Design, Synthesis, Docking Studies, and Investigation of Dual EGFR/VEGFR-2 Inhibitory Potentials of New Pyrazole and Pyrazolopyridine Derivatives.

The anticancer potential of certain newly synthesized pyrazole and pyrazolopyridine derivatives has been estimated. NCI 60 cancer cells cytotoxic screening pointed out compounds 3e and 3f as the highest cytotoxic agents with % mean growth inhibition of 67.69% and 87.34%, respectively. The five dose outcomes outlined 3f as the most potent cytotoxic agent with promising MG-MID GI ₅₀  = 3.3 µM when compared to erlotinib (MG-MID GI ₅₀  = 7.68 µM). In the in vitro assays, compounds 3d, 3e, 3f, and 4a demonstrated dual inhibitory potential on EGFR ^WT and VEGFR-2 with IC ₅₀ range of 0.066-0.184 µM and 0.102-0.418 µM, respectively. The best dual EGFR/VEGRF-2 inhibitory effect was shown by the compound 3f. Moreover, the latter compound stopped the cell cycle at the G1/S phase. Also, it greatly boosted total apoptosis, including early and late apoptosis, by 54.5- and 84.7-fold, respectively, which supposes HCT-116 cell death via inducing apoptosis. This was confirmed by the elevation of the BAX and caspase-3 levels, and the decreased BCL-2 level. Moreover, the safety of the most active compound 3f was assessed and the results showed promising selectivity of compound 3f toward HCT-116 over FHC (selectivity index [SI]: 20.84) when compared to erlotinib (SI: 3.42). Finally, compound 3f demonstrated efficient binding to both EGFR and VEGFR-2 enzymes, which could explain the sufficient inhibition level of each enzyme.
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