LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents
| Autor: | Naoki Ando, Noriko Takaya, Yasushi Kohno, Kosuke Tsuda, Yuko Yamaguchi, Masahiro Nomura, Kazuhiko Iwase, Ryuta Kishii, Haruaki Kurasaki, Mariko Shinoyama |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Gram-negative bacteria Zinc binding biology 010405 organic chemistry Stereochemistry Organic Chemistry biology.organism_classification 01 natural sciences Biochemistry Combinatorial chemistry 0104 chemical sciences 03 medical and health sciences 030104 developmental biology Enzyme Design synthesis chemistry Docking (molecular) Drug Discovery Efflux Antibacterial activity Biological evaluation |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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