Design and Synthesis of 2,4-Thiazolidinedione-Based Derivatives as Potent EGFR-Targeting Anticancer Agents
TL;DR
Structural–activity relationship analysis revealed the importance of the TZD core, electron-rich aromatic moieties, and balanced lipophilicity for enhanced anticancer activity, identifying TZD hybrids as promising EGFR-targeted anticancer leads.
Abstract
A series of quinoline- and naphthalene-based 2,4-thiazolidinedione (TZD) hybrids (5a–5o) were rationally designed and synthesized using a pharmacophore hybridization approach targeting epidermal growth factor receptor (EGFR). The synthesized compounds were evaluated for in vitro antiproliferative activity against human cancer cell lines including MDA-MB-453, A549, PC-3, and MCF-7, along with EGFR inhibitory activity. Several compounds exhibited promising cytotoxicity, with derivatives 5c, 5f, 5g, and 5n showing significant activity (IC₅₀ = 4.6–9.8 µM). Molecular docking studies using EGFR crystal structures (PDB: 1M17 and 4HJO) demonstrated favorable binding affinities and key interactions with the ATP-binding pocket, particularly hydrogen bonding with Met793. Docking results correlated well with experimental EGFR inhibition, supporting an EGFR-mediated mechanism. Structure–activity relationship analysis revealed the importance of the TZD core, electron-rich aromatic moieties, and balanced lipophilicity for enhanced anticancer activity. These findings identify TZD hybrids as promising EGFR-targeted anticancer leads.