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

Abstract

Abstract 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 (IC 50 =5.8 μM) and 12 c (IC 50 = 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.