title: Structure-based design, synthesis, and biological evaluation of isatin derivatives as potential glycosyltransferase inhibitors.
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.
authors.affiliation: Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Fung-Yi
authors.initials: FY
authors.lastname: Chan
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.forename: Hok-Kiu
authors.initials: HK
authors.lastname: Lui
authors.forename: Pui-Kin
authors.initials: PK
authors.lastname: So
authors.forename: Siu-Cheong
authors.initials: SC
authors.lastname: Yan
authors.forename: Kin-Fai
authors.initials: KF
authors.lastname: Chan
authors.forename: Jiachi
authors.initials: J
authors.lastname: Chiou
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Yun-Chung
authors.initials: YC
authors.lastname: Leung
authors.forename: Kwok-Yin
authors.initials: KY
authors.lastname: Wong
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D001455:Bambermycins / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007510:Isatin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D001455:Bambermycins; C437243:moenomycin A; D007510:Isatin; D046928:Peptidoglycan Glycosyltransferase
keywords: STD-NMR; antibacterial activity; glycosyltransferase; isatin derivatives; virtual screening