Design, Synthesis, and Characterization of Some Hybridized Pyrazolone Pharmacophore Analogs against Mycobacterium tuberculosis. Issue 5 (May 2016)

• Record Type: Journal Article
• Authors: Krishnasamy, Sivakumar Kullampalayam; Namasivayam, Vigneshwaran; Mathew, Sincy; Eakambaram, Ragavendran S.; Ibrahim, Ibrahim A.; Natarajan, Adhirajan; Palaniappan, Senthilkumar
• Is Part Of: Archiv der Pharmazie. Volume 349:Issue 5(2016)
• Page Start: 383
• Page End: 397
• Publication Date: 2016-05
• Subjects: Antimycobacterial -- Mycobacterium tuberculosis -- Pyrazolone -- Shikimate kinase inhibitor; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201600019
• Languages: English
• ISSNs: 0365-6233

Abstract

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, and7i, 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 and8c, 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. Compounds8b and8c 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. Abstract : Hybridized pyrazolone analogs were designed, docked, and synthesized in two series. Both compound series were evaluated for their in vitro antimycobacterial properties, showing highly significant activities against all microorganisms tested. No double bond in the imine side chain and hydrophobic clashes at the pyrazolone end were necessary for good accommodation in the binding pocket of shikimate kinase.