Low micromolar concentrations of artemisone inhibited in vitro Neospora development. Prophylactic and post-infection treatment profoundly reduced the number of infected cells and parasites per cell. In the in vivo gerbil model, a non-toxic dose prevented typical cerebral symptoms, in most animals. There were no signs of clinical symptoms and brain PCR was negative. Most treated gerbils produced high specific antibody titer and were protected against a challenge. Overall, artemisone could be considered as a future drug for neosporosis.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.BMCL.2018.08.037
Abstract: Artemisinin-ferrocene conjugates incorporating a 1,2-disubstituted ferrocene analogous to that embedded in ferroquine but attached via a piperazine linker to C10 of the artemisinin were prepared from the piperazine artemisinin derivative, and activities were evaluated against asexual blood stages of chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf). The most active was the morpholino derivative 5 with IC
Publisher: Elsevier BV
Date: 10-2010
Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/CH9891671
Abstract: Lithiated 4-(t- butylsulfinyl)- and 4-(t-butylsulfonyl )-6-methylhept-2-ene, and [(E)-1-isobutylbut-2-enylldiphenylphosphine oxide, undergo conjugate addition with cyclopent-2-enone and 2-methylcyclopent-2-enone to deliver mixtures of diastereomers arising from reaction through C3 of the allyl system. The relative configuration of the major product obtained from the lithiated phosphine oxide and 2-methylcyclopent-2-enone has been determined by an X-ray crystallographic study. The proportions of diastereomers formed are rationalized in terms of carbanions which have a low barrier to rotation about the C1-C2 bond of the allyl system, and steric interactions prevailing in the trans-decalyl and related transition states experienced by the reactions. The reaction of the lithiated phosphine oxide with 2-methylcyclopent-2-enone has a diastereoselection useful for synthetic approaches towards vitamin D derivatives.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2014
Publisher: Elsevier BV
Date: 10-2008
Publisher: CSIRO Publishing
Date: 1978
DOI: 10.1071/CH9780131
Abstract: 1,1'-Bicyclohexenyl and α-terpinene are converted into the corresponding cyclic peroxides in the presence of oxygen and Lewis acids in dichloromethane. In liquid sulphur dioxide under oxygen, the . major product from 1,1'-bicyclohexenyl in the presence of SnCl4, SbF5, and SbCl5, is the corresponding cyclic sulphone, whereas the cyclic peroxide is almost exclusively formed in this medium with MoCl5, WCl6 and VOCl3. Under the same conditions, α-terpinene is quantitatively oxygenated in a dark reaction, in the absence of added Lewis acids. In a 1 : 1 dichloromethane-sulphur dioxide medium, ergosteryl acetate requires irradiation for conversion into the corresponding peroxide. Mechanistic interpretations of these observations are presented.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.IJANTIMICAG.2015.02.020
Abstract: From a panel of 34 artemisinin derivatives tested in vitro, artemisone, GC007 and GC012 were most efficacious at inhibiting Neospora caninum replication (IC50 values of 3-54nM), did not notably impair the invasiveness of tachyzoites and were non-toxic for human foreskin fibroblasts (HFFs). Transmission electron microscopy of drug-treated N. caninum-infected HFFs demonstrated severe alterations in the parasite cytoplasm, changes in the composition of the matrix of the parasitophorous vacuole (PV) and diminished integrity of the PV membrane. To exert parasiticidal activity, parasites had to be cultured continuously in the presence of 5μM artemisone or GC007 for 3 weeks. N. caninum tachyzoites readily adapted to a stepwise increase in concentrations (0.5-10μM) of GC012, but not to artemisone or GC007. Drugs induced the expression of elevated levels of NcBAG1 and NcSAG4 mRNA, but only NcBAG1 could be detected by immunofluorescence. Thus, artemisinin derivatives represent interesting leads that should be investigated further.
Publisher: American Society for Microbiology
Date: 07-2018
DOI: 10.1128/AAC.00288-18
Abstract: Human cytomegalovirus (HCMV) is a major cause of disease in immunocompromised in iduals and the most common cause of congenital infection and neurosensorial disease. The expanding target populations for HCMV antiviral treatment along with the limitations of the currently available HCMV DNA polymerase inhibitors underscore the need for new antiviral agents with alternative modes of action. The antimalarial artemisinin derivative artesunate was shown to inhibit HCMV in vitro yet has demonstrated limited antiviral efficacy in vivo , prompting our search for more potent anti-HCMV artemisinin derivatives. Here we show that the innovative artemisinin derivative artemisone, which has been screened for its activity against malaria parasites in human clinical studies, is a potent and noncytotoxic inhibitor of HCMV. Artemisone exhibited an antiviral efficacy comparable to that of ganciclovir (50% effective concentration, 1.20 ± 0.46 μM) in human foreskin fibroblasts, with enhanced relative potency in lung fibroblasts and epithelial cells. Significantly, the antiviral efficacy of artemisone was consistently ≥10-fold superior to that of artesunate in all cells. Artemisone effectively inhibited both laboratory-adapted and low-passage-number clinical strains, as well as drug-resistant HCMV strains. By using quantitative viral kinetics and gene expression studies, we show that artemisone is a reversible inhibitor targeting an earlier phase of the viral replication cycle than ganciclovir. Importantly, artemisone most effectively inhibited HCMV infection ex vivo in a clinically relevant multicellular model of integral human placental tissues maintained in organ culture. Our promising findings encourage preclinical and clinical studies of artemisone as a new inhibitor against HCMV.
Publisher: Frontiers Media SA
Date: 29-09-2020
Publisher: MDPI AG
Date: 13-07-2018
DOI: 10.3390/MOLECULES23071713
Abstract: According to the precepts that C-10 amino-artemisinins display optimum biological activities for the artemisinin drug class, and that attachment of a sugar enhances specificity of drug delivery, polarity and solubility so as to attenuate toxicity, we assessed the effects of attaching sugars to N-4 of the dihydroartemisinin (DHA)-piperazine derivative prepared in one step from DHA and piperazine. N-Glycosylated DHA-piperazine derivatives were obtained according to the Kotchetkov reaction by heating the DHA-piperazine with the sugar in a polar solvent. Structure of the D-glucose derivative is secured by X-ray crystallography. The D-galactose, L-rhamnose and D-xylose derivatives displayed IC50 values of 0.58–0.87 nM against different strains of Plasmodium falciparum (Pf) and selectivity indices (SI) , on average, with respect to the mouse fibroblast WEHI-164 cell line. These activities are higher than those of the amino-artemisinin, artemisone (IC50 0.9–1.1 nM). Notably, the D-glucose, D-maltose and D-ribose derivatives were the most active against the myelogenous leukemia K562 cell line with IC50 values of 0.78–0.87 µM and SI 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC50 of 0.26 µM, and a SI of 88 with the same cell lines. Overall, the N-glycosylated DHA-piperazine derivatives display antimalarial activities that are greatly superior to O-glycosides previously obtained from DHA.
Publisher: MDPI AG
Date: 22-10-2021
DOI: 10.3390/MOLECULES26216393
Abstract: The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacterial and parasitic infections, most notably, coccidiosis in poultry and in ruminants. We have investigated the effects of treatment of Toxoplasma gondii in infected human foreskin fibroblasts (HFF) with DCQ. This induced distinct alterations in the parasite mitochondrion within 24 h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC50) of 1.1 nM and the high selectivity index of , the efficacy of oral treatment of pregnant mice experimentally infected with T. gondii oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than T. gondii infection alone, and did not prevent vertical transmission. Thus, three quinoline-O-carbamate derivatives of DCQ, anticipated to have better physicochemical properties than DCQ, were assessed in vitro. One such compound, RMB060, displayed an exceedingly low IC50 of 0.07 nM, when applied concomitantly with the infection of host cells and had no impact on HFF viability at 10 µM. As was the case for DCQ, RMB060 treatment resulted in the alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6 h after the commencement of treatment. After 48 h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features reminiscent of bradyzoites. The exposure of infected cultures to 300 nM RMB060 for 52 days did not result in the complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. The treatment of mice infected with T. gondii oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.
