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.

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

“…Structure‐activity relationship of colletochlorin B. IC 50 values for the inhibition of purified recombinant trypanosome alternative oxidase reported by West et al and Saimoto et al (left and right IC 50 values, respectively)…”

“… K i and IC 90 values for the inhibition of Trypanosoma brucei alternative oxidase pathway (inhibition of oxygen uptake) by benzaldehyde and keto derivatives. IC 50 values for the inhibition of purified recombinant trypanosome alternative oxidase…”

“…The natural isoprenoid antibiotic AF ( 188 ) is one of the most potent (subnanomolar) inhibitors of TAO reported to date (Figure ) . The alkoxy analogues of AF substituted in para ( 186 ) and ortho position ( 187 ) with a geranyl tail are less inhibitory than AF by three orders of magnitude . In contrast, the more lipophilic 2‐hydroxy‐4‐alkyloxy derivative ( 180 ) is a nanomolar inhibitor (IC 50 = 73 nM) .…”

“…3‐Chloro‐4‐hydroxybenzonitrile derivatives: influence of tail hydrophilicity and methylene chain length on recombinant trypanosome alternative oxidase inhibition…”

“…For the nitrile analogue 249 , however, a drop in efficacy was observed against T. brucei even though enzyme inhibitory potency was retained. A methyl group at R 2 contributes significantly to the inhibition of TAO ( 189 , 249 , and 258 ) albeit to a lesser extent than that of a chlorine atom at R 3 ( 258 and 259 ) …”