期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 159, 期 -, 页码 90-103出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.09.053
关键词
Isoxazole-containing benzamide; Antibacterial activity; FtsZ inhibitor; Molecular docking analysis; Structure-based optimization
资金
- National Natural Science Foundation of China [81673284]
- Major Project of Research and Development of Shandong Province [2016GSF201202]
- Key Research and Development Project of Shandong Province [2017CXGC1401]
- Major Project of Science and Technology of Shandong Province [2015ZDJS04001]
Antibiotic resistance among clinically significant bacterial pathogens is becoming a prevalent threat to public health, and new antibacterial agents with novel mechanisms of action hence are in an urgent need. Utilizing computational docking method and structure-based optimization strategy, we rationally designed and synthesized two series of isoxazol-3-yl- and isoxazol-5-yl-containing benzamide derivatives that targeted the bacterial cell division protein FtsZ. Evaluation of their activity against a panel of Gram-positive and -negative pathogens revealed that compounds B14 and B16 that possessed the isoxazol-5-yl group showed strong antibacterial activity against various testing strains, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. aureus. Further molecular biological studies and docking analyses proved that the compound functioned as an effective inhibitor to alter the dynamics of FtsZ self-polymerization via a stimulatory mechanism, which finally terminated the cell division and caused cell death. Taken together, these results could suggest a promising chemotype for development of new FtsZ-targeting bactericidal agent. (C) 2018 Elsevier Masson SAS. All rights reserved.
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