New phenylcyclopropane-carbohydrazide furan derivatives with potent anticancer activity and EGFR inhibitory potential

Fifteen new phenylcyclopropane-carbohydrazide-containing furan derivatives are synthesised and thoroughly characterized using FT-IR, ¹H-NMR, ¹³C-NMR, and HRMS spectroscopy techniques in the search for new anticancer drugs. Using the MTT assay, this work examines the antiproliferative capability of these newly synthesized phenylcyclopropane hybrid compounds against cancer cell lines of the liver (HepG-2), lung (A549), and breast (MCF-7 and MDA-MB-231). Results indicated that with IC₅₀ values of 2.08 ± 0.45, 2.15 ± 0.29, 2.17 ± 0.13, and 3.10 ± 0.32 µM for the MCF-7 cell line, compounds 8e, 8i, 8m, and 8n with p-dimethylamino, p-methoxy, p-hydroxy, and p-chloro-o-methoxy groups, respectively, showed the strongest antiproliferative activity, surpassing the reference drug doxorubicin in some cases. Among the synthesized compounds, 8e, 8j, 8m and 8n were the most active compounds with the EGFR^WT inhibitory effect, exhibiting IC₅₀ values of 1.79 ± 0.10, 1.59 ± 0.03, 0.87 ± 0.08, and 0.90 ± 0.60 µM, respectively. Molecular docking studies against the human breast cancer therapy compound and epidermal growth factor receptor (EGFR) (PDB codes: 3HB5 & 1M17) revealed that the furan derivatives exhibited excellent binding affinity (-10.70 and -8.54 kcal mol^-1) through favorable van der Waals, electrostatic, HB-bonding and CH-bonding interactions within the active site. Furthermore, the ADME-T (absorption, distribution, metabolism, excretion, and toxicity) profiling of the synthesized compounds revealed balanced pharmacokinetic profiles and favorable drug-like features, confirming their potential as viable candidates for additional pharmaceutical development. The established procedure is a promising solution for a variety of applications since it uses low-toxic cyclopropane-1-carbohydrazide, furan with a broad substrate scope, and readily available substrates and requires only a short reaction time. Molecule 8n is the most stable conformer among all the compounds optimized at the B3LYP/6-31G level, with significant variations observed in the dipole moments and HOMO-LUMO gaps affecting their stability and reactivity.