A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides 7a–o, serving as dual inhibitors of EGFR
and VEGFR-2 was developed. The antiproliferative effects of compounds 7a–o were assessed against
four cancer cell lines via the MTT assay. Compounds 7g, 7i–7l, and 7o emerged as the most efficient
six derivatives, with GI50 values ranging from 25 nM to 42 nM. Compounds 7j, 7k, and 7o (GI50 values
of 27, 25, and 30, respectively) demonstrated greater potency than erlotinib (GI50 value of 33 nM),
particularly against breast (MCF-7) cancer cell lines, and were identified as the most potent dual
EGFR/VEGFR-2 inhibitors. Apoptotic markers assay results showed that increased levels of p53 and
Bax proteins, along with lower levels of antiapoptotic Bcl-2, govern the apoptosis process in these
new compounds. Computational analyses, encompassing molecular docking, molecular dynamics
(MD) simulations, and density functional theory (DFT) computations, elucidated the binding
interactions of these drugs with EGFR and VEGFR-2.