Publisher: Elsevier BV
Date: 07-1996
Publisher: Springer Science and Business Media LLC
Date: 17-02-2016
Publisher: Wiley
Date: 12-1997
Publisher: Wiley
Date: 07-12-2020
Publisher: American Chemical Society (ACS)
Date: 11-0011
DOI: 10.1021/JA00150A009
Publisher: Elsevier BV
Date: 04-2023
Publisher: Elsevier BV
Date: 08-1999
Publisher: American Society for Microbiology
Date: 08-2003
Publisher: CSIRO Publishing
Date: 1987
DOI: 10.1071/CH9870281
Abstract: (E)- and (Z)-1-(Pheny1thio)oct-2-ene, (E)-1-(methylthio)- and 1-(t-butylthio)-oct-2-ene, S-[(E-oct-2-enyl] N,N- dimethylthiocarbamate , S-[(E)-oct-2-enyl] N,N- dimethylthiocarbamate , (E)-(oct-2-enylthio) benzothiazole , and S-[(E)-oct-2-enyl] N,N,N',N'- tetramethylphosphorodi - amidothioate have been prepared by nucleophilic substitution reactions and [1,3]- and [3,3]-sigma- tropic shifts involving intermediates prepared from oct-1-en-3-ol and (E)- and (Z)-oct-2-en-1-ol.
Publisher: American Society for Microbiology
Date: 10-2012
DOI: 10.1128/AAC.00283-12
Abstract: The declining efficacy of artemisinin derivatives against Plasmodium falciparum highlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against both P. falciparum and P. vivax malaria, comparative ex vivo antimalarial activity against Plasmodium isolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP). Ex vivo drug susceptibility was assessed in 46 field isolates (25 P. falciparum and 21 P. vivax ). The novel endoperoxide compounds exhibited potent ex vivo activity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC 50 s) in both species (median IC 50 s between 1.9 and 3.6 nM in P. falciparum and 0.7 and 4.6 nM in P. vivax ). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the two Plasmodium species: whereas their ex vivo activity correlated positively with CQ, PIP, AS, and DHA in P. falciparum , the same was not apparent in P. vivax . The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistant P. vivax . The high activity against drug-resistant strains of both Plasmodium species confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.
Publisher: American Chemical Society (ACS)
Date: 02-1995
DOI: 10.1021/JO00109A009
Publisher: Elsevier BV
Date: 1985
Publisher: American Psychological Association (APA)
Date: 11-2010
DOI: 10.1037/A0020796
Publisher: CSIRO Publishing
Date: 1988
DOI: 10.1071/CH9880881
Abstract: β- Sulfonylacrylate phenyl and t-butyl thioesters , and β- sulfonylvinyl ketones have been prepared by oxidation of the corresponding β-aryl- and β-alkyl- thio compounds. In one case the β- sulfonylvinyl ketone was obtained from an epoxy sulfone . The β-aryl- and β-alkyl- thio compounds were obtained by chlorination- dehydrochlorination of saturated precursors. The reactions of 3-( phenylthio ) propionyl chloride with organocadmium and Grignard reagents were used to prepare some of the saturated precursors of the β- sulfonylvinyl ketones.
Publisher: Bentham Science Publishers Ltd.
Date: 31-01-2014
DOI: 10.2174/1871526513666131129155708
Abstract: The isolation of artemisinin from the traditional medicinal herb qīng hāo (Artemisia annua), its characterization as a peroxide and preparation of the derivatives dihydroartemisinin, artemether and artesunate in the 1970s and 1980s by Chinese scientists under the umbrella of Project 523 collectively represents one of the great events in medicine in the latter third of the 20(th) Century. Artemisinins have become the most important component of chemotherapy of malaria: although used initially in monotherapy, they are now used in combination therapies or ACTs with longer half-life quinolines or arylmethanols. Nevertheless, the recent emergence of artemisinin-tolerant strains of the malaria parasite as reflected in increased clearance times of parasitaemia in patients treated with ACTs represents the greatest threat to control of malaria since resistance to chloroquine was first reported over 55 years ago. Importantly, the event brings into sharp focus the realization that relatively little is precisely understood, as opposed to widely assumed, for the mechanism of drug action of artemisinins and their synthetic peroxide analogues. Thus, we review here their antimalarial activities, the use of artemisinins in combination therapies, drug-drug interactions with the quinolines and arylmethanols, and metabolism of the artemisinins and synthetic peroxides. The mechanism of action of quinolines and arylmethanols, in particular their ability to induce redistribution of heme into the parasite cytosol, is also highlighted. This collective information is then used as a counterpoint to screen the validity of two of the prevailing hypotheses of drug action of artemisinins and synthetic peroxides, namely i. 'the C-radical hypothesis' wherein the peroxide undergoes 'bioactivation' by ferrous iron to generate C-radicals that are held to be the cytotoxic agents and ii. the 'heme hypothesis' wherein ferrous heme may generate either the same type of 'cytotoxic' C-radical, or the peroxide forms heme adducts that apparently inherit the exquisite cytotoxicities of the parent peroxide in one way or another. In a subsequent review, we screen the third and fourth hypotheses: the SERCA hypothesis wherein artemisinins modulate operation of the malaria parasite sarcoendo plasmic reticulum calcium pump SERCA Ca(2+)-ATPase ATP6 and the co-factor hypothesis wherein artemisinins act as oxidant drugs through rapidly oxidizing reduced conjugates of flavin cofactors, or those of flavin cofactor precursors such as riboflavin, and other susceptible endogenous substrates that play a role in maintaining intraparasitic redox homeostasis. For the C-radical hypothesis, details of in vitro chemical studies in the context of established chemistry of C-radicals and their ability to react with radical trapping agents such as nitroso compounds, cyclic nitrones, persistent nitroxyl radicals and atmospheric oxygen (dioxygen) are summarized. Overall, there is no correlation between antimalarial activities and abilities of the derived C-radicals to react with trapping agents in a chemical flask. This applies in particular to the reactions of C-radicals from artemisinins and steroidal tetraoxanes with the trapping agents vis-a-vis those from adamantyl capped systems. In an intraparasitic medium, it is not possible to intercept C-radicals either through use of a vast excess of a nitroxyl radical or dioxygen. The lack of correlation of antimalarial activities also applies to the Fe(2+)-mediated decomposition of artemisinins and synthetic peroxides, where literature data taken as indicating otherwise are critically assessed. The antagonism to antimalarial activities of artemisinins exerted by desferrioxamine (DFO) and related Fe(3+)-chelating agents is due to formation of stable chelates with bioavailable Fe(3+) that shuts down redox cycling through Fe(2+) and the subsequent generation of reactive oxygen species (ROS) via the Fenton reaction. The generation of ROS by Fe(2+) complements the action of artemisinins, to be discussed in Part 2 there is no need to posit a reaction of Fe(2+) with the artemisinins to account for their antimalarial activity. The ability of artemisinins and synthetic peroxides to elicit membrane damage is examined in the light of established processes of autoxidation. The oxidant character of the intraparasitic environment is incompatible with the reducing conditions required for generation of C-radicals, and in contrast to the expectation raised by the C-radical hypothesis, and indeed by the heme hypothesis outlined below, antimalarial activities of artemisinins are enhanced under higher partial pressures of dioxygen. Structure-activity data from a wide variety of artemisinins and synthetic peroxides cannot be accommodated within the bounds of the C-radical hypothesis. Finally, the antimalarial Cradical construct sharply contrasts with that of the potently antitumour-active ene-diyne antibiotics such as neocarzinostatin. In an iron-free process, these compounds generate highly reactive aryl C-radicals that abstract H atoms from deoxyribose units in DNA to generate alkyl C-radicals. The last do react with dioxygen in a normal intracellular environment to initiate DNA strand cleavage. Overall, it must be concluded that the C-radical hypothesis as the basis for antimalarial activities of artemisinins and synthetic peroxides is untenable. Heme has been intensively studied as an 'activator' of artemisinins and other antimalarial peroxides, and indeed the hypothesis seemingly has become firmly embedded in the underlying brickwork of the scientific edifice. The locus of activity of the peroxides interacting with the heme is considered to be the parasite digestive vacuole. The basis for the nanomolar activities of artemisinins and synthetic peroxides is variously ascribed to heme-Fe(2+)-mediated generation of C-radicals from the peroxides, formation of heme-artemisinin adducts that are held either to engage in redox cycling with concomitant generation of ROS or to inhibit formation of hemozoin. In the last case, just like the aminoquinolines and arylmethanols, the peroxides are not the active agents, but exert their parasiticidal effects through allowing the build-up of free heme-Fe(3+), the ultimate cytotoxic entity. We assess the literature relating to generation of heme by hemoglobin digestion, and the stage at which this process becomes