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Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline

Lee, Patrick and Lapointe, Guillaume and Madera, Ann Marie and Simmons, Bob and Xu, Wenjian and Yifru, Aregahegn and Tjandra, Meiliana and Karur, Subramanian and Rico, Alice and Thompson, Katherine and Bojkovic, Jade and Xie, Lili and Uehara, Kyoko and Liu, Amy and Shu, Wei and Bellamacina, Cornelia and Mckenney, David and Morris, Laura and Osborne, Colin and Benton, Bret and McDowell, Laura and Fu, Jiping and Sweeney, Zachary (2018) Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline. Journal of medicinal chemistry.

Abstract

This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.

Item Type: Article
Date Deposited: 02 Oct 2018 00:45
Last Modified: 02 Oct 2018 00:45
URI: https://oak.novartis.com/id/eprint/37183

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