Design and evaluation of pyridine-linked 1,3,4-oxadiazole-triazole heterocycles: a synthetic, computational and biological study

Abstract

Pyridine, 1,3,4-oxadiazole and 1,2,3-triazole are known for their wide range of biological properties such as anticancer, antifungal, antimicrobial and anti-tubercular activities. It is evident that Click reactions have evolved as one of the most powerful tools to deduce such types of heterocyclic moieties. In this study, a library of pyridine-linked 1,2,3-triazol-4-yl-1,3,4-oxadiazole derivatives was synthesized through a multi-step process. This involved the propargylation of 5-(2-arylaminopyridin-3-yl)-1,3,4-oxadiazole-2(3H)-thiones, followed by a Click reaction, to produce 2-(3-arylaminopyridin-3-yl)-5-[{(1-(aryl)-1H-1,2,3-triazol-4-yl)methyl}thio]-1,3,4-oxadiazoles. The synthesized compounds were characterized by elemental analysis, FT-IR, LC-MS, sup(1)H NMR, and sup(13)C NMR techniques. The electron donor properties of the derivatives were validated using a quantum chemical approach. The in vitro anticancer activity of the synthesized derivatives was evaluated against A549 (lung), HepG2 (liver), and PC-3 (prostate) cancer cell lines using the MTT assay, where compounds 4b, 4c, 4f, and 4k demonstrated significant cytotoxicity. Clonogenic and wound healing assays revealed that compounds 4c and 4f effectively inhibited colony formation and cell migration in a time-dependent manner. In addition, compounds 4e and 4c exhibited notable antidiabetic potential by inhibiting alpha-amylase and alpha-glucosidase enzymes with IC sub(50) values of 46.53 plus-minus 0.56, 49.31 plus-minus 0.83 Mu g/mL and 32.54 plus-minus 0.89, 33.13 plus-minus 1.02 Mu g/mL, respectively, surpassing the activity of the standard drug acarbose. Molecular docking studies were conducted against the EGFR kinase domain (PDB ID: 1XKK), revealing favorable binding interactions for the active compounds, thereby supporting their potential mechanism of action at the molecular level. Collectively, these findings highlight the therapeutic promise of pyridine-linked oxadiazole-triazole hybrids as multifunctional agents with anticancer and antidiabetic activities.