Novel Pyrazole Derivatives Bearing Carbonitrile and Substituted Thiazole Moiety for Selective COX-2 Inhibition

In this study, a series of derivatives of pyrazole hybrid structures containing carbonitrile and substituted thiazole moiety were designed to search for selective COX-2 inhibition. The designed target structures were synthesized with easy, practical, and efficient procedures. COX-1/2 inhibition and cytotoxic effects of the synthesized compounds were evaluated in NIH/3T3 and MDA-MD-231 cell lines for inhibition concentration and selectivity index. The results showed that the compounds have an inhibitory effect with higher selectivity towards COX-2 overall in both cell lines and moderate antiproliferative activity by targeting the breast cancer cell line MDA-MB-231. Among the 19 compounds synthesized (19 a-t), especially compound 19 m was found to be highly effective with COX-2 inhibition of 5.63 mu M in the NIH/3T3 cell line and 4.12 mu M in the MDA-MB-231 cell line. Moreover, molecular docking studies showed that the compounds indeed exhibited higher affinity for the COX-2 active site. The theoretical ADMET properties of the presented compounds were calculated, and the results showed that the compounds may have a more favorable pharmacokinetic effect profile than the selective COX-2 inhibitor Celecoxib, thus promising COX-2 inhibitor drug candidates for the future.

A series of derivatives of pyrazole hybrid structures were designed to search for selective COX-2 inhibition. COX-1/2 inhibition and cytotoxic effects of the synthesized compounds were evaluated in NIH/3T3 and MDA-MD-231 cell lines. Moreover, molecular docking, SAR, and ADMET studies showed that the compounds may have a more favorable pharmacokinetic profile, thus promising COX-2 inhibitor drug candidates for the future.image