Urea Derivatives of 2‑Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis

A previous
publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24, 2451–2465) explored the antitrypanosomal activities
of novel derivatives of 2-(2-benzamido)­ethyl-4-phenylthiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human
African trypanosomiasis. While a number of these compounds, particularly
the urea analogues, were quite potent, these molecules as a whole
exhibited poor metabolic stability. The present work describes the
synthesis of 65 new analogues arising from medicinal chemistry optimization
at different sites on the molecule. The most promising compounds were
the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue,
(S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)­benzothiazole (57) was chosen for in
vivo efficacy studies based upon in vitro activity, metabolic stability,
and brain penetration. This compound attained 5/5 cures in murine
models of both early and late stage human African trypanosomiasis,
representing a new lead for the development of drugs to combat this
neglected disease.

本实验室此前发表的一项研究（Patrick等，《Bioorg. Med. Chem.》2016, 24, 2451–2465）曾针对2-(2-苯甲酰胺基)乙基-4-苯基噻唑（2-(2-benzamido)ethyl-4-phenylthiazole，化合物1）的新型衍生物的抗锥虫活性（antitrypanosomal activities）展开探索。该母核化合物曾被鉴定为抗布鲁氏锥虫（Trypanosoma brucei）——人非洲锥虫病（human African trypanosomiasis）的致病病原体——的命中化合物。尽管此类化合物中多款（尤其脲类类似物）活性强劲，但整体而言这类分子的代谢稳定性（metabolic stability）较差。本研究通过对该分子不同位点进行药物化学优化，合成了65种全新类似物。其中最具开发潜力的化合物为2-芳基-苯并噻唑-5-胺的脲类衍生物。其中一款类似物——(S)-2-(3,4-二氟苯基)-5-(3-氟-N-吡咯烷基甲酰胺基)苯并噻唑（57）——凭借其体外活性（in vitro activity）、代谢稳定性（metabolic stability）及血脑屏障穿透性（brain penetration），被选中开展体内药效学（in vivo efficacy）研究。该化合物在针对早期和晚期人非洲锥虫病的小鼠模型中实现了5/5的治愈率，为对抗这一被忽视疾病的药物研发提供了全新先导化合物。