期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 8, 期 3, 页码 350-354出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.7b00011
关键词
Antiparasitic agents; Trypanosoma brucei; Trypanosoma cruzi; Leishmania major; Plasmodium falciparum; Chagas disease; leishmaniasis; human African trypanosomiasis
资金
- National Institutes of Health [R01A1124046, R56A1099476]
- Northeastern University
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.
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