Devine William, Thomas Sarah M, Erath Jessey, Bachovchin Kelly A, Lee Patricia J, Leed Susan E, Rodriguez Ana, Sciotti Richard J, Mensa-Wilmot Kojo, Pollastri Michael P
Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
Department of Cellular Biology, University of Georgia , Athens, Georgia 30602, United States.
ACS Med Chem Lett. 2017 Feb 5;8(3):350-354. doi: 10.1021/acsmedchemlett.7b00011. eCollection 2017 Mar 9.
Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis present a significant burden across the developing world. Existing therapeutics for these protozoal neglected tropical diseases suffer from severe side effects and toxicity. Previously, NEU-1045 () was identified as a promising lead with cross-pathogen activity, though it possessed poor physicochemical properties. We have designed a library of analogues with improved calculated physicochemical properties built on the quinoline scaffold of incorporating small, polar aminoheterocycles in place of the 4-(3-fluorobenzyloxy)aniline substituent. We report the biological activity of these inhibitors against (HAT), (Chagas disease), and (cutaneous leishmaniasis) and describe the identification of -(5-chloropyrimidin-2-yl)-6-(4-(morpholinosulfonyl)phenyl)quinolin-4-amine () as a promising inhibitor of proliferation and 6-(4-(morpholinosulfonyl)phenyl)--(pyrimidin-4-yl)quinolin-4-amine (), a potent inhibitor of proliferation with improved drug-like properties.
人类非洲锥虫病（HAT）、恰加斯病和利什曼病给发展中世界带来了沉重负担。针对这些被忽视的热带原生动物疾病的现有疗法存在严重的副作用和毒性。此前，NEU - 1045（）被确定为一种有前景的先导化合物，具有跨病原体活性，不过其物理化学性质较差。我们基于的喹啉骨架设计了一系列类似物库，通过并入小的极性氨基杂环取代4 - （3 - 氟苄氧基）苯胺取代基来改善计算得到的物理化学性质。我们报告了这些抑制剂对（HAT）、（恰加斯病）和（皮肤利什曼病）的生物活性，并描述了-（5 - 氯嘧啶 - 2 - 基）- 6 - （4 - （吗啉磺酰基）苯基）喹啉 - 4 - 胺（）作为一种有前景的增殖抑制剂以及6 - （4 - （吗啉磺酰基）苯基）- - （嘧啶 - 4 - 基）喹啉 - 4 - 胺（）的鉴定，后者是一种具有改善的类药物性质的增殖强效抑制剂。
