SYNTHESIS, MOLECULAR DOCKING, AND ANTICANCER ACTIVITY OF NOVEL COUMARIN DERIVATIVES

Abstract

Coumarin scaffolds are attractive templates for anticancer drug discovery because they modulate multiple molecular targets, including receptor tyrosine kinases, apoptosis regulators, and topoisomerases. This study aimed to synthesize, characterize, and evaluate three novel coumarin derivatives: 3-(4-fluorophenyl)-7-hydroxycoumarin (C1), 3-(3,4-dimethoxyphenyl)-7-methoxycoumarin (C2), and 6-bromo-3-(4-chlorophenyl) coumarin (C3). The compounds were synthesized using modified Pechmann or Knoevenagel condensation routes, purified by column chromatography, and characterized by FTIR, UV–Vis, ¹H/¹³C NMR, LC–MS/MS, HRMS, elemental analysis, melting point, and TLC. Molecular docking was performed against EGFR, VEGFR-2, PI3K, CDK2, Bcl-2, and Topoisomerase II using validated protein structures, while drug-likeness and ADMET properties were predicted using SwissADME, pkCSM, and ADMETlab. Anticancer activity was assessed by MTT assay against MCF-7, A549, HeLa, and HCT-116 cell lines. The compounds were obtained in 58–74% yields with confirmed structures. C1 demonstrated the strongest binding toward EGFR (−9.1 kcal/mol) and Bcl-2 (−8.0 kcal/mol), forming key interactions with Met793 and hydrophobic residues, and exhibited the highest cytotoxicity against MCF-7 (IC₅₀ = 6.8 ± 0.9 µM) and HCT-116 (IC₅₀ = 9.5 ± 1.1 µM). C2 preferentially targeted CDK2 and PI3K, whereas C3 showed favorable binding to Topoisomerase II and VEGFR-2 with selective activity against A549 cells (IC₅₀ = 8.9 ± 1.2 µM). ADMET analysis predicted favorable oral drug-likeness for C1 and C2 with acceptable pharmacokinetic profiles. Overall, C1 emerged as the most promising lead for further optimization as a multitarget anticancer agent, while C2 and C3 provide complementary scaffolds for future medicinal chemistry and mechanistic investigations.