title: Design, Synthesis, and Characterization of Some Hybridized Pyrazolone Pharmacophore Analogs against Mycobacterium tuberculosis.
abstract: Twenty-seven hybridized pyrazolone analogs were designed, docked, synthesized in two series and evaluated for their in vitro antimycobacterial properties. In the first series, four Schiff base derivatives, 6b, 7b, 7h, and 7i, show good antitubercular activity with minimum inhibition concentration (MIC) values in the range of 32.56-42.55 µM. In the second series, two compounds, 8b and 8c, possessed significant antitubercular activity with MIC <0.37 and <0.44 μM, respectively; they were even more potent than the standards pyrazinamide (12.99 μM), ciprofloxacin (4.82 μM), and streptomycin (5.36 μM), with a selectivity index of >630. Compounds 8b and 8c showed shikimate kinase inhibition activity at 5.84 and 6.93 µM, respectively. The activity and docking results lead to the conclusion that the compounds without double bond in the imine side chain and hydrophobic clashes at the pyrazolone end are necessary for good accommodation in the binding pocket and for imparting flexibility. All the compounds were also tested for antimicrobial activity (antibacterial and antifungal) and show highly significant activities against all the microorganisms tested.
authors.affiliation: Department of Pharmaceutical Chemistry, Medicinal Chemistry Research, KMCH College of Pharmacy, Kovai Estate, Coimbatore, India.
authors.forename: Sivakumar Kullampalayam
authors.initials: SK
authors.lastname: Krishnasamy
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Chemistry I, Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors.forename: Vigneshwaran
authors.initials: V
authors.lastname: Namasivayam
authors.affiliation: Department of Pharmaceutical Chemistry, Medicinal Chemistry Research, KMCH College of Pharmacy, Kovai Estate, Coimbatore, India.
authors.forename: Sincy
authors.initials: S
authors.lastname: Mathew
authors.affiliation: Department of Pharmaceutical Chemistry, Medicinal Chemistry Research, KMCH College of Pharmacy, Kovai Estate, Coimbatore, India.
authors.forename: Ragavendran S
authors.initials: RS
authors.lastname: Eakambaram
authors.affiliation: Department of Pharmaceutical Chemistry, Medicinal Chemistry Research, KMCH College of Pharmacy, Kovai Estate, Coimbatore, India.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Ibrahim
authors.affiliation: Department of Pharmaceutical Biotechnology, KMCH College of Pharmacy, Kovai Estate, Coimbatore, India.
authors.forename: Adhirajan
authors.initials: A
authors.lastname: Natarajan
authors.affiliation: Department of Pharmaceutical Chemistry, Medicinal Chemistry Research, KMCH College of Pharmacy, Kovai Estate, Coimbatore, India.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Palaniappan
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D011718:Pyrazinamide / Q000494:pharmacology; D047069:Pyrazolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012545:Schiff Bases / Q000737:chemistry / Q000494:pharmacology; D013307:Streptomycin / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D047069:Pyrazolones; D012545:Schiff Bases; D011718:Pyrazinamide; D002939:Ciprofloxacin; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase; D013307:Streptomycin
keywords: Antimycobacterial; Mycobacterium tuberculosis; Pyrazolone; Shikimate kinase inhibitor