Antiparasitic Lead Discovery: Toward Optimization of a Chemotype with Activity Against Multiple Protozoan Parasites.
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 of3incorporating small, polar aminoheterocycles in place of the 4-(3-fluorobenzyloxy)aniline substituent. We report the biological activity of these inhibitors againstTrypanosoma brucei(HAT),T. cruzi(Chagas disease), andLeishmania major(cutaneous leishmaniasis) and describe the identification ofN-(5-chloropyrimidin-2-yl)-6-(4-(morpholinosulfonyl)phenyl)quinolin-4-amine (13t) as a promising inhibitor ofL. majorproliferation and 6-(4-(morpholinosulfonyl)phenyl)-N-(pyrimidin-4-yl)quinolin-4-amine (13j), a potent inhibitor ofT. bruceiproliferation with improved drug-like properties.
Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
William
W
Devine
Department of Cellular Biology, University of Georgia , Athens, Georgia 30602, United States.
Sarah M
SM
Thomas
Anti-Infectives Screening Core, New York University School of Medicine , New York, New York 10010, United States.
Jessey
J
Erath
Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
Kelly A
KA
Bachovchin
Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
Patricia J
PJ
Lee
Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
Susan E
SE
Leed
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.
Ana
A
Rodriguez
Experimental Therapeutics, Walter Reed Army Institute for Research , 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
Richard J
RJ
Sciotti
Department of Cellular Biology, University of Georgia , Athens, Georgia 30602, United States.
Kojo
K
Mensa-Wilmot
Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
Michael P
MP
Pollastri
Antiparasitic agents; Chagas disease; Leishmania major; Plasmodium falciparum; Trypanosoma brucei; Trypanosoma cruzi; human African trypanosomiasis; leishmaniasis