Design and Synthesis of Brain Penetrant Trypanocidal N‑Myristoyltransferase Inhibitors

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.N-肉豆蔻酰基转移酶（N-Myristoyltransferase, NMT）是寄生性原生生物布氏锥虫（Trypanosoma brucei, T. brucei）——引发人类非洲锥虫病（human African trypanosomiasis, HAT，俗称昏睡病）的致病病原体——内极具潜力的药物靶点。我们此前已验证布氏锥虫NMT可作为治疗该疾病1期与2期非洲人类锥虫病的潜在可药用靶点。本研究报道了以已公开报道的DDD85646（1）为设计起始骨架，开发一类强效且可穿透血脑屏障的布氏锥虫NMT抑制剂的相关工作。