significant in the intraerythrocytic parasite. The claims of production of heme and conversion into hemozoin occurring in a lipid environment may have to be put aside based on recent literature data that indicates crystallization of hemozoin must take place an aqueous interface association of lipids with the heme/hemozoin is likely to be a reflection of attractive van der Waals interactions involving the hydrophobic surface of the heme or hemozoin aggregates. In addition, the observation leading to the claim that hemozoin manufacture commences at the mid-ring stage cannot be independently verified. That the quinoline and arylmethanol antimalarials have essentially no activities on the ring stage parasites and exert greatest efficacy at the trophozoite stage where heme production is maximal is consistent with this. Conversely, artemisinins, and indeed redox active drugs such as methylene blue and others, are highly active against early ring stage parasites. Thus, there is a prominent disconnect between stage specificities of artemisinins vis-a-vis those of 4-aminoquinolines and arylmethanols suggesting that heme is not the target of the former class of drug. Further, the ability of the Fe(3+) chelate DFO to antagonize antimalarial activities of artemisinins, but not the activities of 4-aminoquinolines, cannot be explained by involvement of heme as a target for artemisinins. We critically examine the basis for formation of products obtained from reaction of heme with artemisinins and synthetic peroxides under conditions ranging from biomimetic - reactions employing catalytic reagents under aqueous or semi-aqueous conditions - to those conducted under highly reducing and eminently artificial conditions, usually in the solvent dimethyl sulfoxide (DMSO) that both forms well characterized complexes with heme-Fe(2+) and actually assists in driving single electron transfer processes. It is noted that alkylated products tend to form in high yields under the last conditions, and this aspect is readily explained. Irrespective of product yields obtained under various conditions, an overarching correlation between facility of the reaction of the peroxide with heme and their antimalarial activities does not exist. The is underscored by the reproducible outcomes of reactions conducted under biomimetic conditions indicating adducts cannot form in physiologically meaningful concentrations and that heme is a recalcitrant reaction partner to artemisinins in general. Again, as in the case of the C-radical hypothesis, structure-activity data from a wide variety of artemisinins and synthetic peroxides is difficult to reconcile with the heme hypothesis. This applies in particular to dimeric and trimeric artemisinin derivatives where the ascribing of biological activity to reactions of the derived radicals or to the vastly encumbered artemisinin-heme adducts is physically unrealistic. Finally, the facile metabolism and induction of metabolism of the current clinically used artemisinins by members of the CYP superfamily - heme proteins that require an intimate interaction of the heme with the artemisinin for metabolism to occur - is incompatible with the oft-cited proclivity of the peroxide to associate via complex formation with heme as a prelude to its 'activation' as an antimalarial agent within the malaria parasite. (ABSTRACT TRUNCATED)
Publisher: CSIRO Publishing
Date: 1987
DOI: 10.1071/CH9870273
Abstract: Methyl 7-hydroxyhept-5-ynoate, methyl 7-bromo- and 7-iodo-hept-5-ynoate, 7-hydroxyhept-5- ynenitrile, 7-bromohept-5-ynenitrile, 7-hydroxyhept-5-ynoic acid and 7-bromohept-5-ynoic acid have been prepared from 2-(prop-2-yny1oxy)tetrahydro-2 H-pyran and 1-bromo-3-chloropropane or 1-bromo-4-chlorobutane.
Publisher: Frontiers Media SA
Date: 18-02-2019
Publisher: Wiley
Date: 08-2003
Publisher: Elsevier BV
Date: 07-1996
Publisher: Springer Science and Business Media LLC
Date: 05-06-2005
DOI: 10.1038/NSMB947
Abstract: Artemisinins are the most important class of antimalarial drugs. They specifically inhibit PfATP6, a SERCA-type ATPase of Plasmodium falciparum. Here we show that a single amino acid in transmembrane segment 3 of SERCAs can determine susceptibility to artemisinin. An L263E replacement of a malarial by a mammalian residue abolishes inhibition by artemisinins. Introducing residues found in other Plasmodium spp. also modulates artemisinin sensitivity, suggesting that artemisinins interact with the thapsigargin-binding cleft of susceptible SERCAs.
Publisher: Elsevier BV
Date: 1980
Publisher: CSIRO Publishing
Date: 1984
DOI: 10.1071/CH9842037
Abstract: The preparation of ethyl 4-ethoxy-2-methylcyclohexa-1,3-diene-1-carboxyate, ethyl 4-isopropoxy- 2-methylcyclohexa-1,3-diene-1-carboxylate, t-butyl 4-isopropoxy-2-methylcyclohexa-1,3-diene-1- carboxylate, ethyl 4-(t-butylcarbonyloxy)-2-methylcyclohexa-1,3-diene-1-carboxylate, and t-butyI 4-(t-butylcarbonyloxy)-2-methylcyclohexa-1,3-diene-1-carboxylate from Hagemann's ester and its t-butyl analogue in the presence of diethyl or diisopropyl sulfates and sodium hydride in dimethyl sulfoxide, or pivaloyl chloride and N,N,N',N'-tetramethylethylenediamine in tetrahydrofuran is described. The foregoing dienol ethers and esters are smoothly deprotonated by lithium diisopropyl- amide in tetrahydrofuran at -78" to give the corresponding ester dienolates, which react regio- specifically with a number of electrophiles, either a or y to the alkoxycarbonyl group of the dienol ether or ester. A number of the products, which are generally obtained in good yields, have been hydrolysed to Hagemann's ester derivatives substituted exclusively at C1.
Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/CH9891455
Abstract: The lithium enolates arising by aprotic conjugate addition of lithiated but-2-enyl sulfoxides and a phosphine oxide to cyclopent-2-enone react efficiently with methyl cyanoformate to give the corresponding methyl 5-oxocyclopentanecarboxylates in good yields. The sulfoxides are smoothly deoxygenated with tributylphosphine diiodide in ether at 0�, and the resulting sulfides undergo intramolecular cyclization in the presence of tin(IV)chloride to give methyl oxobicyclo [3.3.0] octanecarboxylates , again in good to excellent yields. The cyclizations are highly stereoselective in that the syn- and anti-stereochemistries of the enolate trapped products obtained from (E)-and (Z)- sulfoxides are quantitatively reflected in the products obtained from the cyclization reactions.
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.MICINF.2004.09.002
Abstract: Multidrug-resistant malaria caused by Plasmodium falciparum has severely limited treatment options over recent years. Artemisinins are still effective for treating uncomplicated as well as severe malaria, because resistance is not yet clinically apparent. This article reviews some clinically useful properties of artemisinins and how they might work.
Publisher: American Society for Microbiology
Date: 05-2007
DOI: 10.1128/AAC.01544-06
Abstract: Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.
Publisher: CSIRO Publishing
Date: 1984
DOI: 10.1071/CH9841183
Abstract: A series of (methylthio)- and (methylseleno)-triphenylphosphonium salts and the analogous tributylphosphonium salts have been prepared by methylation of the corresponding tertiary phosphine sulfides and selenides. Details of their 1H, 13C and 31P n.m.r. spectra are given. Whereas the (methylthio)- and (methylseleno)-triphenylphosphonium salts undergo rapid decomposition in the presence of tertiary ammonium carboxylates or tertiary amines, the (methy1thio)- and (methylseleno)-tributylphosphonium salts convert such carboxylates into methanethiol and methaneselenol esters in acceptable yields. A tris(dimethylamino)(methylthio)phosphonium salt, on the other hand, converts benzoate into methyl benzoate in quantitative yield. Inferior yields of (methy1thio)- and (methylseleno)-alkanes are obtained from two primary alcohols and the tributylphosphonium salts.
Publisher: CSIRO Publishing
Date: 1987
DOI: 10.1071/CH9871249
Abstract: The conjugate addition of (E)-1-(pheny1thio)oct-2-enyllithium in tetrahydrofuran containing hexamethylphosphoric triamide to γ-crotonolactone (but-2-en-4-olide) followed by treatment of the resulting lactone enolate with either methyl 7-bromohept-5-ynoate or 7-bromohept-5-ynenitrile gave the corresponding enolate trapped products in yields of 50-55% from the octenyllithium reagent. Use of 7-iodohept-5-ynoate gave a slightly higher yield than the first electrophile. Treatment of the enolate with triphenyltin chloride prior to addition of the electrophiles resulted in approximately 5-10% enhancement of the yields of the products. The products obtained from the methyl 7-halohept-5-ynoates were converted into the 9-oxo-l0-oxaprostanoids through the corresponding sulfoxides and the allylically transposed alcohols by a standard sequence of reactions. In an attempt to convert the lactone ring of the enolate-trapped products into the fully carbocyclic nucleus of primary prostaglandins, the nucleophilic ring opening of the lactone nucleus with the lithiated carbanion derived from t-butyl methyl sulfone in the presence of N, N, N', N'- tetramethylethylenediamine was carried out. However, attempts to oxidize the resulting hemiacetals to the requisite diketone precursors of the carbocyclic prostaglandins were unsuccessful.
