Design, Synthesis, and Molecular Docking of Novel Miscellaneous Chalcones as p38 Mitogen-Activated Protein Kinase Inhibitors

New chalcones were synthesized and evaluated to serve as p38-alpha type of mitogen-activated protein kinase (MAPK) inhibitors. According to the National Cancer Institute, the findings indicated that at a 10 mu M dosage, compounds 3a and 6 were the most active among all the compounds examined, with mean growth inhibition% of 94.83 and 58.49, respectively. In 5-dose testing, they showed anticancer activity in the micro-molar range with GI(50) in the range of 1.41-46.1 and 2.07-31.3 mu M, respectively. Besides, powerful activity, especially against the leukaemia cell lines and good selectivity to cancer cells compared to normal PCS-800-017 with a selectivity index=12.41 and 23.77, respectively. Compounds 3a and 6 inhibited p38 alpha MAPK with IC50 values of 0.1462 +/- 0.0063 and 0.4356 +/- 0.0189 mu M, correspondingly. 3a showed good inhibition for HL-60(TB) cells and induced cell cycle arrest in HL-60(TB) cells at the G2/M phase. Besides, it elevated the total apoptosis by 14.68-fold and increased the caspase-3 level by 3.52-fold compared with doxorubicin, which raised it by 4.30-fold, inducing apoptosis by acting as caspase-dependent inducers. These results suggest that 3a is a promising antiproliferative and p38 alpha MAPK inhibitor, confirmed by molecular docking with high compatibility 3a with the p38 alpha MAPK binding site.