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- Title
Structure-based Design, Synthesis, and Biological Evaluation of Isatin Derivatives as Potential Glycosyltransferase Inhibitors.
- Authors
Wang, Yong; Chan, Fung ‐ Yi; Sun, Ning; Lui, Hok ‐ Kiu; So, Pui ‐ Kin; Yan, Siu ‐ Cheong; Chan, Kin ‐ Fai; Chiou, Jiachi; Chen, Sheng; Abagyan, Ruben; Leung, Yun ‐ Chung; Wong, Kwok ‐ Yin
- Abstract
Peptidoglycan glycosyltransferase ( PGT) has been shown to be an important pharmacological target for the inhibition of bacterial cell wall biosynthesis. Structure-based virtual screening of about 3 000 000 commercially available compounds against the crystal structure of the glycosyltransferase ( GT) domain of the Staphylococcus aureus penicillin-binding protein 2 ( S. aureus PBP2) resulted in identification of an isatin derivative, 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)- N-(m-tolyl)acetamide ( 4) as a novel potential GT inhibitor. A series of 4 derivatives were synthesized. Several compounds showed more active antimicrobial activity than the initial hit compound 4, in particular 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)- N-(3-nitrophenyl)acetamide ( 4l), against Gram-positive Bacillus subtilis and S. aureus with MIC values of 24 and 48 μg/mL, respectively. Saturation transfer difference ( STD) NMR study revealed that there is a binding contact between 4l and the GT domain of S. aureus PBP2. Competitive STD- NMR further proved that 4l and moenomycin A bind to GT domain in a competitive manner. Molecular docking study suggests a potential binding pocket of 4l in the GT domain of S. aureus PBP2. Taken together, compound 4l would provide a new scaffold for further development of potent GT inhibitors.
- Subjects
ANTIBACTERIAL agents; GLYCOSYLTRANSFERASES; ISATIN; MAGNETIZATION transfer; POSITRON emission tomography; PEPTIDOGLYCAN hydrolase; OLIGOSACCHARIDES; THERAPEUTICS
- Publication
Chemical Biology & Drug Design, 2014, Vol 84, Issue 6, p685
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12361