Publisher: Royal Society of Chemistry (RSC)
Date: 1990
DOI: 10.1039/C39900001102
Publisher: American Society for Microbiology
Date: 08-2009
DOI: 10.1128/AAC.00471-09
Abstract: Artemisone (single oral dose, 10 mg/kg of body weight) cured nonimmune Aotus monkeys of their Plasmodium falciparum infections when combined with mefloquine (single oral dose, 5 and 10 mg/kg but not 2.5 mg/kg). In combination with amodiaquine (20 mg/kg/day), artemisone (10 mg/kg/day) given orally for 3 days cured all infected monkeys. Three days of treatment with artemisone (30 mg/kg/day) and clindamycin (100 mg/kg/day) was also curative.
Publisher: CSIRO Publishing
Date: 1988
DOI: 10.1071/CH9880505
Abstract: Whereas the oxygenation of 1-t-butylcyclohexa-1,3-diene (4) in the presence of catalytic amounts of trityl tetrafluoroborate in dichloromethane at -78° under irradiation from a tungsten l gives two dimeric epidioxides as major products, cholesta-2,4-diene (5) gives under the same conditions a monomeric endoperoxide. The structures of the dimeric epidioxides have been established by a combination of chemical degradation, high-field 1H n.m.r. and an X-ray crystallographic study on the diketone (12) derived from one of the epidioxides. A mechanism involving the generation of intermediate monomer and dimer cation radicals is used to account for the formation of the dimeric epidioxides. The dimer cation radicals are expected to be more reactive than the monomer cation radicals towards oxygen. The dimerization is assumed to take place when the diene (4) and its monomer cation radical are aligned so that one reactant lies above the other whereby π-orbital overlap between the rings is maximized oxygen is constrained to attack the one exposed face of the allylic radical system in the dimer cation radical. This accounts for the unique stereochemistry of the epidioxide products. Crystal data for diketone (12): a 29.975(4), b 5.767(1), c 11.758(2)Ǻ, β 111.67(2)° C2/c Z4.
Publisher: Elsevier BV
Date: 2001
Publisher: MDPI AG
Date: 25-09-2023
DOI: 10.3390/PH16101348
Publisher: Wiley
Date: 11-12-2003
Abstract: Three cyclic hexapeptide units based on the parent loloatin C scaffold have been identified by a ‘sliding window’ method as part of an expeditious SAR search for the basis of the antibiotic activity of the loloatins. Modified Fmoc‐based solid‐phase synthesis was used to prepare cyclic( L ‐valyl‐ L ornithyl‐ D ‐phenylalanyl‐ L ‐asparaginyl‐ L ‐aspartyl‐ L ‐tryptophanyl) and cyclic( L ‐valyl‐ L ‐ornithyl‐ L ‐leucyl‐ L ‐tryptophanyl‐ D ‐phenylalanyl‐ L ‐asparaginyl) in overall yields of 42%−47%. A new solution method combined with an in situ indirect cyclization was specifically developed to prepare cyclic( L ‐ornithyl‐ L ‐leucyl‐ D ‐tyrosyl‐ L ‐prolyl‐ L ‐tryptophanyl D ‐phenylalanyl), involving cyclization of the linear peptide through the amino group in leucine, liberated selectively from the Fmoc‐protected amine in situ, with the activated p ‐nitrophenyl ester of ornithine. The method was also effectively used for cyclization of the linear precursors of the first two cyclic hexapeptides. NOE analyses coupled with peptide backbone modelling were used to establish conformations of the target compounds. All have helix‐like structures with γ‐turns. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Publisher: Wiley
Date: 11-12-2003
Abstract: NMR experiments combined with molecular simulation with X‐PLOR have been employed to determine the solution conformation of the cyclic decapeptide loloatin C in three different solutions. In DMSO, the molecule possesses a hydrophobic aromatic “wall” consisting of Trp 6 and Phe 7 , and a type I β‐turn structure involving Val 1 , Trp 10 , Asp 9 and Asn 8 with a hydrophobic head at Val 1 /Trp 10 and a hydrophilic tail at Asp 9 and Asn 8 another type II′ β‐turn was also located between Leu 3 , Tyr 4 , Pro 5 , and Trp 6 . In 70/30 [D 3 ]TFE/H 2 O, however, loloatin C possesses a dumbbell structure with all the hydrophobic side chains projecting upward on one side, forming a hydrophobic surface, and the hydrophilic side chains projecting to the other side, together with most of carbonyl oxygen atoms, thereby forming a hydrophilic surface. However, in 30:70 [D 3 ]TFE/H 2 O, loloatin C possesses an inverse γ‐turn incorporating Tyr 4 , Pro 5 , and Trp 6 , a hydrophobic zone involving the side chains of Leu 3 , Trp 6 , Trp 10 , and Phe 7 and a hydrophilic tail involving the hydrophilic side chains of Orn 2 , Asn 8 , and Asp 9 . The hiphilicity of the dumbbell structure in 70/30 [D 3 ]TFE/H 2 O is of interest in relation to the antibiotic activity of loloatin C. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Publisher: Public Library of Science (PLoS)
Date: 26-08-2013
Publisher: MDPI AG
Date: 23-09-2021
DOI: 10.3390/PH14100954
Abstract: Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to screen antimalarial compounds from different chemical classes, with the aim of identifying small molecules interfering with the RBD-ACE2 interaction and, consequently, with cell invasion. Docking studies showed that the compounds interfere with the same region of the RBD, but different interaction patterns were noted for ACE2. Virtual screening indicated pyronaridine as the most promising RBD and ACE2 ligand, and molecular dynamics simulations confirmed the stability of the predicted complex with the RBD. Bio-layer interferometry showed that artemisone and methylene blue have a strong binding affinity for RBD (KD = 0.363 and 0.226 μM). Pyronaridine also binds RBD and ACE2 in vitro (KD = 56.8 and 51.3 μM). Overall, these three compounds inhibit the binding of RBD to ACE2 in the μM range, supporting the in silico data.
Publisher: Wiley
Date: 08-12-2017
Abstract: Dihydroartemisinin (DHA), either used in its own right or as the active drug generated in vivo from the other artemisinins in current clinical use-artemether and artesunate-induces quiescence in ring-stage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11-azaartemisinin 5 and selected N-sulfonyl derivatives were screened against intraerythrocytic asexual stages of drug-sensitive Pf NF54 and drug-resistant K1 and W2 parasites. Most displayed appreciable activities against all three strains, with IC
Publisher: CSIRO Publishing
Date: 1978
DOI: 10.1071/CH9780121
Abstract: Some qualitative observations on the catalytic activity of Lewis acids in converting ergosteryl acetate into its 5α,8α peroxide are presented. The peroxide has an inhibiting effect on the reaction, which is ascribed to complex formation between it and the Lewis acid catalyst. This complex formation is used to explain the dual thermal and photochemical activity displayed by FeCl3 and MoCl5. A mixed oxygenation experiment with ergosteryl and lumisteryl acetates indicates that singlet oxygen is not an intermediate in this reaction. ��� A model for the reaction, involving formation of a diene cation radical within a charge-transfer complex, is advanced.
Publisher: American Chemical Society (ACS)
Date: 08-1994
DOI: 10.1021/JO00096A015
Publisher: American Chemical Society (ACS)
Date: 04-2021
DOI: 10.1021/JO00282A038
Publisher: Wiley
Date: 03-08-2021
DOI: 10.1111/ADD.15146
Publisher: Informa Healthcare
Date: 10-02-2014
DOI: 10.1517/17425255.2014.885503
Abstract: The objectives were to determine the pharmacokinetics (PK) of artemisone and artemisone formulated in the Pheroid® drug delivery system in primates and to establish whether the formulation affects the in vitro metabolism of artemisone in human and monkey liver and intestinal microsomes. For the PK study, a single oral dose of artemisone was administered to vervet monkeys using a crossover design. Plasma s les were analyzed by means of liquid chromatography-tandem mass spectrometry. For the in vitro metabolism study, clearance was determined using microsomes and recombinant CYP3A4 enzymes, and s les were analyzed by means of ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Artemisone and M1 plasma levels were unexpectedly low compared to those previously recorded in rodents and humans. The in vitro intrinsic clearance (CLint) of the reference formulation with monkey liver microsomes was much higher (1359.33 ± 103.24 vs 178.86 ± 23.42) than that of human liver microsomes. The in vitro data suggest that microsomal metabolism of artemisone is inhibited by the Pheroid delivery system. The in vivo results obtained in this study indicate that the Pheroid delivery system improves the PK profile of artemisone. The in vitro results indicate that microsomal metabolism of artemisone is inhibited by the Pheroid delivery system.
