Potential c-Met-targeted pyrazole-pyridine-oxadiazole hybrids: synthesis, anticancer activity, and computational rationale.

Abstract

A novel series of pyrazole-pyridine-1,3,4-oxadiazole hybrid derivatives (10a-m) was designed, synthesized, and characterized by IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The multi-step route proceeded via nucleophilic aromatic substitution, cyclocondensation, oxidative aromatization, and S-alkylation, affording target compounds in good to excellent yields (88-93%). Derivatives were screened for anticancer activity against A549 (lung) and MCF-7 (breast) cell lines using Foretinib as reference. Compound 10d (2,4-di-OCH3) was most potent, with IC50 values of 0.29 ± 0.15 μM (A549) and 3.1 ± 0.5 μM (MCF-7), comparable to, or numerically better than, Foretinib (IC50 = 0.49 ± 0.026 μM, A549); no formal statistical comparison was performed. SAR analysis showed electron-donating substituents, especially methoxy groups, enhanced potency. Compounds 10c, 10d, and 10h were markedly less cytotoxic toward non-cancerous NIH/3T3 fibroblasts (IC50 = 138.41, 66.36, and 95.03 μM) than toward the cancer lines, indicating a favorable selectivity margin. Docking against c-Met (PDB: 3LQ8) showed 10d had the highest binding affinity (-5.54 kcal mol-1), forming hydrogen-bond and π-cation interactions with ASP 1222 and ARG 1203, consistent with c-Met as a plausible target, though direct biochemical confirmation is needed. DFT calculations (B3LYP/6-311++G(d,p)) for 10c, 10d, and 10h confirmed that 10d has the smallest HOMO-LUMO gap (3.74 eV) and highest chemical softness, consistent with its superior activity. Collectively, these findings identify 10d as a promising scaffold for further optimization and biological evaluation.