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LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents
Haruaki Kurasaki1, Kosuke Tsuda1, Mariko Shinoyama1
1Watarase Research Center, Kyorin Pharmaceutical Co., Ltd. , 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Abstract:
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.
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