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African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase
journal contribution
posted on 2023-06-09, 09:11 authored by Ryan A West, Oran G O'Doherty, Trevor Askwith, John Atack, Paul Beswick, Jamie Laverick, Michael Paradowski, Lewis E Pennicott, Srinivasa P S Rao, Gareth Williams, Simon E WardAfrican trypanosomiasis is a parasitic disease affecting 5000 humans and millions of livestock animals in sub-Saharan Africa every year. Current treatments are limited, difficult to administer and often toxic causing long term injury or death in many patients. Trypanosome alternative oxidase is a parasite specific enzyme whose inhibition by the natural product ascofuranone (AF) has been shown to be curative in murine models. Until now synthetic methods to AF analogues have been limited, this has restricted both understanding of the key structural features required for binding and also how this chemotype could be developed to an effective therapeutic agent. The development of 3 amenable novel synthetic routes to ascofuranone-like compounds is described. The SAR generated around the AF chemotype is reported with correlation to the inhibition of T. b. brucei growth and corresponding selectivity in cytotoxic assessment in mammalian HepG2 cell lines. These methods allow access to greater synthetic diversification and have enabled the synthesis of compounds that have and will continue to facilitate further optimisation of the AF chemotype into a drug-like lead.
History
Publication status
- Published
File Version
- Published version
Journal
European Journal of Medicinal ChemistryISSN
0223-5234Publisher
ElsevierExternal DOI
Volume
141Page range
676-689Department affiliated with
- Chemistry Publications
Research groups affiliated with
- Sussex Drug Discovery Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-12-05First Open Access (FOA) Date
2018-02-21First Compliant Deposit (FCD) Date
2018-02-21Usage metrics
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