ORCID Profile
0000-0001-9921-4399
Current Organisation
University of St Andrews
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Publisher: Wiley
Date: 10-06-2016
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.BMC.2017.01.021
Abstract: The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the world's very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity. Several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor.
Publisher: Wiley
Date: 21-08-2014
Publisher: Wiley
Date: 29-05-2019
Abstract: The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp . are responsible for the severely debilitating neglected Tropical diseases of African sleeping sickness, Chagas disease and leishmaniasis, respectively. As part of our ongoing programme exploring the potential of simplified analogues of the acetogenin chamuvarinin we identified the T. brucei FoF1‐ATP synthase as a target of our earlier triazole analogue series. Using computational docking studies, we hypothesised that the central triazole heterocyclic spacer could be substituted for a central 2,5‐substituted furan moiety, thus ersifying the chemical framework for the generation of compounds with greater potency and/or selectivity. Here we report the design, docking, synthesis and biological evaluation of new series of trypanocidal compounds and demonstrate their on‐target inhibitory effects. Furthermore, the synthesis of furans by the modular coupling of alkyne‐ and aldehyde‐THPs to bis‐THP 1,4‐alkyne diols followed by ruthenium/xantphos‐catalysed heterocyclisation described here represents the most complex use of this method of heterocyclisation to date.
Publisher: Public Library of Science (PLoS)
Date: 05-09-2017
Publisher: American Chemical Society (ACS)
Date: 09-01-2018
DOI: 10.1021/ACSINFECDIS.7B00187
Abstract: Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani. In addition, we demonstrate the utility of the photoaffinity probes for target identification through preliminary cellular localization studies.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Gordon Florence.