University of Sussex
Browse

African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase

Download (1.09 MB)
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 Ward
African 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 Chemistry

ISSN

0223-5234

Publisher

Elsevier

Volume

141

Page range

676-689

Department affiliated with

  • Chemistry Publications

Research groups affiliated with

  • Sussex Drug Discovery Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-12-05

First Open Access (FOA) Date

2018-02-21

First Compliant Deposit (FCD) Date

2018-02-21

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC