Abstract
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.