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Antibacterial and Solubility Optimization of Thiomuracin A

Leeds, Jennifer and Brewer, Jason and Dean, Karl and Ding, Jian and Gamber, Gabriel and Jain, Akash and Kerrigan, John and Krastel, Philipp and Lee, Kwangho and Lombardo, Franco and Mckenney, David and Neckermann, Georg and Osborne, Colin and Palestrant, Deborah and Patane, Michael and Rann, Elin and Robinson, Zach and Schmitt, Esther and Stams, Travis and Yu, Donghui and Whitehead, Lewis (2016) Antibacterial and Solubility Optimization of Thiomuracin A. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

Abstract

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogs 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 analogs (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.

Item Type: Article
Date Deposited: 20 Jul 2016 00:45
Last Modified: 20 Jul 2016 00:45
URI: https://oak.novartis.com/id/eprint/28989

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