Design, synthesis, and biological evaluation of fluorinated α-cyanoacrylohydrazide derivatives as promising EGFR-targeted anticancer agents: Structure–activity relationship and integrated computational

A novel series of fluorinated α-cyanoacrylohydrazide derivatives 5(a–p) was systematically designed, synthesized, and characterized by FT-IR, ¹ H NMR, ¹³ C NMR, MS, and elemental analysis as potential EGFR-targeted anticancer agents. In vitro antiproliferative evaluation against five human cancer cell lines (A549, H1975, MCF-7, HeLa, and HT-29) via MTT assay revealed prominent cytotoxicity for leads 5d , 5h , and 5p , with 5h displaying highest potency against MCF-7 cells (IC ₅₀  = 8.60 ± 0.43 µM). Structure–activity relationship analysis demonstrated that combining fluorine with meta-trifluoromethyl substituents optimizes electronic and lipophilic properties. Molecular docking into EGFR active sites (PDB IDs: 1M14 and 2ITY) revealed conserved hinge-region interactions aligning with experimental potencies. The structural stability of the EGFR– 5d complex was validated through an all-atom 50 ns molecular dynamics simulation, supported by RMSD, RMSF, Rg, SASA, hydrogen-bond occupancy, DCCM, FEL, and MM-GBSA binding free energy (ΔGbind = −65.1 ± 4.6 kcal/mol) calculations. DFT and in silico ADMET analyses confirmed favorable electronic stability, balanced reactivity, and drug-like pharmacokinetic profiles. These findings highlight fluorinated α-cyanoacrylohydrazides as promising lead scaffolds for developing novel EGFR-targeted cancer therapeutics.