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

  • ACS Med Chem Lett. 2017 Feb 5;8(3):350-354. doi: 10.1021/acsmedchemlett.7b00011.
William Devine  1 ,  Sarah M Thomas  2 ,  Jessey Erath  3 ,  Kelly A Bachovchin  1 ,  Patricia J Lee  4 ,  Susan E Leed  4 ,  Ana Rodriguez  5 ,  Richard J Sciotti  4 ,  Kojo Mensa-Wilmot  2 ,  Michael P Pollastri  1
Affiliations
  • 1. Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
  • 2. Department of Cellular Biology, University of Georgia , Athens, Georgia 30602, United States.
  • 3. Anti-Infectives Screening Core, New York University School of Medicine , New York, New York 10010, United States.
  • 4. Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
  • 5. Department of Microbiology, Division of Parasitology, New York University School of Medicine, 341 East 25th Street New York, New York 10010, United States; Anti-Infectives Screening Core, New York University School of Medicine, New York, New York 10010, United States.
PMID: 28337329 DOI: 10.1021/acsmedchemlett.7b00011
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 (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-yl)-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.

Keywords
Antiparasitic agents; Chagas disease; Leishmania major; Plasmodium falciparum; Trypanosoma brucei; Trypanosoma cruzi; human African trypanosomiasis; leishmaniasis.