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Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria

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journal contribution
posted on 16.12.2015, 20:55 by Richard W. Heidebrecht, Carol Mulrooney, Christopher P. Austin, Robert H. Barker, Jennifer A. Beaudoin, Ken Chih-Chien Cheng, Eamon Comer, Sivaraman Dandapani, Justin Dick, Jeremy R. Duvall, Eric H. Ekland, David A. Fidock, Mark E. Fitzgerald, Michael Foley, Rajarshi Guha, Paul Hinkson, Martin Kramer, Amanda K. Lukens, Daniela Masi, Lisa A. Marcaurelle, Xin-Zhuan Su, Craig J. Thomas, Michel Weïwer, Roger C. Wiegand, Dyann Wirth, Menghang Xia, Jing Yuan, Jinghua Zhao, Michelle Palmer, Benito Munoz, Stuart Schreiber
Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure–activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.