Structural, Electronic and In Silico Biological Activity Evaluation of 5-methyl-3-phenyl-1H-1,2,4-triazole-5carboxaldehyde Molecule

Abstract

In this study, the structural, electronic, and biological interaction properties of 5-methyl-3-phenyl-1H-1,2,4-triazole-5-carboxaldehyde(MPTrzCHO), a 1,2,4-triazole derivative, were investigated using density functional theory (DFT) and molecular docking approaches.To determine the most stable geometry of the molecule, conformational analysis was first performed using the MMFF force field approach,followed by geometry optimization at the DFT/B3LYP/6-311++G(d,p) theoretical level. To evaluate the reliability of the calculatedresults, comparative calculations were additionally carried out using the cc-pVDZ basis set and the IEFPCM model in a water solventenvironment. The electronic structure of the molecule was investigated through frontier molecular orbital (HOMO–LUMO), molecularelectrostatic potential (MEP), APT, Hirshfeld, and NBO atomic charge distribution, natural bond orbital (NBO), and reduced densitygradient–non-covalent interaction (RDG–NCI) analyses. The obtained results revealed a stable and highly polarized electronic structurecharacterized by electron density concentration around the O and N heteroatoms. The similar distributions obtained from different basissets and solvent environments in the HOMO–LUMO, MEP, and atomic charge analyses demonstrated the methodological consistencyof the theoretical results. Molecular docking studies performed with the VEGFR-2 (PDB: 4ASD) enzyme showed that the MPTrzCHOmolecule can establish hydrogen bonding and hydrophobic interactions within the active site. In addition, in silico toxicity estimationsperformed using the ProTox 3.0 platform revealed that the molecule exhibits inactive cytotoxicity and immunotoxicity profiles; however,possible hepatotoxic, carcinogenic, and mutagenic effects were also predicted. Overall, the obtained findings indicate that MPTrzCHOpossesses remarkable interaction capability toward biological targets and may serve as a potentially biologically active 1,2,4-triazolederivative and a promising starting scaffold for the development of new pharmacological structures in future experimental studies.