Publisher: Elsevier BV
Date: 03-1997
Publisher: MDPI AG
Date: 03-11-2021
DOI: 10.20944/PREPRINTS202111.0072.V1
Abstract: Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1 DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5 & ndash 2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage). Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.
Publisher: MDPI AG
Date: 27-09-2022
Abstract: A family of: 1:1 cocrystals 11-Aza:4-X-SalA have been prepared from the potent anti-malarial compound 11-azaartemisinin with 4-halosalicylic acids. When X = 4-Cl, 4-Br and 4-I, two conformational polymorphs can be isolated in each case. Monoclinic type-I was found previously for parent 11-Aza:SalA (1) and 11-Aza:4-Br-SalA (3a) which have polar 21 stacks of molecular pairs with no short halogen bond contacts between stacks. Orthorhombic type-II is found for 4-Cl (3b) and 4-I (4b) from solution growth. This has a translational stack of molecular pairs involving a conformational change of the acid-lactam hetero-synthon and supramolecular association of stacks via halogen bonds. Notably, phase pure polymorph type-I can be formed for 4-Cl (3a) and 4-I (4a) by hetero-seeding with 11-Aza:SalA, whist conversely phase pure type-II for 4-Br (2b) can be formed using homo-seeding from liquid assisted grinding (LAG) product. This work demonstrates both the viability of engineering polymorphic cocrystal forms using hetero-seeds and the involvement of halogen bonds in helping to discriminate quite different polymorphic types.
Publisher: American Society for Microbiology
Date: 03-2003
Publisher: MDPI AG
Date: 29-06-2022
DOI: 10.3390/PATHOGENS11070740
Abstract: This study evaluated the in vitro activity of the arylaminoartemisinin GC012, readily obtained from dihydroartemisinin (DHA), against clinical strains of Helicobacter pylori (H. pylori) with different antibiotic susceptibilities in the planktonic and sessile state. The activity was assessed in terms of bacteriostatic and bactericidal potential. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined by the broth microdilution method. After treatment with GC012, all bacterial strains showed significantly lower MIC and MBC values compared to those of DHA. The effect of combination of GC012 with antibiotics was examined using the checkerboard method. GC012 displayed synergistic interactions with metronidazole, clarithromycin, and amoxicillin in all the strains. The antibiofilm activity was evaluated via crystal violet staining, AlamarBlue® assay, colony-forming unit count, and fluorescence microscopy. At ½ MIC and ¼ MIC concentration, both GC012 and DHA inhibited biofilm formation, but only GC012 showed a minimal biofilm eradication concentration (MBEC) on mature biofilm. Furthermore, both compounds induced structural changes in the bacterial membrane, as observed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). It is thereby demonstrated that GC012 has the potential to be efficacious against H. pylori infection.
Publisher: CSIRO Publishing
Date: 1987
DOI: 10.1071/CH9871223
Abstract: The lithiated carbanions of (E)- and (Z)-1-(phenylthio)oct-2-ene, (E)-1-(methylthio)oct-2-ene, S-[(E)-oct-2-enyl] N,N-dimethyl( thiocarbamate ), S-[(a-oct-2-enyl] N,N-dimethyl- ( thiocarbamate ), and (E)- and (Z)-1-(phenylsulfony1)oct-2-ene undergo conjugate addition to γ-crotonolactone (but-2-en-4-olide) in tetrahydrofuran at -70� to give as predominant products, syn and anti allylic sulfides, thiocarbamates and sulfones arising from reaction through C1 of the octenyl carbanions . Also formed are smaller amounts of syn and anti vinylic sulfides, thiocarbamates and sulfones arising by reaction through C3 of the octenyl carbanions. The carbanions of the octenyl sulfones give smaller amounts of the vinylic products than do the other carbanions. In the presence of hexamethylphosphoric triamide (hmpa), the relative amounts of the latter compounds are depressed in favour of the former. The diastereoselection of these reactions is significantly smaller than the corresponding reactions involving 4-t-butoxycyclopent-2-enone. The constitutions and stereostructures of all the products was established by analysis of 1H n.m.r. data and n.O.e. difference experiments conducted at 400 MHz. The enhancement of the amounts of the allylic at the expense of the vinylic compounds induced by the hmpa is tentatively ascribed to frontier molecular orbital effects, and suggests that the operation of chelation and charge control in the reactions of related allylic carbanions with carbonyl compounds is less important than is generally considered to be the case. The various factors which cause carbanions to undergo conjugate addition to α β-unsaturated carbonyl compounds and the role played by the hmpa in these reactions are critically discussed in terms of the model of Seyden-Penne and coworkers.
Publisher: Wiley
Date: 14-01-2019
DOI: 10.1002/IUB.2002
Abstract: The observations that the innate immune system employs copper to eliminate bacterial infection and that resistance to copper enhances virulence of Mycobacterium tuberculosis (Mtb) prompted us to examine the effects the anti-cancer agent elesclomol on Mtb. As a bis-thionohydrazide, elesclomol chelates with copper to form a copper complex in situ that via redox cycling of the metal ion greatly enhances oxidative stress in tumour cells. Here, we demonstrate that elesclomol is relatively potent against Mtb H37Rv with minimum inhibitory concentration of 10 μM (4 mg/L) and against multidrug resistant clinical isolates of Mtb, displays additive interactions with known tuberculosis drugs such as isoniazid and ethambutol, and a synergistic interaction with rif icin. Controlled supplementation of elesclomol with copper in culture medium increased Mtb sensitivity by >65 fold. Overall, the activities of elesclomol in principle indicate the possibility of repurposing elesclomol or designing new thionohydrazides as potential drugs for use against Mtb. © 2019 IUBMB Life, 71(5):532-538, 2019.
Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/CH9891473
Abstract: Treatment of the neutral cyclopentanone adducts derived from the conjugate addition of each of lithiated 3-methylbut-2-enyl phenyl sulfoxide, (E)- and (Z)-but-2-enyldiphenylphosphine oxide to cyclopentenone with potassium t-butoxide results in intramolecular conjugate addition of the enolate arising from deprotonation at C5 of the cyclopentanone with the vinyl sulfoxide or phosphine oxide in the side chain togenerate bicyclo[2.2.l]heptanones in good yields. The use of an excess of lithium diisopropylamide at low temperature on the other hand results in kinetic deprotonation of the vinylic sulfoxide or phosphine oxide, and intramolecular nucleophilic addition of the resulting vinylic anions to the carbonyl groups in the respective adducts to generate bicyclo[3.2.l]octanols in acceptable yields. Application of the latter reaction to the lactone adduct of lithiated 3-methylbut-2-enyl phenyl sulfoxide and crotonolactone results in ring opening of the lactone to give a 2-(phenylsulfinyl)cyclohex-2-enone.
Publisher: CSIRO Publishing
Date: 1987
DOI: 10.1071/CH9870937
Abstract: The carbanions of (E)- and (Z)-1-(pheny1thio)oct-2-ene, (E)-1-(methy1thio)- and 1-(t-butyl- thio )oct-2-ene, N,N-dimethyl S-[(E)-oct-2-enyllthiocarbamate and (E)-oct-2-enyl benzothiazole undergo conjugate addition to 4-t-butoxycyclopent-2-enone in the presence of hexamethyl - phosphoric triamide ( hmpa ) in tetrahydrofuran at -70� to give as predominant products diastereomeric mixtures of syn and anti allylic sulfides arising from reaction through C1 of the octenyl carbanions. Also formed in some cases are small amounts of diastereomeric mixtures of syn and anti vinylic sulfides arising from reaction through C3 of the octenyl carbanions. In the absence of the hmpa, carbonyl addition is the major reaction pathway of the carbanions of each of the (E)- and (Z)- octenyl thiocarbamates. The constitutions and stereostructures of all the products have been established through chemical shift and coupling constant correlations of their IH n.m.r. data obtained at 400 MHz. The relative proportions of the regioisomeric allylic and vinylic sulfides are dependent both upon the nature of the non-allylic substituent attached to the sulfur atom, and the geometry of the double bond in the starting octenyl sulfide. While there is no apparent connection between the electronic properties or sizes of the non-allylic substituent and the diastereomer ratios of the allylic and vinylic sulfides, it is noted that the (2)-(phenylthio) octene delivers an allylic sulfide mixture enriched in the syn isomer. It is concluded that the carbanions are configurationally stable at-70� and that the configurations of the vinylic sulfides reflect the configurations of the carbanions from which they are derived. It is also concluded that the reactions proceed under orbital control, as this best accounts for the formation of the vinylic sulfides and is in accord with the results of STO-3G calculations carried out on a series of sulfur-bearing allylic carbanions . The likely angle of attack of the carbanions on the enone system is briefly discussed in terms of a published model relating to the attack of a simple nucleophile on an electrophilic double bond.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.BMCL.2016.05.024
Abstract: As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected ex les exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones.
