Synthesis, Cytotoxicity Evaluation, and Molecular Dynamics of 4-Thiazolidinone Derivatives: A Potential Path to EGFR-Targeted Anticancer Therapy.

Abstract

Introduction: Heterocyclic compounds remain cornerstones of contemporary drug discovery because their ring-embedded heteroatoms confer adaptable electronics, conformational flexibility, and a broad spectrum of biological activities. The skeleton structure of 4-thiazolidinone is present in many cytotoxically active compounds and is often used in the design of new antitumor agents. This study aimed to synthesize, characterize, and evaluate the anticancer potential of fifteen new (2-imino-4-oxo-1,3-thiazolidin- 5-yl)acetic acid derivatives.

Method: Compounds were synthesized using a consistent synthetic route involving a reaction between a thiourea derivative and maleic anhydride, which formed the thiazolidin- 4-one ring through cyclization. The compounds were then categorized into three sets based on the attached heterocyclic rings (tryptamine, thiazole, and 1,2,4-triazole). The NMR and X-ray analysis followed the synthesis. Apoptotic effects, cell cycle arrest, IL-6 suppression, docking, and dynamics simulations were conducted. Preliminary cytotoxic activity was tested on metastatic colorectal cancer (SW620) and human breast adenocarcinoma (MDA-MB-231) cell lines using the MTT assay.

Result: Compounds 5, 6, and 7 demonstrated notable selectivity indexes (4.73, 2.42, 4.16, respectively) and were further investigated for their mechanisms of action, revealing pro-apoptotic properties and the ability to induce cell cycle arrest. Additionally, compound 5 inhibited IL-6 secretion by 76%. in silico studies revealed the formation of an energetically stable complex between compound 5 and the EGFR crystal structure (min/- max binding affinities of -9.4|-8.0 kcal/mol, compared to the -7.71 kcal/mol for the native ligand).

Discussion: This preliminary study provides compelling data on synthesized derivatives, but more advanced testing is needed to assess their therapeutic value fully. Compared with earlier reports on related thiazolidinone scaffolds, the present derivatives exhibit improved potency, clearer selectivity, and mechanistic features consistent with EGFR inhibition and cytokine modulation.

Conclusion: These findings validate (2-imino-4-oxo-1,3-thiazolidin-5-yl)acetic acid as a privileged core for cytotoxic lead generation and indicate that strategic substitution with either a tryptamine moiety (compound 5) or a 1,2,4-triazole ring (compound 7) is particularly advantageous. These compounds are promising EGFR-targeting anticancer candidates, warranting further investigation.