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

Yong Wang, Fung Yi Chan, Ning Sun, Hok Kiu Lui, Pui Kin So, Siu Cheong Yan, Kin Fai Chan, Jia-chi Chiou, Sheng Chen, Ruben Abagyan, Yun Chung Leung, Kwok Yin Wong

Research output: Journal article publicationJournal articleAcademic researchpeer-review

21 Citations (Scopus)


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 lg/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.
Original languageEnglish
Pages (from-to)685-696
Number of pages12
JournalChemical Biology and Drug Design
Issue number6
Publication statusPublished - 1 Jan 2014


  • Antibacterial activity
  • Glycosyltransferase
  • Isatin derivatives
  • Virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine


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