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Two series of cyanopyrimidine hybrids were synthesized bearing either benzo[<i>d</i>]imidazole, benzo[<i>d</i>]oxazole, benzo[<i>d</i>]thiazole, and benzo[<i>b</i>]thiophene derivatives via methylene amino linker <b>3a</b>–<b>3d</b> (Formula A) or various sulphonamide phenyl moieties <b>5a</b>–<b>5d</b> (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 <b>3b</b>, <b>5b</b>, and <b>5d</b> 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 <b>3b</b>, <b>5b</b>, and <b>5d</b> 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 <b>5d</b> on cell cycle progression and apoptosis induction was investigated, and it was found that compound <b>5d</b> 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 <b>3b</b>, <b>5b</b>, and <b>5d</b> 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.