Abstract
Crystallography has guided the hybridization of two series of Trypanosoma bruceiN-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood–brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.
Highlights
Human African trypanosomiasis (HAT), or sleeping sickness, is caused by two different subspecies of the protozoan parasite Trypanosoma brucei: T.b. gambiense and T.b. rhodensiense
We have reported the successful chemical validation of TbNMT using the prototype NMT inhibitor DDD85646 [2] derived from pyrazole sulfonamide screening hit DDD64558 [1] (Scheme 1), which is highly effective at curing mouse models of hemolymphatic infection
Methyl ester 4 (Scheme 2), identified as a singleton by Scheme 3 high throughput screening, was at least 10-fold more selective for TbNMT over HsNMT compared to the pyrazole sulfonamide hit 1, making it a potentially attractive start point for optimization
Summary
Human African trypanosomiasis (HAT), or sleeping sickness, is caused by two different subspecies of the protozoan parasite Trypanosoma brucei: T.b. gambiense and T.b. rhodensiense. The disease, which is fatal unless treated, is transmitted by the bite of an infected tsetse fly. It has two stages: an initial peripheral infection during which the parasites are found in the bloodstream, giving rise to nonspecific symptoms, and a second stage when the parasites enter the central nervous system, causing the classic symptoms of HAT, eventually leading to coma and death. We have reported the successful chemical validation of TbNMT using the prototype NMT inhibitor DDD85646 [2] derived from pyrazole sulfonamide screening hit DDD64558 [1] (Scheme 1), which is highly effective at curing mouse models of hemolymphatic (peripheral) infection.. N-Myristoyltransferase (NMT) represents a potential drug target for HAT because in T. brucei RNAi knockdown of NMT has been shown to cause cidality in cell culture and to abrogate infectivity in several animal models. We have reported the successful chemical validation of TbNMT using the prototype NMT inhibitor DDD85646 [2] derived from pyrazole sulfonamide screening hit DDD64558 [1] (Scheme 1), which is highly effective at curing mouse models of hemolymphatic (peripheral) infection. we were not able to obtain conclusive evidence for TbNMT validation in stage 2 disease as the blood−brain barrier penetrant compounds we developed did not have a sufficient therapeutic window.
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