New Thiazole Carboxamide Derivatives as COX Inhibitors: Design, Synthesis, Anticancer Screening, In Silico Molecular Docking, and ADME Profile Studies.

The goal of this work was to create and test a new series of thiazole carboxamide derivatives for their cyclooxygenase (COX) suppressor and anticancer effects. The compounds were characterized using 1H, 13C NMR, and HRMS spectrum analysis, and their selectivity toward COX-1 and COX-2 was assessed using an in vitro COX inhibition assay kit. Cytotoxicity was assessed using an MTS assay against a panel of cancer and normal cell lines. The docking studies were aided by the Prime MM-GBSA method for estimating binding affinities. The density functional theory (DFT) analysis was performed to assess compound chemical reactivity, which was calculated by computing the border orbital energy of both HOMO and LUMO orbitals, as well as the HOMO-LUMO energy gap. For ADME-T analysis, the QiKProp module was employed. Furthermore, using human X-ray crystal structures, molecular docking studies were carried out to discover the probable binding patterns of these drugs within both COX-1 and COX-2 isozymes. The results demonstrated that the most effective compound against the COX-1 enzyme was with an IC of 0.239 μM. It also showed potent activity against COX-2 with an IC value of 0.191 μM and a selectivity ratio of 1.251. The highest selectivity ratio was 2.766 for compound against COX-2 with an IC dose of 0.958 μM relating to the celecoxib ratio of 23.8 and its IC against COX-2 of 0.002 μM. Compound also showed good selectivity toward COX-2 (1.507) with an IC value of 0.957 μM. All compounds showed negligible cytotoxic activity against the evaluated normal cell lines, and the IC values were more than 300 μM, except for compound , whose IC values were 203.71 ± 1.89 and 116.96 ± 2.05 μM against LX-2 and Hek293t cell lines, respectively. Moreover, compound showed moderate anticancer activity against COLO205 and B16F1 cancer cell lines with IC values of 30.79 and 74.15 μM, respectively.