Heterocyclic compounds play a key role in the development of novel biologically active agents, among which pyrrole and 1,2,4-triazole attract particular attention. The combination of these fragments within a single molecule is considered a promising strategy for the design of new drug candidates.

The aim of this study was the in silico evaluation of toxicological, pharmacokinetic and pharmacodynamic properties of S-alkylderivatives of 4-methyl-5-(pyrrol-2-yl)-1,2,4-triazole-3-thiol to assess their potential as bioactive substances.

Materials and methods. The studied series of S-alkylderivatives of 4-methyl-5-(pyrrol-2-yl)-1,2,4-triazole was designed considering synthetic feasibility. Toxicity predictions were performed using TEST, while physicochemical and pharmacokinetic properties were evaluated via SwissADME. Molecular docking was conducted to assess ligand interactions with enzyme active sites, using MarvinSketch, HyperChem, AutoDock Tools and AutoDock Vina.

Results. Toxicity prediction using the TEST software indicated that the LD50 values in rats ranged from 341.55 to 528.74 mg/kg, with a trend toward reduced toxicity upon elongation of the thioalkyl substituent. Conversely, for aquatic organisms, an opposite trend was observed: elongation of the alkyl chain increased lipophilicity and toxicity. Molecular docking demonstrated the ability of the compounds to form stable complexes with the active sites of COX-2, lanosterol 14α-demethylase (CYP51) and ALK kinase. The highest affinities were observed for compound 4 (COX-2), compound 7 (CYP51) and compound 11 (ALK kinase). Interactions included hydrophobic contacts, π-π stacking, π-cation and electrostatic interactions. Pharmacokinetic modeling using SwissADME indicated good oral bioavailability and absorption for most derivatives (2–10), blood-brain barrier permeability, no CYP3A4 inhibition and compliance with drug-likeness criteria. Elongation of the thioalkyl fragment was associated with increased LogP and decreased aqueous solubility, which may limit certain pharmacokinetic parameters. The most balanced profiles were observed for compounds 3–10.

Conclusions. The results indicate that S-alkylderivatives of 4-methyl-5-(pyrrol-2-yl)-1,2,4-triazole-3-thiol are promising candidates for further preclinical studies as potential anti-inflammatory, antifungal and anticancer agents.