In-silico studies, synthesis, and pharmacological screening of novel multitarget diphenylpyrazole scaffold as EGFR/BRAF and cyclooxygenase-2 inhibitors

Multi-targeting drug design has become a prevalent attitude in exploring effective potent anticancer agents. In this regard, cyclooxygenase II (COX 2), tubulin, and focal adhesion kinase (FAK) are emerging as highly effective targets in the battle against cancer. Pyrazoles AS-(1-16) were prepared, and their structures were confirmed using NMR and IR tools. The designed compounds AS-(1-16) were investigated for their COXs inhibition and antiproliferative activities. Compounds AS-1, 2, and 14 showed high activities as COX inhibitors and antiproliferatives. Compounds AS-1, 2, and 14 were further investigated for their inhibitory activities towards tubulin polymerization, FAK, EGFR, BRAF and AS-14 showed the highest pronounced activities. AS-14 was subjected to cell cycle and showed activity at cell growth arrest G2/M. Likely the apoptotic activity of AS-14 in this cell line is triggered by pathways involving up-regulation of the proapoptotic proteins p53, Bax, and caspase-7 and down-regulation of the anti-apoptotic protein, Bcl-2. These findings illustrate the role of AS-14 in triggering the apoptotic pathway and shed light on a novel therapeutic drug in breast cancer. Docking studies were performed for the potent ligands to confirm the mechanism of action and showed good binding and a low energy score compared with the standard, especially for AS-14 as COX-2 inhibitor (-11.3 kcal/mol). Its molecular dynamics simulation with the target enzyme revealed high stability over the 200 ns trajectory.