Cytotoxic potential of novel triazole-based hybrids: design, synthesis, in silico evaluation, and in vitro assessment against cancer cell lines

Abstract

For the past two decades, 1,2,4-triazoles and 1,3,4-oxadiazoles have captured the interest of chemists due to their diverse therapeutic potential, with research primarily guided by the principles of combinatorial chemistry and their broad spectrum of biological activity. The newly synthesized S-derivatives with 1,2,4-triazole and 1,3,4-oxadiazole skeletons were evaluated for cytotoxic activity in human cervical cancer (HeLa), human non-small-cell lung cancer (A-549) and healthy embryonic kidney (HEK-293 T) cell lines. WST-1 assays revealed that only two of the 25 compounds in the series showed significant selective toxicity: Compound 4 exhibited the strongest activity in A-549 cells with an IC₅₀ of 15.65 ± 0.72 μM, while compound 5 showed significant activity in HeLa cells with an IC₅₀ of 24.90 ± 0.62 μM. Both compounds exhibited a cancer-selective profile, with >50 % survival in HEK-293 T cells over the same concentration range. Additionally, the compounds were found to exhibit moderate inhibitory ability (IC₅₀ = 51.72–247.55 μM) against the acetylcholinesterase enzyme; however, these enzyme data are not directly related to cytotoxicity. The in vitro anticholinergic effect of these newly synthesized molecules was investigated and IC50 values were calculated. Accordingly, IC50 values were found between 51.72 and 247.55 μM for acetylcholinesterase enzyme activity. To explore Novel 1,2,4-Triazole and 1,3,4-Oxadiazole S-Derivatives at the B3LYP, HF, and M062X levels, Gaussian calculations were performed using the 6-31++g (d,p) basis set. These calculations were carried out in order to analyze the molecules. Calculations using the molecular docking technique were performed on a number of proteins, one of which being the protein that has been linked to cervical cancer (PDB ID: 2EWL and 2OCJ), lung cancer protein (PDB ID: 4ZXT and 5ZMA), and acetylcholinesterase protein (PDB ID: 4M0E). Calculations are performed using the ADME/T approach in order to explore the possible effects and responses that these drugs may have on the metabolism of humans.