Structure-based design, synthesis, and biological evaluation of isatin derivatives as potential glycosyltransferase inhibitors

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Yong Wang
  • Fung-Yi Chan
  • Ning Sun
  • Hok-Kiu Lui
  • Pui-Kin So
  • Siu-Cheong Yan
  • Kin-Fai Chan
  • Jiachi Chiou
  • Ruben Abagyan
  • Yun-Chung Leung
  • Kwok-Yin Wong

Detail(s)

Original languageEnglish
Pages (from-to)685-696
Journal / PublicationChemical Biology and Drug Design
Volume84
Issue number6
Online published2 Jun 2014
Publication statusPublished - Dec 2014
Externally publishedYes

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.

Research Area(s)

  • Antibacterial activity, Glycosyltransferase, Isatin derivatives, STD-NMR, Virtual screening

Citation Format(s)

Structure-based design, synthesis, and biological evaluation of isatin derivatives as potential glycosyltransferase inhibitors. / 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.

In: Chemical Biology and Drug Design, Vol. 84, No. 6, 12.2014, p. 685-696.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review