New Anti‐Inflammatory Hybrid N‐Acyl Hydrazone‐Linked Isoxazole Derivatives as COX‐2 Inhibitors:Rational Design, Synthesis and Biological Evaluation

Selectivity of a drug becomes a major problem in the treatment of a clinical disease and many nonsteroidal anti-inflammatory drugs (NSAID's) are classic examples of this conundrum. In the present study, we designed a set of hybrid compounds (11 a-p, 12 a-i) that compose new N-acyl hydrazones (NAH) linked with isoxazoles, using rational drug design approach. The binding affinities of newly designed compounds were calculated and compared with known non anti-inflammatory NAH and cyclooxygenase-2 (COX-2) inhibitors (coxibs) at the active sites of cyclooxygenase-1 (COX-1) and COX-2. The comparison revealed that the hybrid compounds bind with COX-2 active site in a fashion quite similar to known non anti-inflammatory compounds (4). Based on these findings, we further synthesized the compounds (11 a-p, 12 a-i) and subjected them to in vitro, in vivo anti-inflammatory studies. Compound 11 l (IC50=5.8 μM) and 12 c (IC50 = 4.1 μM) were found to be active COX-2 inhibitors. Compounds 12 a, 12 b and 12 e displayed COX-2 enzyme inhibition at lower micro molar concentrations. The compounds were also evaluated for antioxidant activity and compound 11 h exhibited an effective antioxidant activity when compared with ascorbic acid. Additionally, these compounds were screened for anti-bacterial activities and compound 11 l and 12 h were exhibited greater anti-bacterial activity against gram +ve and -ve than standards Ciprofloxacin and Flucloxacillin.