COX-2

A series of pyridinamide-containing naproxen derivatives were synthesized through different routes starting with naproxenoyl chloride (2) which, upon reaction with 2-or 3-aminopyridine, gave the corresponding naproxenamide derivatives 3a,b. Also, urea derivatives 5a,b were obtained through the reaction of compound 2 with sodium azide followed by reaction with 2-or 3-aminopyridene via Curtius rearrangement. In addition, naproxenoyl isothiocyanate was synthesized and reacted with 2- or 3-aminopyridine, where the thiourea derivatives 7a,b were obtained. Furthermore, cyanoacetanilide 9 was synthesized and reacted with acetylacetone, arylidenemalononitriles or arylidenecyanoacetate to furnish the corresponding pyridine amide derivatives 10-13. All compounds were screened for anti-inflammatory activity using an in vivo rat paw edema model, from which six of them exhibited higher potency than naproxen. The ulcerogenic effect of most of the active compounds was also screened. In ulcerogenicity screening, the potent anti-inflammatory compounds 3b, 5a and 5b were devoid of any ulcerative effect. This is contrary to naproxen which caused 100% ulcerative effect on all tested animals. Structure-based molecular modeling described that the virtual screening agrees with the SAR of in vivo anti-inflammatory and ulcerogenic activities. Furthermore, all the synthesized compounds were screened for their anti-microbial activity.

Triazine derivatives were reported to show a wide range of biological activities. Hence, it was planned to perform docking studies, synthesize and screen these designed compounds for their in vivo anti-inflammatory activity. In order to study the interaction of ligands with the binding site of the enzyme, the triazine derivatives were docked on cyclooxygenase-2 (COX-2) enzyme using the drug design software Maestro 9.5, Schrodinger, USA. The series of 8 compounds showing good Glide score (G-score) was synthesized to form 4-anilinoquinoline triazines. The structures of the compounds were confirmed by IR, 1H NMR and mass spectroscopy and the compounds were screened for anti-inflammatory activity by carrageenan- induced rat hind paw edema method, using Diclofenac as the standard. The G-scores of all the 8 compounds were closer to the scores displayed by the standard drugs, celecoxib and SC-558, there by suggesting that all the compounds interacted very well with the COX-2 enzyme. The in vivo anti-inflammatory activity results revealed that all the compounds displayed % inhibition of edema more than 90, which was better than that shown by the standard drug, Diclofenac. Amongst all the compounds, 3b demonstrated the highest G-score as well as the highest anti-inflammatory activity. Hence, this compound may be explored as a potential lead molecule for further development.