ORCID Profile
0000-0003-1432-1705
Current Organisations
Deakin University
,
Harvard University
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Publisher: Informa UK Limited
Date: 31-07-2023
Publisher: MDPI AG
Date: 07-03-2021
DOI: 10.3390/PH14030227
Abstract: The use of plant-derived natural products for the treatment of tropical parasitic diseases often has ethnopharmacological origins. As such, plants grown in temperate regions remain largely untested for novel anti-parasitic activities. We describe here a screen of the PhytoQuest Phytopure library, a novel source comprising over 600 purified compounds from temperate zone plants, against in vitro culture systems for Plasmodium falciparum, Leishmania mexicana, Trypanosoma evansi and T. brucei. Initial screen revealed 6, 65, 15 and 18 compounds, respectively, that decreased each parasite’s growth by at least 50% at 1–2 µM concentration. These initial hits were validated in concentration-response assays against the parasite and the human HepG2 cell line, identifying hits with EC50 1 μM and a selectivity index of . Two sesquiterpene glycosides were identified against P. falciparum, four sterols against L. mexicana, and five compounds of various scaffolds against T. brucei and T. evansi. An L. mexicana resistant line was generated for the sterol 700022, which was found to have cross-resistance to the anti-leishmanial drug miltefosine as well as to the other leishmanicidal sterols. This study highlights the potential of a temperate plant secondary metabolites as a novel source of natural products against tropical parasitic diseases.
Publisher: Public Library of Science (PLoS)
Date: 28-07-2016
Publisher: Oxford University Press (OUP)
Date: 29-10-2019
DOI: 10.1093/JAC/DKZ443
Abstract: Rapid rate-of-kill (RoK) is a key parameter in the target candidate profile 1 (TCP1) for the next-generation antimalarial drugs for uncomplicated malaria, termed Single Encounter Radical Cure and Prophylaxis (SERCaP). TCP1 aims to rapidly eliminate the initial parasite burden, ideally as fast as artesunate, but minimally as fast as chloroquine. Here we explore whether the relative RoK of the Medicine for Malaria Venture (MMV) Malaria Box compounds is linked to their mode of action (MoA) and identify scaffolds of medicinal chemistry interest. We used a bioluminescence relative RoK (BRRoK) assay over 6 and 48 h, with exposure to equipotent IC50 concentrations, to compare the cytocidal effects of Malaria Box compounds with those of benchmark antimalarials. BRRoK assay data demonstrate the following relative RoKs, from fast to slow: inhibitors of PfATP4& arasite haemoglobin catabolism& dihydrofolate reductase-thymidylate synthase (DHFR-TS)& dihydroorotate dehydrogenase (DHODH)& bc1 complex. Core-scaffold clustering analyses revealed intrinsic rapid cytocidal action for diamino-glycerols and 2-(aminomethyl)phenol, but slow action for 2-phenylbenz-imidazoles, 8-hydroxyquinolines and triazolopyrimidines. This study provides proof of principle that a compound’s RoK is related to its MoA and that the target’s intrinsic RoK is also modified by factors affecting a drug’s access to it. Our findings highlight that as we use medicinal chemistry to improve potency, we can also improve the RoK for some scaffolds. Our BRRoK assay provides the necessary throughput for drug discovery and a critical decision-making tool to support development c aigns. Finally, two scaffolds, diamino-glycerols and 2-phenylbenzimidazoles, exhibit fast cytocidal action, inviting medicinal chemistry improvements towards TCP1 candidates.
Publisher: Oxford University Press (OUP)
Date: 20-12-2016
DOI: 10.1093/JAC/DKW449
Abstract: A future treatment for uncomplicated malaria will contain at least one component that exerts a rapid rate of kill. We describe here the validation and application of a simple, robust and rapid bioluminescence-based assay for the determination of the initial rate of kill in intra-erythrocytic asexual stages of Plasmodium falciparum . A modification to the concentration-response bioluminescence [here termed bioluminescence relative rate of kill (BRRoK)] assay, utilizing exposure to fold-IC 50 concentrations (0.33× to 9×), was used to monitor the immediate cytocidal effect of 372 open-source compounds for antimalarial drug discovery available through the Medicines for Malaria Venture Malaria Box. Antimalarial drugs that exert a rapid cytocidal effect produce a concentration-dependent loss of bioluminescence signal that correlates with available in vitro and in vivo estimates of parasite clearance time and parasite reduction ratio. Following the measurement of IC 50 for the Malaria Box compounds in Dd2 luc , the BRRoK assay was used to identify and rank 372 compounds for their initial cytocidal activity. Fifty-three compounds in the Malaria Box show an initial relative rate of kill greater than that of chloroquine, with 17 of these having an initial relative rate of kill greater than that of dihydroartemisinin. The BRRoK assay provides a rapid assay format for the estimation of a key pharmacodynamic property of antimalarial drug action. The simplicity and robustness of the assay suggests it would be readily scalable for high-throughput screening and a critical decision-making tool for antimalarial drug development.
Publisher: Wiley
Date: 06-03-2021
Abstract: Despite the numerous benefits associated with state‐funded festivals, little is known about how New Public Management ideals (e.g. emphasis on economic returns, short‐term funding cycles) influence the extent to which these events can create value across social, cultural, and economic dimensions. Drawing on recent theoretical advancements around ecology of culture, we used a single‐case study design that included an embedded sub‐case to examine how value is assessed in an Australian‐based regional music festival and the implications for generating economic (e.g. ticket sales), social (e.g. sense of belonging), and cultural value (e.g. revitalising local traditions). The findings suggest that although prioritising economic value ahead of social and cultural outcomes can ultimately prove counterproductive, the experiences of those involved in the sub‐case indicate that a more holistic approach to festival self‐assessment can strengthen social, cultural, and economic outcomes and enhance the functioning of the sub‐case. These findings have important theoretical and practical implications, particularly in terms of reinforcing key elements of the ecosystem framework and helping to identify the ways in which festival ecosystems can be supported to enhance value creation.
Location: United Kingdom of Great Britain and Northern Ireland
Location: No location found
Location: United States of America
No related grants have been discovered for Imran Ullah.