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

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.

SUBMITTER: Kurasaki H

PROVIDER: S-EPMC4904260 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Kurasaki Haruaki H Tsuda Kosuke K Shinoyama Mariko M Takaya Noriko N Yamaguchi Yuko Y Kishii Ryuta R Iwase Kazuhiko K Ando Naoki N Nomura Masahiro M Kohno Yasushi Y

ACS medicinal chemistry letters 20160405 6

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 ...[more]

PMID: 27326338

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