Antibacterial and Solubility Optimization of Thiomuracin A

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• 作者：Matthew J. LaMarche ; Jennifer A. Leeds ; Jason Brewer ; Karl Dean ; Jian Ding ; Joanne Dzink-Fox ; Gabe Gamber ; Akash Jain ; Ryan Kerrigan ; Philipp Krastel ; Kwangho Lee ; Franco Lombardo ; David McKenney ; Georg Neckermann ; Colin Osborne ; Deborah Palestrant ; Michael A. Patane ; Elin M. Rann ; Zachary Robinson ; Esther Schmitt ; Travis Stams ; Stacey Tiamfook ; Donghui Yu ; Lewis Whitehead
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 28, 2016
• 年：2016
• 卷：59
• 期：14
• 页码：6920-6928
• 全文大小：561K
• 年卷期：0
• ISSN：1520-4804

文摘

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogues in the Northern region (C2–C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., 3) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster C. difficile models of disease. Optimal efficacy in the hamster model of C. difficile was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility.