Heterocyclic compounds play a key role in the development of new biologically active substances, among which 1,2,4-triazole derivatives attract particular attention. The combination of this heterocyclic core with other heterocyclic pharmacophoric fragments within a single molecule is considered a promising strategy for the design of potential drug candidates.

The aim of this study was to evaluate the potential antimicrobial activity of 4-((furan-2-ylmethyl)amino)-3,5-dimethyl-1-(2-aryl-2-oxoethyl)-1,2,4-triazolium bromides using molecular docking to the peptide deformylase (PDF) of Escherichia coli and Staphylococcus aureus.

Materials and methods. The three-dimensional structures of the ligands were modeled using ChemSketch software, while the crystallographic structures of the peptide deformylase (PDF) enzyme were obtained from the Protein Data Bank: the Escherichia coli isoform (EcPDF, PDB ID: 1BSK) and the Staphylococcus aureus isoform (SaPDF, PDB ID: 1LQW) were used. Molecular docking was performed using AutoDock Vina, and the types of intermolecular interactions were analyzed with Discovery Studio Visualizer. The minimum binding energy (Emin), reflecting the stability of the “ligand – enzyme” complex, was used as an indicator of binding efficiency.

Results. Nitro-substituted compounds exhibited the highest affinity towards the active sites of both enzymes. In particular, the ortho-nitro derivative showed Emin values of -7.5 kcal/mol for the E. coli PDF complex and -7.9 kcal/mol for the S. aureus PDF complex, surpassing the activity of the standard inhibitor actinonin (Emin = -6.7 kcal/mol). Hydroxy-substituted derivatives demonstrated moderate activity, whereas the introduction of a methoxy group into the aryl fragment decreased the affinity of the ligands toward the enzyme.

Conclusions. A clear structure – activity relationship (SAR) was established, indicating that antimicrobial activity increases in the order of aryl substituents: -OCH3 < -OH < -NO2. The ortho-nitro derivative proved to be the most promising, forming multiple hydrogen bonds, π-cation and hydrophobic interactions with amino acid residues in the catalytic site of PDF. The obtained results can be used for the further design and optimization of novel peptide deformylase inhibitors of bacterial origin.