Integrated computational and biological assessment of novel piperazine and piperidine-substituted 1,2,4-oxadiazoles for lung cancer therapy.

AIMS: To design and synthesize a novel series of piperazine- and piperidine-substituted 1,2,4-oxadiazole derivatives and evaluate their anticancer potential, with particular interest in possible interaction with the epidermal growth factor receptor (EGFR).

MATERIALS AND METHODS: The target compounds were synthesized using established heterocyclic strategies and characterized by standard spectroscopic techniques. Molecular docking studies were performed using the EGFR tyrosine kinase domain (PDB ID: 3OW4) to predict binding modes and ligand-receptor interactions. In vitro cytotoxic activity was assessed against A549 human lung carcinoma cells using the MTT assay.

RESULTS: Docking analysis suggested favorable binding orientations within the EGFR ATP-binding site and predicted interactions with key amino acid residues. In vitro studies demonstrated dose-dependent antiproliferative activity for all compounds. Among them, compound 9be exhibited the highest activity, with an IC50 value of 26.98 µM.

CONCLUSIONS: The synthesized 1,2,4-oxadiazole derivatives display moderate antiproliferative activity and represent preliminary lead structures for further optimization. While molecular modeling suggests potential EGFR interaction, additional biochemical studies are required to confirm the precise mechanism of action.