title: Synthesis and biological evaluation of cationic fullerene quinazolinone conjugates and their binding mode with modeled Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase enzyme.
abstract: The present work reports a series of novel cationic fullerene derivatives bearing a substituted-quinazolinone moiety as a side arm. Fullerene-quinazolinone conjugates synthesized using the 1,3-dipolar cycloaddition reaction of C60 with azomethine ylides generated from the corresponding Schiff bases of substituted quinazolinone were characterized by elemental analysis, FT-IR, (1)H NMR, (13)C NMR and ESI-MS and screened for their antibacterial activity against Mycobacterium tuberculosis (H 37 Rv strain). All the compounds exhibited significant activity with the most effective having MIC in the range of 1.562-3.125 μg/mL. Compound 9f exhibited good biological activity compared to standard drugs. We developed a computational strategy based on the modeled M. tuberculosis hypoxanthine-guanine phosphoribosyltransferase (HGPRT) using homology modeling techniques and studied its binding pattern with synthesized fullerene derivatives. We then explored the surface geometry of the protein to place the cage adjacent to the active site while optimizing its quinazolinone side arm to establish H bonding with active site residues.
authors.affiliation: Department of Chemistry, University School of Sciences, Gujarat University, Ahmedabad, Gujarat 380009, India.
authors.forename: Manishkumar B
authors.initials: MB
authors.lastname: Patel
authors.forename: Sivakumar Prasanth
authors.initials: SP
authors.lastname: Kumar
authors.forename: Nikunj N
authors.initials: NN
authors.lastname: Valand
authors.forename: Yogesh T
authors.initials: YT
authors.lastname: Jasrai
authors.forename: Shobhana K
authors.initials: SK
authors.lastname: Menon
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020134:Catalytic Domain; D002412:Cations; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D037741:Fullerenes / Q000737:chemistry*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding; D052999:Quinazolinones / Q000737:chemistry*; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D002412:Cations; D004791:Enzyme Inhibitors; D037741:Fullerenes; D052999:Quinazolinones; D007041:Hypoxanthine Phosphoribosyltransferase