Antiparasitic Lead Discovery: Toward Optimization of a Chemotype with Activity Against Multiple Protozoan Parasites

作者：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^*

来源：ACS Medicinal Chemistry Letters, 2017, 8(3): 350-354.

DOI：10.1021/acsmedchemlett.7b00011

• Antiparasitic agents
• Trypanosoma brucei
• Trypanosoma cruzi
• Leishmania major
• Plasmodium falciparum
• Chagas disease
• leishmaniasis
• human African trypanosomiasis

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 (3) 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 3 incorporating small, polar aminoheterocycles in place of the 4-(3-fluorobenzyloxy)aniline substituent. We report the biological activity of these inhibitors against Trypanosoma brucei (HAT), T. cruzi (Chagas disease), and Leishmania major (cutaneous leishmaniasis) and describe the identification of N-(5-chloropyrimidin-2-y1)-6(4-(morpholinosulfonyl)phenyl)quinolin-4-amine (13t) as a promising inhibitor of L. major proliferation and 6-(4-(morpholinosulfonyl)phenyl)-N-(pyrimidin-4-yl)quinolin-4-amine (13j), a potent inhibitor of T. brucei proliferation with improved drug-like properties.

• 出版日期2017-3
• 单位东北大学