Synthesis and Biological Assessment of Cyanopyridine-Based 1,3,4-Oxadiazole Derivatives: Anticancer Potential, Antioxidant Activity, Molecular Docking, and DFT Calculations

Abstract

A series of six novel cyanopyridine derivatives bearing a 1,3,4-oxadiazole ring have been synthesized and characterized by FTIR, ¹³C NMR, ¹H NMR, and elemental analysis. DFT calculations were carried out to determine their molecular geometries, electronic properties, and chemical reactivity. Their cytotoxicity has been evaluated against MCF-7 and CaCo-2 human cancer cell lines using the MTT assay. Most compounds displayed poor cytotoxic activity against the MCF-7 cell line except for compound 4e, which showed potent activity with IC₅₀ = 8.352 µM. However, the CaCo-2 cell line was highly sensitive toward most tested compounds with an IC₅₀ range from 2.612 µM to 8.394 µM except for compound 4 d. Molecular docking studies targeting human topoisomerase-IIβ revealed that all compounds exhibited excellent binding affinity within the enzyme's active site, with binding energies ranging from −7.33 to −8.28 kcal/mol. These findings suggest a potential anticancer mechanism underlying the observed cytotoxic activities. All tested compounds revealed low antioxidant activity in the DPPH assay. However, compounds 5b and 5 d presented moderate metal chelating activity. These findings underscore the potential anticancer properties of the synthesized cyanopyridine derivatives.