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ACS medicinal chemistry letters DOI:10.1021/ml200244k

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

Publication TypeJournal Article
Year of Publication2012
AuthorsHeidebrecht RW, J, Mulrooney, C, Austin, CP, Barker RH, J, Beaudoin, JA, Cheng, KC, Comer, E, Dandapani, S, Dick, J, Duvall, JR, Ekland, EH, Fidock, DA, Fitzgerald, ME, Foley, M, Guha, R, Hinkson, P, Kramer, M, Lukens, AK, Masi, D, Marcaurelle, LA, Su, XZ, Thomas, CJ, Weïwer, M, Wiegand, RC, Wirth, D, Xia, M, Yuan, J, Zhao, J, Palmer, M, Munoz, B, Schreiber, S
JournalACS medicinal chemistry letters
Date Published2012/02/09

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.