Publisher: American Chemical Society (ACS)
Date: 08-1988
DOI: 10.1021/JA00224A029
Publisher: American Chemical Society (ACS)
Date: 06-1988
DOI: 10.1021/JO00248A001
Publisher: American Chemical Society (ACS)
Date: 02-1997
DOI: 10.1021/AR950058W
Publisher: Royal Society of Chemistry (RSC)
Date: 1972
DOI: 10.1039/P19720000396
Publisher: Elsevier BV
Date: 10-2004
DOI: 10.1016/J.DRUP.2004.07.001
Abstract: Artemisinins form the most important class of antimalarial currently available, particularly because they are effective against parasites resistant to almost all the other classes. Their mechanism of action is controversial. Some aspects of this controversy are reviewed here. Whilst there is no clinical resistance yet identified to artemisinins, the potential to examine the relationship between polymorphisms in PfATP6 (a target of artemisinins) in multidrug resistant isolates of Plasmodium falciparum, is also discussed.
Publisher: CSIRO Publishing
Date: 1987
DOI: 10.1071/CH9871211
Abstract: Reaction of 4-t-butoxycyclopent-2-enone with (E)-1-(pheny1thio)oct-2-enyllithium in tetrahydrofuran containing 1.5 equivalents of hexamethylphosphoric triamide at - 78� followed by treatment of the resulting enolate with one equivalent of triphenyltin chloride and then with methyl 7-iodohept-5-ynoate at - 20� gives the vicinally dialkylated cyclopentanone, methyl (a-9-oxo-1l-t-butoxy-13-(phenylthio)prost-14-en-5-ynoate, as a 1 : 1 mixture of diastereomers epimeric at C13, in 70-72% overall yields from the octenyllithium reagent. Stereoselective reduction of the C9 carbonyl, conversion of the sulfide into the allylically transposed alcohol, and removal of the t-butyl group by means of iron(III) chloride in acetic anhydride at 0� provides a triacetate which is converted into racemic methyl 5,6-didehydroprostaglandin F2a methyl ester as a 1 : 1 mixture of diastereomers epimeric at C15.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2001
DOI: 10.1097/00001432-200112000-00010
Abstract: The isolation in 1972 of artemisinin by Chinese scientists, and their development of all the derivatives now used in the treatment of malaria today, were of outstanding importance. The results which have accumulated both from the Chinese work and from that subsequently conducted on a worldwide basis provide for a relatively comprehensive understanding of the chemistry, pharmacological profiles, toxicology, metabolism, and effects on the malaria parasite. The optimal regimens for use in the field are also apparent, particularly in combinations with longer half-life quinoline antimalarials. Thus the future use of the artemisinin class of drug appears assured. However, the mechanism of action needs to be clarified. More importantly from a clinical viewpoint, problems inherent in the current derivatives must be addressed, particularly that of neurotoxicity, if new artemisinin derivatives are to be introduced in a normal drug regulatory environment. The application of established principles of modern drug design should indeed allow for the first truly rationally designed, in so far as the target is still unknown, derivatives to come to hand.
Publisher: CSIRO Publishing
Date: 1987
DOI: 10.1071/CH9871331
Abstract: The cyclization of compounds obtained from ethyl dienol ether and dienyl pivalate derivatives of Hagemann's ester has been examined. The carbanions of methyl phenyl sulfone and methyl phenyl sulfoxide react with the methylated dienol ether (4) to give the β-keto sulfone (8) and sulfoxide (9), the former of which was converted into the oxabicyclo[4.3.0]non-1-en-3-one (16). The iodide (17) with potassium t-butoxide in t-butyl alcohol gave the octahydronaphthalenone (18). With lithium ethoxide in tetrahydrofuran the octahydronaphthalenedione (22) was obtained from the dienyl pivalate (24). Both reactions involve the generation and intramolecular cyclization of a dienolate produced by cleavage of the pivaloyl group in each of (17) and (24). The scope and limitations of these reactions are briefly discussed.
Publisher: American Society for Microbiology
Date: 11-2019
DOI: 10.1128/AAC.01010-19
Abstract: Mycobacterium tuberculosis , the causative agent of tuberculosis, remains a leading infectious killer globally, demanding the urgent development of faster-acting drugs with novel mechanisms of action. Riminophenazines such as clofazimine are clinically efficacious against both drug-susceptible and drug-resistant strains of M. tuberculosis .
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.IJPHARM.2016.02.041
Abstract: The artemisinin derivative artemisone has antitumor activity. In particular when encapsulated in solid lipid nanoparticles (SLNs) and niosomes, it is active against human melanoma A-375 cells, although such formulations have a negligible effect on human keratinocyte cells. The aim here was to determine whether these formulations could enhance the topical delivery and skin permeation of artemisone as a prelude to evaluating use of artemisone and related compounds for melanoma treatment. In vitro skin permeation studies were conducted to determine the concentration of artemisone delivered into the stratum corneum-epidermis and epidermis-dermis. Artemisone-SLNs delivered artemisone into the stratum corneum-epidermis at significantly higher concentration (62.632 μg/mL) than the artemisone-niosomes (12.792 μg/mL). Neither of the controls delivered artemisone into the stratum corneum-epidermis. In the epidermis-dermis, artemisone (13.404 μg/mL) was only detected after application of the SLN formulation. Overall, the excellent topical delivery of artemisone with the SLN formulation coupled with the intrinsic activity of formulated artemisone confirms potential for use in treatment of melanoma.
Publisher: International Union of Crystallography (IUCr)
Date: 06-05-2021
DOI: 10.1107/S2053229621004460
Abstract: The X-ray structures of three new 1:1 pharmaceutical cocrystals of 11-azaartemisinin (11-Aza systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.0 4,13 .0 8,13 ]hexadecan-10-one, C 15 H 23 NO 4 ) with bromo-substituted salicylic acids [namely, 5-bromo- (5-BrSalA, C 7 H 5 BrO 3 ), 4-bromo- (4-BrSalA, C 7 H 5 BrO 3 ) and 3,5-dibromosalicylic acid (3,5-Br 2 SalA, C 7 H 4 Br 2 O 3 )] are reported. All the structures are related to the parent 11-Aza:SalA cocrystal (monoclinic P 2 1 ) reported previously. The 5-BrSalA analogue is isostructural with the parent, with lattice expansion along the c axis. The 4-BrSalA and 3,5-Br 2 SalA cocrystals retain the highly preserved 2 1 stacks of the molecular pairs, but these pack with a varying degree of slippage with respect to neighbouring stacks, altering the close contacts between them, and represent two potential alternative homostructural arrangements for the parent compound. Structure redeterminations of the bromosalicylic acids 5-BrSalA, 4-BrSalA and 3,5-Br 2 SalA at 100 K show that the packing efficiency of the cocrystals need not be higher than the parent coformers, based on specific-volume calculations, attributable to the strong O—H...O=C hydrogen bonds of 2.54 Å in the cocrystals.
Publisher: Wiley
Date: 15-12-2017
Abstract: To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin-cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC
Publisher: Bentham Science Publishers Ltd.
Date: 17-04-2020
DOI: 10.2174/1573406415666190430143535
Abstract: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7CE01875D
Abstract: The R22(8) lactam : acid hetero-synthon, found in several new 1 : 1 and 2 : 1 cocrystals between the anti-malarial 11-azaartemisinin and organic acids.
Publisher: Oxford University Press (OUP)
Date: 06-1994
DOI: 10.1016/0035-9203(94)90466-9
Abstract: The preparation of artemether from artemisinin is reviewed. Firstly, the extraction of artemisinin from Artemisia annua is described and an estimation of the yield per hectare based on literature data is given. Artemisinin is reduced with sodium borohydride to produce dihydroartemisinin as a mixture of epimers. The mixture is treated with methanol and an acid catalyst to provide artemether. Increasing demand for use of artemether places pressure on the supply of artemisinin, and an alternative means of preparing the drug from artemisinic acid, an abundant constituent of A. annua, which could triple current yields, is described. In anticipation of problems of drug resistance emerging with the continued use of artemether and artesunate to treat malaria, development of new derivatives of artemisinin which have enhanced stability is required. Ex les of such derivatives which have been prepared in our laboratories, or proposed, are described.
