Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors.

Tracy Bayliss,Stephen Brand,Victoria C Smith,Chido Mpamhanga,Stuart P Mcelroy,Paul G Wyatt,Ruth Brenk,Ian H Gilbert,Laste Stojanovski,Kevin D Read,Leah S Torrie,David A Robinson,Julie A Frearson,Suzanne Norval

doi:10.1021/acs.jmedchem.7b01255

Tracy Bayliss, Stephen Brand + Show 12 more

Open Access

https://doi.org/10.1021/acs.jmedchem.7b01255

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Journal: Journal of Medicinal Chemistry	Publication Date: Nov 22, 2017
Citations: 14	License type: cc-by

Affiliation: University of Dundee

Abstract

N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trypanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stages 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a starting point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.

Highlights

Human African trypanosomiasis (HAT) or sleeping sickness is prevalent in sub-Saharan Africa1 with an estimated “at risk” population of 65 million
The causative agents of HAT are the protozoan parasites Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense3,4 transmitted through the bite of an infected tsetse fly
There are a number of treatments available for HAT, though none are without issues, including toxicity and inappropriate routes of administration for a disease of rural Africa

Summary

■ INTRODUCTION

Human African trypanosomiasis (HAT) or sleeping sickness is prevalent in sub-Saharan Africa with an estimated “at risk” population of 65 million. The causative agents of HAT are the protozoan parasites Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense transmitted through the bite of an infected tsetse fly. Optimization of 29 focused on modifications to the central 2,6dichlorophenyl ring to increase enzymatic selectivity relative to HsNMT1 (0.3 μM, 3-fold compared to TbNMT IC50) These modifications were made employing the same chemistry as outlined in Scheme 1, by varying the starting substituted bromophenol used in the Mitsunobu step. These compounds were made using the same common phenol intermediate (Scheme 2), applying solid phase reagents such as polystyrene bound triphenylphosphine, and running reactions and purifications in parallel using commercially available alcohols or alcohols derived from commercially available carboxylic acids or esters after reduction with borane or lithium aluminum hydride (see Supporting Information). Compound 81 represents a good lead for further optimization to identify development candidates for stage

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES