title: EVALUATION OF AROMATIC 6-SUBSTITUTED THIENOPYRIMIDINES AS SCAFFOLDS AGAINST PARASITES THAT CAUSE TRYPANOSOMIASIS, LEISHMANIASIS, AND MALARIA.
abstract: Target repurposing is a proven method for finding new lead compounds that targetTrypanosoma brucei, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog2with excellent potency againstT. brucei(EC50= 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound11eto have an EC50of 84 nM againstT. bruceicells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas' disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies forT. cruzi(4j) andPlasmodium falciparum(11j) were discovered, along with an analog with considerable potency againstLeishmania majoramastigotes (4e). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites.
authors: Northeastern University Department of Chemistry & Chemical Biology, 360 Huntington Avenue, Boston, MA 02115 USA. Tel: 617-373-2703.
authors: Jennifer L
authors: JL
authors: Woodring
authors: Northeastern University Department of Chemistry & Chemical Biology, 360 Huntington Avenue, Boston, MA 02115 USA. Tel: 617-373-2703.
authors: Gautam
authors: G
authors: Patel
authors: New York University School of Medicine, Department of Microbiology, Division of Parasitology, 341 E. 25 St. New York, NY 10010 USA.
authors: Jessey
authors: J
authors: Erath
authors: University of Georgia, Department of Cellular Biology, Athens, GA 30602 USA.
authors: Ranjan
authors: R
authors: Behera
authors: Experimental Therapeutics, Walter Reed Army Institute for Research,2460 Linden Lane, Silver Spring, MD 20910 USA.
authors: Patricia J
authors: PJ
authors: Lee
authors: Experimental Therapeutics, Walter Reed Army Institute for Research,2460 Linden Lane, Silver Spring, MD 20910 USA.
authors: Susan E
authors: SE
authors: Leed
authors: New York University School of Medicine, Department of Microbiology, Division of Parasitology, 341 E. 25 St. New York, NY 10010 USA ; Anti-Infectives Screening Core, New York University School of Medicine, New York, NY 10010 USA.
authors: Ana
authors: A
authors: Rodriguez
authors: Experimental Therapeutics, Walter Reed Army Institute for Research,2460 Linden Lane, Silver Spring, MD 20910 USA.
authors: Richard J
authors: RJ
authors: Sciotti
authors: University of Georgia, Department of Cellular Biology, Athens, GA 30602 USA.
authors: Kojo
authors: K
authors: Mensa-Wilmot
authors: Northeastern University Department of Chemistry & Chemical Biology, 360 Huntington Avenue, Boston, MA 02115 USA. Tel: 617-373-2703.
authors: Michael P
authors: MP
authors: Pollastri