Publisher: Elsevier BV
Date: 11-2022
Publisher: Springer Science and Business Media LLC
Date: 2019
DOI: 10.1208/S12249-018-1251-5
Abstract: Vesicles are widely investigated as carrier systems for active pharmaceutical ingredients (APIs). For topical delivery, they are especially effective since they create a "depot-effect" thereby concentrating the APIs in the skin. Artemisone, clofazimine and decoquinate were selected as a combination therapy for the topical treatment of cutaneous tuberculosis. Delivering APIs into the skin presents various challenges. However, utilising niosomes, liposomes and transferosomes as carrier systems may circumvent these challenges. Vesicles containing 1% of each of the three selected APIs were prepared using the thin-film hydration method. Isothermal calorimetry, differential scanning calorimetry and hot-stage microscopy indicated no to minimal incompatibility between the APIs and the vesicle components. Encapsulation efficiency was higher than 85% for all vesicle dispersions. Vesicle stability decreased and size increased with an increase in API concentration and ultimately, niosomes were found the least stable of the different vesicle types. Skin diffusion studies were subsequently conducted for 12 h on black human female skin utilising vertical Franz diffusion cells. Transferosomes and niosomes delivered the highest average concentrations of clofazimine and decoquinate into the skin, whereas artemisone was not detected and no APIs were present in the receptor phase. Finally, efficacy against tuberculosis was tested against the Mycobacterium tuberculosis H37Rv laboratory strain. All the dispersions depicted some activity, surprisingly even the blank vesicles portrayed activity. However, the highest percentage inhibition (52%) against TB was obtained with niosomes containing 1% clofazimine.
Publisher: Georg Thieme Verlag KG
Date: 1992
DOI: 10.1055/S-1992-21384
Publisher: Wiley
Date: 07-2020
DOI: 10.1002/1099-0690(200207)2002:14<2350::AID-EJOC2350>3.0.CO;2-R
Publisher: Oxford University Press (OUP)
Date: 02-03-2007
DOI: 10.1093/JAC/DKL563
Abstract: The in vitro and in vivo efficacy and drug-drug interactions of the novel semi-synthetic endoperoxide artemisone with standard antimalarials were investigated in order to provide the basis for the selection of the best partner drug. Antimalarial activity and drug interactions were evaluated in vitro against Plasmodium falciparum by the incorporation of [(3)H]hypoxanthine. In vivo efficacy and drug interactions were assessed using the standard 4-day Peters' test. Artemisone was 10 times more potent than artesunate in vitro against a panel of 12 P. falciparum strains, independent of their susceptibility profile to antimalarial drugs, and consistently 4 to 10 times more potent than artesunate in rodent models against drug-susceptible and primaquine- or sulfadoxine yrimethamine-resistant Plasmodium berghei lines and chloroquine- or artemisinin-resistant lines of Plasmodium yoelii. Slight antagonistic trends were found between artemisone and chloroquine, amodiaquine, tafenoquine, atovaquone or pyrimethamine and additive to slight synergistic trends with artemisone and mefloquine, lumefantrine or quinine. Various degrees of synergy were observed in vivo between artemisone and mefloquine, chloroquine or clindamycin. These results confirm the increased efficacy of artemisone over artesunate against multidrug-resistant P. falciparum and provide the basis for the selection of potential partner drugs for future deployment in areas of multidrug-resistant malaria. Artemisone represents an important addition to the repertoire of artemisinin combination therapies currently in use, as it has enhanced antimalarial activity, improved bioavailability and stability over current endoperoxides.
Publisher: Elsevier BV
Date: 1985
Publisher: Wiley
Date: 26-09-2007
Abstract: The results of Fe(2+)-induced decomposition of the clinically used artemisinins, artemisone, other aminoartemisinins, 10-deoxoartemisinin, and the 4-fluorophenyl derivative have been compared with their antimalarial activities and their ability to inhibit the parasite SERCA PfATP6. The clinical artemisinins and artemisone decompose under aqueous conditions to give mixtures of C radical marker products, carbonyl compounds, and reduction products. The 4-fluorophenyl derivative and aminoartemisinins tend to be inert to aqueous iron(II) sulfate and anhydrous iron(II) acetate. Anhydrous iron(II) bromide enhances formation of the carbonyl compounds and provides a deoxyglycal from DHA and enamines from the aminoartemisinins. Ascorbic acid (AA) accelerates the aqueous Fe(2+)-mediated decompositions, but does not alter product distribution. 4-Oxo-TEMPO intercepts C radicals from a mixture of an antimalaria-active trioxolane, 10-deoxoartemisinin, and anhydrous iron(II) acetate to give trapped products in 73 % yield from the trioxolane, and 3 % from the artemisinin. Artemisone provides a trapped product in 10 % yield. Thus, in line with its structural rigidity, only the trioxolane provides a C radical eminently suited for intermolecular trapping. In contrast, the structural flexibility of the C radicals from the artemisinins allows facile extrusion of Fe(2+) and collapse to benign isomerization products. The propensity towards the formation of radical marker products and intermolecular radical trapping have no relationship with the in vitro antimalarial activities of the artemisinins and trioxolane. Desferrioxamine (DFO) attenuates inhibition of PfATP6 by, and antagonizes antimalarial activity of, the aqueous Fe(2+)-susceptible artemisinins, but has no overt effect on the aqueous Fe(2+)-inert artemisinins. It is concluded that the C radicals cannot be responsible for antimalarial activity and that the Fe(2+)-susceptible artemisinins may be competitively decomposed in aqueous extra- and intracellular compartments by labile Fe(2+), resulting in some attenuation of their antimalarial activities. Interpretations of the roles of DFO and AA in modulating antimalarial activities of the artemisinins, and a comparison with antimalarial properties of simple hydroperoxides and their behavior towards thapsigargin-sensitive SERCA ATPases are presented. The general basis for the exceptional antimalarial activities of artemisinins in relation to the intrinsic activity of the peroxide within the uniquely stressed environment of the malaria parasite is thereby adumbrated.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2010
DOI: 10.1007/S00280-010-1355-4
Abstract: Artemisinins are now established drugs for treatment of malaria. These agents have been shown to possess impressive anti-cancer properties. We have investigated the role of artemisone (ATM), a novel derivative of artemisinin (ART) in a cancer setting both alone and in combination with established chemotherapeutic agents. The anti-proliferative effects of ART and ATM were tested on a panel of human cancer cells in vitro using the methylthiazoletetrazolium assay, and the effect on cell cycling established by flow cytometry. Immunoblot analyses were performed to determine effects at the molecular level. Finally, ART and ATM were combined with the common anti-cancer agents oxaliplatin, gemcitabine and thalidomide. ART and ATM caused dose dependent decreases in cell number. ATM was consistently superior to ART, with IC50 s significantly lower in the former. Neither drug caused significant changes to the cell viability (%viable cells >95%), but arrested cell cycling. Blockade was either exclusively at the level of G1, or at all phases of the cell cycle, and associated with reductions in cyclin D1, CDK4 and pRb. Combination studies showed the anti-proliferative effect of ATM was often enhanced by addition of the other drugs, whilst ART exhibited antagonistic properties. ART and ATM are active in cancer cell lines, with ATM displaying the greater anti-proliferative effect when used alone. ATM also enhances the effects of the above drugs, with ART being less likely to improve activities. Taken together, ATM should be thought of as the ART-derived compound next in line for further study.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2012
Publisher: Bentham Science Publishers Ltd.
Date: 03-2006
DOI: 10.2174/156802606776743129
Abstract: The artemisinin derivatives, dihydroartemisinin (DHA), artesunate, atemether and arteether, are currently used for treatment of malaria in artemisinin combination therapies (ACT) with longer half-life drugs. The demand is enormous--in 2005, the estimated global demand for one such ACT alone, artemether-lumifantrine, which constitutes about 70% of all current clinically-used ACTs, is for 120 million adult treatment courses. At 0.5 gm of artemether per total dose regimen, the amount of artemisinin required is approximately 114 tons. This has placed substantial stress on total artemisinin supplies world-wide, and considerable attention is being focussed on enhancing availability of artemisinin by improvement in horticultural practice and extraction of artemisinin from Artemisia annua. Artemisinic acid, which also occurs in A. annua, can be converted into artemisinin and is the ultimate target of a biotechnological approach, which if successful, will augment artemisinin supply in the future. The conversion of artemisinin into the known artemisinin derivatives, and problems with the methods are critically reviewed. Some attention is paid to mechanistic aspects which clarify stereochemistry. The current artemisinins are by no means ideal drugs. Artesunate in particular is incompatible with basic quinolines by virtue of proton transfer, and has intrinsic chemical instability. At pH 1.2, conversion to DHA is rapid, with t(1/2) 26 min, and at pH 7.4, t(1/2) is about 10 hours. With a pK(a) of 4.6, over 99% of artesunate will be ionized at pH 7.4, and thus uptake by passive diffusion from the intestinal tract will be minimal. Although a considerable effort has been vested in the search for new artemisinins, largely through functionalization of artemisinin at C-10, O-11 or at C-15 via artemisitene, or of DHA at C-10, deliberate enhancement of the 'druggability' of artemisinins by reducing lipophilicity, which at the same time will attenuate the neurotoxicity characteristic of the current derivatives, and enhance absorption, by and large has not been considered. A review of the various types of newer derivatives is given together with a consideration of medicinal chemistry aspects.
