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

Abstract

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