Diversity-Oriented Synthesis-Facilitated Medicinal Chemistry: Toward the Development of Novel Antimalarial Agents

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• 作者：Eamon Comer ; Jennifer A. Beaudoin ; Nobutaka Kato ; Mark E. Fitzgerald ; Richard W. Heidebrecht ; Maurice duPont Lee ; IV ; Daniela Masi ; Marion Mercier ; Carol Mulrooney ; Giovanni Muncipinto ; Ann Rowley ; Keila Crespo-Llado ; Adelfa E. Serrano ; Amanda K. Lukens ; Roger C. Wiegand ; Dyann F. Wirth ; Michelle A. Palmer ; Michael A. Foley ; Benito Munoz ; Christina A. Scherer ; Jeremy R. Duvall ; Stuart L. Schreiber
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8496-8502
• 全文大小：400K
• ISSN：1520-4804

文摘

Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure鈥揳ctivity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.