Unraveling Structural and Anticancer Properties of Pyridine-Oxadiazole Derivatives: Single-Crystal XRD, Hirshfeld Analysis, and Cytotoxicity against A549 Cells

A new series of pyridine-based 1,3,4-oxadiazole derivatives was synthesized and structurally characterized using FTIR, NMR, HRMS, and single-crystal X-ray diffraction. Hirshfeld surface analysis of the meta-methyl-substituted derivative revealed key intermolecular interactions. Cytotoxicity was evaluated against A549 lung cancer cells via MTT assay, where compound 5k (3,5-dichloro substitution) showed the highest activity (IC₅₀ = 6.99 ± 3.15 μM), comparable to 5-fluorouracil. Structure-activity relationship analysis indicated that meta-substituents enhance activity, while bulky or strongly electron-withdrawing groups reduce it. In silico studies demonstrated favorable ADME properties, and molecular docking with CDK2 revealed strong binding affinities. Molecular dynamics simulations confirmed the stability of the 5k-CDK2 complex over 100 ns. These findings suggest that pyridine-oxadiazole hybrids, particularly 5k, are promising candidates for further development as anticancer agents.