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

[Image: see text] 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 relatio...

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Detalles Bibliográficos
Autores principales: Heidebrecht, Richard W., Mulrooney, Carol, Austin, Christopher P., Barker, Robert H., Beaudoin, Jennifer A., Cheng, Ken Chih-Chien, Comer, Eamon, Dandapani, Sivaraman, Dick, Justin, Duvall, Jeremy R., Ekland, Eric H., Fidock, David A., Fitzgerald, Mark E., Foley, Michael, Guha, Rajarshi, Hinkson, Paul, Kramer, Martin, Lukens, Amanda K., Masi, Daniela, Marcaurelle, Lisa A., Su, Xin-Zhuan, Thomas, Craig J., Weïwer, Michel, Wiegand, Roger C., Wirth, Dyann, Xia, Menghang, Yuan, Jing, Zhao, Jinghua, Palmer, Michelle, Munoz, Benito, Schreiber, Stuart
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2011
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276110/
https://www.ncbi.nlm.nih.gov/pubmed/22328964
http://dx.doi.org/10.1021/ml200244k
Descripción
Sumario:[Image: see text] 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.

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