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

Publication TypeJournal Article
AuthorsHeidebrecht RW, Jr, Mulrooney C., Austin CP, Barker RH Jr, 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., and Schreiber S.
AbstractHere, 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.
Year of Publication2012
JournalACS medicinal chemistry letters
Volume3
Issue2
Pages112-117
Date Published (YYYY/MM/DD)2012/02/09
DOI10.1021/ml200244k
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22328964?dopt=Abstract