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

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

doi:10.1016/j.ejmech.2017.09.067

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.

Highlights

African Trypanosomiasis is a parasitic protozoan infection in mammals spread by the tsetse fly (Glossina) [1]
Trypanosoma brucei gambiense and T. b. rhodesiense cause the chronic western and acute eastern infections respectively, these two species have developed strategies to neutralize the immunity conferred by apolipoprotein A1, a trypanosomal lytic factor (TLF) in normal human sera [3], and evade host immune response by antigenic variation of their variant surface glycoprotein coat [4]. 60 million people are at risk of human African trypanosomiasis (HAT) with 5000 new cases reported annually [5,6]
Ascofuranone was described as a nanomolar inhibitor of TAO in the late 1990s [27], exploitation of this opportunity has been severely limited due to the availability of robust synthetic routes to these molecules

Summary

Introduction

African Trypanosomiasis is a parasitic protozoan infection in mammals spread by the tsetse fly (Glossina) [1]. The high morbidity is evinced by the 1.79 million disability-adjusted life years (DALYs) calculated for HAT, over five times greater than that for the related disease leishmaniasis [10] This infection is not limited to humans; animal African trypanosomiasis (AAT) is the single largest infection of cattle in Africa necessitating 35 million doses of trypanocidal agents, costing up to 140 million USD annually and impacting nutrition, livelihoods and development across sub-Saharan Africa. We report TAO inhibition data for the molecules prepared during these synthetic investigations

Synthetic chemistry

TAO activity assay

Structure-activity relationships

Conclusions

Experimental section

Synthesis