Integrated synthesis, antiproliferative potential, and in silico analysis of novel pyrazole-based hydrazones derived from 3-(2-(4-chlorophenyl)hydrazineylidene)-5-phenylfuran-2(3H)-one

Abstract

Azofuranone was transformed into a series of pyrazole-based hydrazones with 71–79% yields through hydrazinolysis using hydrazine hydrate at room temperature followed by condensation with selected aromatic aldehydes in refluxing ethanol. The antiproliferative activity of the obtained derivatives was evaluated against MCF-7 (breast) and HCT-116 (colon) cancer cell lines using the MTT assay. Among the tested compounds, the chlorobenzylidene derivative (3a) exhibited the most pronounced cytotoxic activity (IC₅₀ = 6.33 ± 1.3 µM against HCT-116 and IC₅₀ = 8.61 ± 1.6 µM against MCF-7), while the remaining hydrazones also showed moderate to strong effects in both cell models. Computational target predictions suggested possible involvement of kinase-related pathways. Molecular docking studies were performed using CDK2 (PDB ID: 2 A4L) to explore potential binding modes. Compound 3a displayed a favorable docking score compared with the reference ligands and formed hydrogen-bond interactions with key residues within the active site. Molecular dynamics simulations indicated stable ligand–protein interaction patterns over the simulation period. In addition, in silico ADME analysis revealed acceptable physicochemical and pharmacokinetic characteristics, with compound 3a demonstrating the most balanced profile. Overall, the combined biological and computational findings identify compound 3a as a promising scaffold for further optimization in the development of antiproliferative agents.