Coumarinyl pyrazole derivatives of INH: promising antimycobacterial agents
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Med Chem Res (2013) 22:2279–2283 DOI 10.1007/s00044-012-0222-8
ORIGINAL RESEARCH
Coumarinyl pyrazole derivatives of INH: promising antimycobacterial agents Prashant Aragade • Mahesh Palkar • Pradeepkumar Ronad • Darbhamulla Satyanarayana
Received: 10 April 2012 / Accepted: 24 August 2012 / Published online: 6 September 2012 Ó Springer Science+Business Media, LLC 2012
Abstract The purpose of this study was to evaluate the antimycobacterial activity of various pyrazole derivatives derived from the isoniazid pharmacophore along with coumarin scaffold. The synthesized title compounds (4a–4k) were investigated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using Resazurin MIC assay. The synthesized compounds exhibited MIC ranging from 0.625 to 2.50 lg/ml. Among the series tested, compound 3-[3-(4-fluorophenyl)-1-isonicotinoyl-1H-pyrazol-5-yl]-2H-chromen-2-one 4i was found to be the most active with MIC of 0.625 lg/ml. Keywords Antimycobacterial activity Coumarin Isonicotinic acid hydrazide Pyrazole Mycobacterium tuberculosis
Introduction Tuberculosis (TB) is still a challenging worldwide health problem and Mycobacterium tuberculosis remains one of the single most deadly human pathogens. The resurgence of TB over the last two decades, even in industrialized countries Authors sincerely dedicate the article in the name of Late. Dr. V. S. Maddi. P. Aragade M. Palkar (&) P. Ronad Department of Medicinal Chemistry, KLES’ College of Pharmacy, Vidyanagar, Hubli, Karnataka, India e-mail: [email protected] D. Satyanarayana Department of Medicinal Chemistry, NGSM Institute of Pharmaceutical Sciences, Paneer, Deralakatte, Mangalore, Karnataka, India
where it was almost eradicated, has been favored by the pathogenic synergy with human immunodeficiency virus (HIV) infection. In fact, TB and other atypical mycobacterioses are now diseases frequently associated with AIDS; HIV infection significantly increases the risk that new or latent TB infections will progress to active diseases (Collins, 1989; Graham et al., 1996; Halsey et al., 1998; Inderlied et al., 1993). The emergence of TB has also been accompanied by the appearance of single-drug-resistant (SDR) and multidrug-resistant (MDR) strains of M. tuberculosis which are insensitive to one or more of the first-line anti-TB drugs (isoniazid [INH], rifampin, ethambutol, streptomycin, and pyrazinamide) (Telzak et al., 1995). Indeed, a great amount of work has been done in order to acquire useful knowledge about the mechanisms of action and resistance to available anti-TB drugs (Dessen et al., 1995). M. tuberculosis often becomes drug resistant as a consequence of spontaneous genetic mutations involving the molecular targets of drugs. The primary mechanism of multidrug resistance in TB is the accumulation of mutations in individual drug target genes (Morris et al., 1995). However, such knowledge is not sufficient to rationally overcome drug resistance in mycobacteria. In fact, currently, combinations of two or more ant
