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

Abstract：

: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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

West RA,O'Doherty OG,Askwith T,Atack J,Beswick P,Laverick J,Paradowski M,Pennicott LE,Rao SPS,Williams G,Ward SE

doi

10.1016/j.ejmech.2017.09.067

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

676-689

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(17)30781-X

journal_volume

141

pub_type

杂志文章

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