LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents

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• 作者：Haruaki Kurasaki ; Kosuke Tsuda ; Mariko Shinoyama ; Noriko Takaya ; Yuko Yamaguchi ; Ryuta Kishii ; Kazuhiko Iwase ; Naoki Ando ; Masahiro Nomura ; Yasushi Kohno
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：7
• 期：6
• 页码：623-628
• 全文大小：425K
• 年卷期：0
• ISSN：1948-5875

文摘

Herein we report a scaffold-hopping approach to identify a new scaffold with a zinc binding headgroup. Structural information was used to give novel oxazolidinone-based LpxC inhibitors. In particular, the most potent compound, 23j, showed a low efflux ratio, nanomolar potencies against E. coli LpxC enzyme, and excellent antibacterial activity against E. coli and K. pneumoniae. Computational docking was used to predict the interaction between 23j and E. coli LpxC, suggesting that the interactions with C207 and C63 contribute to the strong activity. These results provide new insights into the design of next-generation LpxC inhibitors.