Publisher: CSIRO Publishing
Date: 1990
DOI: 10.1071/CH9901375
Abstract: Tandem conjugate addition-ring closure involving reaction of the lithium enolate arising from conjugate addition of lithiated (E)-but-2- enyldiphenylphosphine oxide to 2-methyl-cyclopent-2-enone with two moles of t-butylthioacrylate generates a hydrindanol, and, in the presence of copper(I), a lactone derived from the hydrindanol. β-Sulfonylacrylate phenyl and t-butyl thioesters, β-chlorovinyl, β- sulfonyl- and β-sulfinyl-vinyl ketones react with the foregoing enolate, and with the enolate generated through conjugate addition of a methylcuprate to 2-methylcyclohexenone to give unsaturated 1,5-dicarbonyl compounds. The β-chlorovinyl ketones in particular react rapidly and in high yield. 2-Methylcyclohexenone has thereby been converted into a cis-dimethyl octalone the conversion illustrates the effectiveness of β-chlorovinyl methyl ketone in the Robinson annelation. Reactions of the lithium enolate and titanium enol of 2,6- dimethylcyclohexanone with the β-substituted enones to give the corresponding unsaturated 1,5-dicarbonyl compounds and other products are also recorded.
Publisher: Royal Society of Chemistry (RSC)
Date: 1990
DOI: 10.1039/C39900000451
Publisher: Springer Science and Business Media LLC
Date: 06-08-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 1972
DOI: 10.1039/P19720000813
Publisher: American Chemical Society (ACS)
Date: 08-1988
DOI: 10.1021/JA00224A030
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 06-2001
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1016/S0378-4347(99)00232-7
Abstract: A sensitive, selective, and reproducible GC-MS-SIM method was developed for determination of artemether (ARM) and dihydroartemisinin (DHA) in plasma using artemisinin (ART) as internal standard. Solid phase extraction was performed using C18 Bond Elut cartridges. The analysis was carried out using a HP-5MS 5% phenylmethylsiloxane capillary column. The recoveries of ARM, DHA and ART were 94.9 +/- 1.6%, 92.2 +/- 4.1% and 81.3 +/- 1.2%, respectively. The limit of quantification in plasma was 5 ng/ml (C.V. or = 0.988. Within day coefficients of variation were 3-10.4% for ARM and 7.7-14.5% for DHA. Between day coefficients of variations were 6.5-15.4% and 7.6-14.1% for ARM and DHA. The method is currently being used for pharmacokinetic studies. Preliminary data on pharmacokinetics showed Cmax of 245.2 and 35.6 ng/ml reached at 2 and 3 h and AUC0-8 h of 2463.6 and 111.8 ngh/ml for ARM and DHA, respectively.
Publisher: American Society for Microbiology
Date: 09-2008
DOI: 10.1128/AAC.01585-07
Abstract: In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life ( t 1/2 ) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t 1/2 , its pharmacokinetics were comparable after single and multiple dosing. Plasma s les taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t 1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.
Publisher: Elsevier BV
Date: 1985
Publisher: Royal Society of Chemistry (RSC)
Date: 1987
DOI: 10.1039/C39870000340
Publisher: American Society for Microbiology
Date: 08-2018
DOI: 10.1128/AAC.02214-17
Abstract: The emergence of resistance toward artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, the development of new artemisinins in combination with new drugs that impart activities toward both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular, those of resistant parasites, is urgently required.
Publisher: Wiley
Date: 02-03-2004
Publisher: Wiley
Date: 23-07-2010
Abstract: The antimalarial drug methylene blue (MB) affects the redox behaviour of parasite flavin-dependent disulfide reductases such as glutathione reductase (GR) that control oxidative stress in the malaria parasite. The reduced flavin adenine dinucleotide cofactor FADH(2) initiates reduction to leucomethylene blue (LMB), which is oxidised by oxygen to generate reactive oxygen species (ROS) and MB. MB then acts as a subversive substrate for NADPH normally required to regenerate FADH(2) for enzyme function. The synergism between MB and the peroxidic antimalarial artemisinin derivative artesunate suggests that artemisinins have a complementary mode of action. We find that artemisinins are transformed by LMB generated from MB and ascorbic acid (AA) or N-benzyldihydronicotinamide (BNAH) in situ in aqueous buffer at physiological pH into single electron transfer (SET) rearrangement products or two-electron reduction products, the latter of which dominates with BNAH. Neither AA nor BNAH alone affects the artemisinins. The AA-MB SET reactions are enhanced under aerobic conditions, and the major products obtained here are structurally closely related to one such product already reported to form in an intracellular medium. A ketyl arising via SET with the artemisinin is invoked to explain their formation. Dihydroflavins generated from riboflavin (RF) and FAD by pretreatment with sodium dithionite are rapidly oxidised by artemisinin to the parent flavins. When catalytic amounts of RF, FAD, and other flavins are reduced in situ by excess BNAH or NAD(P)H in the presence of the artemisinins in the aqueous buffer, they are rapidly oxidised to the parent flavins with concomitant formation of two-electron reduction products from the artemisinins regeneration of the reduced flavin by excess reductant maintains a catalytic cycle until the artemisinin is consumed. In preliminary experiments, we show that NADPH consumption in yeast GR with redox behaviour similar to that of parasite GR is enhanced by artemisinins, especially under aerobic conditions. Recombinant human GR is not affected. Artemisinins thus may act as antimalarial drugs by perturbing the redox balance within the malaria parasite, both by oxidising FADH(2) in parasite GR or other parasite flavoenzymes, and by initiating autoxidation of the dihydroflavin by oxygen with generation of ROS. Reduction of the artemisinin is proposed to occur via hydride transfer from LMB or the dihydroflavin to O1 of the peroxide. This hitherto unrecorded reactivity profile conforms with known structure-activity relationships of artemisinins, is consistent with their known ability to generate ROS in vivo, and explains the synergism between artemisinins and redox-active antimalarial drugs such as MB and doxorubicin. As the artemisinins appear to be relatively inert towards human GR, a putative model that accounts for the selective potency of artemisinins towards the malaria parasite also becomes apparent. Decisively, ferrous iron or carbon-centered free radicals cannot be involved, and the reactivity described herein reconciles disparate observations that are incompatible with the ferrous iron-carbon radical hypothesis for antimalarial mechanism of action. Finally, the urgent enquiry into the emerging resistance of the malaria parasite to artemisinins may now in one part address the possibilities either of structural changes taking place in parasite flavoenzymes that render the flavin cofactor less accessible to artemisinins or of an enhancement in the ability to use intra-erythrocytic human disulfide reductases required for maintenance of parasite redox balance.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.EXPPARA.2013.10.006
Abstract: Artemisone was evaluated, in in vitro and in vivo, for control of bovine babesiosis caused by Babesia bigemina and Babesia bovis parasites. In vitro, artemisone reduced parasitemia in a dose-dependent manner: the inhibitory effects increased gradually, reaching a maximum inhibition of 99.6% and 86.4% for B. bigemina and B. bovis, respectively 72 h after initiation of treatment with initial parasitemia of 0.5%. In calves infected with either B. bigemina or B. bovis artemisone treatment was well tolerated and prevented development of acute babesiosis in all animals except for one B. bovis-infected calf. The treatment did not eliminate all blood parasites, and recovered animals carried a persistent low-level infection. Treatment with artemisone may be useful as an alternative drug for preventing the pathology that results from babesiosis, without interfering with acquired immune protection following recovery from an acute babesiosis infection or vaccination.
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2014
End Date: 2017
Funder: South African Medical Research Council
View Funded ActivityStart Date: 2014
End Date: 2019
Funder: South African National Research Foundation
View Funded Activity