Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A

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• 作者：Matthew J. LaMarche ; Jennifer A. Leeds ; Joanne Dzink-Fox ; Eric Gangl ; Philipp Krastel ; Georg Neckermann ; Deborah Palestrant ; Michael A. Patane ; Elin M. Rann ; Stacey Tiamfook ; Donghui Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：55
• 期：15
• 页码：6934-6941
• 全文大小：389K
• 年卷期：v.55,no.15(August 9, 2012)
• ISSN：1520-4804

文摘

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2鈥揅7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.