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

被引：31

作者：

Comer, Eamon ^{[1
]}

Beaudoin, Jennifer A. ^{[1
]}

Kato, Nobutaka ^{[1
]}

Fitzgerald, Mark E. ^{[1
]}

Heidebrecht, Richard W. ^{[1
]}

Lee, Maurice duPont ^{[1
]}

Masi, Daniela ^{[1
]}

Mercier, Marion ^{[1
]}

Mulrooney, Carol ^{[1
]}

Muncipinto, Giovanni ^{[1
]}

Rowley, Ann ^{[1
]}

Crespo-Llado, Keila ^{[4
]}

Serrano, Adelfa E. ^{[4
]}

Lukens, Amanda K. ^{[5
,6
]}

Wiegand, Roger C. ^{[5
]}

Wirth, Dyann F. ^{[5
,6
]}

Palmer, Michelle A. ^{[1
]}

Foley, Michael A. ^{[1
]}

Munoz, Benito ^{[1
]}

Scherer, Christina A. ^{[1
]}

Duvall, Jeremy R. ^{[1
]}

Schreiber, Stuart L. ^{[1
,2
,3
]}

机构：

[1] Broad Inst, Ctr Sci Therapeut, Cambridge Ctr 7, Cambridge, MA 02142 USA

[2] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

[3] MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA

[4] Univ Puerto Rico, Sch Med, Dept Microbiol & Med Zool, San Juan, PR 00936 USA

[5] Broad Inst, Infect Dis Initiat, Cambridge Ctr 7, Cambridge, MA 02142 USA

[6] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 20期

基金：

美国国家卫生研究院; 比尔及梅琳达.盖茨基金会;

关键词：

COLLECTION; LEAD;

D O I：

10.1021/jm500994n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：8496 / 8502

页数：7

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