New Pyrimidine-5-Carbonitriles as COX-2 Inhibitors: Design, Synthesis, Anticancer Screening, Molecular Docking, and In Silico ADME Profile Studies

Two series of cyanopyrimidine hybrids were synthesized bearing either benzo[d]imidazole, benzo[d]oxazole, benzo[d]thiazole, and benzo[b]thiophene derivatives via methylene amino linker 3a–3d (Formula A) or various sulphonamide phenyl moieties 5a–5d (Formula B) at the C-2 position. All compounds’ cyclooxygenase COX-2 inhibitory activities were evaluated, and all synthesized compounds demonstrated potent activity at minimal concentrations, with IC₅₀ values in the submicromolar range. Compounds 3b, 5b, and 5d were discovered to be the most active pyrimidine derivatives, with the highest COX-2 percent inhibition and IC₅₀ values being nearly equal to Celecoxib and approximately 4.7-, 9.3-, and 10.5-fold higher than Nimesulide. Furthermore, the pyrimidine derivatives 3b, 5b, and 5d demonstrated anticancer activity comparable to or better than doxorubicin against four cell lines, i.e., MCF-7, A549, A498, and HepG2, with IC₅₀ values in nanomolar in addition to low cytotoxicity on the normal W38-I cell line. The effect of compound 5d on cell cycle progression and apoptosis induction was investigated, and it was found that compound 5d could seize cell growth at the sub-G1 and G2/M phases, as well as increase the proportion of early and late apoptotic rates in MCF-7 cells by nearly 13- and 60-fold, respectively. Moreover, in silico studies for compounds 3b, 5b, and 5d revealed promising findings, such as strong GIT absorption, absence of BBB permeability, nil-to-low drug–drug interactions, good oral bioavailability, and optimal physicochemical properties, indicating their potential as promising therapeutic candidates.