期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 20, 页码 8496-8502出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500994n
关键词
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资金
- Broad Compound Management and Analytical teams
- Bill & Melinda Gates Foundation [OPP1032518, OPP1053644]
- NIH-MLPCN program [1U54HG005032-1]
- National Institutes of Health [AI093716-01A1, G12-MD 007600]
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-activity 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.
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