Design, synthesis, and molecular docking of novel 1,3, 4-triaryl pyrazole derivatives bearing methylsulfonyl moiety with anticancer activity through dual targeting CDK2 and COX-2 enzymes

Novel 3-(4-methylsulfonylphenyl) pyrazole derivatives with different substitutions at position four were designed, synthesized, characterized by spectroscopic techniques, and investigated as potential anticancer agents via inhibition of cyclin-dependent kinase 2 and cyclooxygenase-2 enzymes. All the synthesized compounds were screened against three cancer cell line panels, hepatocellular carcinoma (HepG-2), mammary gland breast cancer (MCF-7), and colorectal carcinoma (HCT-116), to determine their antiproliferative properties by MTT assay. Compounds 5a, 6a, 6c, and 10c exhibited a considerable antiproliferative effect on HepG-2 cell line with IC50 value of 2.88 to 8.57 µM, on HCT-116 cell line with IC50 value of 6.34 to 17.84 µM, and on MCF-7 cell line with IC50 value of 1.75 to 9.58 µM. Compounds 5a, 6a, 6c, and 10c had weak toxicity towards normal HEK-293T, especially 10c displayed the highest IC50 with a value of 101.21 μM against normal cells. Furthermore, mechanistic studies for the antiproliferative activity were performed on the most active compounds 5a, 6a, 6c, and 10c. Compound 6c exhibited significant inhibitory activity against CDK2 enzyme with IC50 value of 0.614 µM compared to R-roscovitine (IC50 = 0.533 µM) as a reference drug. Additionally, compounds 5a, 6a, 6c, and 10c have significant potency and selectivity for the COX-2 enzyme (IC50 = 0.058 – 0.089 µM) over COX-1 enzyme (IC50 = 9.7 – 11.6 µM) compared to celecoxib and indomethacin. Accordingly, compounds 5a and 6c showed potent COX-2 inhibitory activity with IC50 values of 0.058 and 0.075 µM with a selectivity index of 198.27 and 154.66, respectively, in comparison to celecoxib and indomethacin with COX-2 IC50 value of 0.046 and 0.079 µM and a selectivity index of 315.21 and 1.25. compound 6c, with the potent CDK2 and COX-2 inhibitory activity, demonstrated apoptotic activity on HepG-2 cancer cells by inducing a strong G1 phase cell cycle arrest. Also, compound 6c significantly elevated the Bax/Bcl-2 ratio by 14.54 folds compared to the untreated control, which is clearly correlated with its sensitivity to apoptosis. Molecular docking and dynamics simulations were conducted to illustrate the binding modes inside the active sites. Finally, the hit compound 6c was discovered to have antiproliferative activity against HepG-2, MCF-7, and HCT-116 cancer cell lines by inhibiting CDK2 and COX-2 enzymes as proposal mechanisms.