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 IC 50 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 IC 50 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 IC 50 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.