Rational design of novel biologically active compounds relies on the use of effective structural fragments capable of providing high bioaffinity, favorable pharmacokinetic properties, and an adequate safety profile. Among them, scaffolds based on 1,2,4-triazole and indole occupy a special place; they are widely represented in pharmacologically active molecules due to their ability to participate in diverse types of molecular interactions.

Combining 1,2,4-triazole and indole fragments within a single molecule promotes the formation of conjugated systems with potentially multifunctional activity, thereby expanding opportunities for the development of new therapeutic agents. Computer-aided prediction of toxicological and pharmacokinetic properties at early stages of development remains a key strategy for optimizing screening. The use of in silico methods enables timely assessment of safety, the ADME profile and biological potential prior to experimental studies.

The aim of the study was an in silico evaluation of ADME parameters and molecular docking results for 3-((indol-3-yl)methyl)-6-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-carbohydrazide and its N′-arylidene carbohydrazide derivatives, to substantiate the feasibility of their synthesis and further experimental investigations.

Materials and methods. The study was performed using computational methods. Drug-likeness and pharmacokinetic parameters were calculated with the SwissADME online platform. Molecular docking was carried out using AutoDock Vina and Discovery Studio Visualizer, applying the optimal parameters of the docking grid and analysis of interactions between the ligands and active sites of the target proteins. The following targets were selected: lanosterol 14α-demethylase (CYP51, PDB: 5V5Z), cyclooxygenase-2 (COX-2, PDB: 5IKR), peptide deformylase from Staphylococcus aureus (PDF, PDB: 1Q1Y), peptide deformylase from Escherichia coli (PDF, PDB: 1G2A), and anaplastic lymphoma kinase (ALK, PDB: 2XP2).

Results. The studied compounds have a high proportion of aromatic fragments and low saturation, accompanied by variable solubility and a generally acceptable drug-likeness profile. Molecular docking revealed target-specific lead compounds. The highest stability of COX-2 complexes was predicted for compounds 4 and 6 (ΔG = -10.2 kcal/mol). Compound 5 demonstrated the strongest binding to lanosterol 14α-demethylase with a binding energy of -11.0 kcal/mol. For peptide deformylase from S. aureus, compound 6 showed the most favorable interaction (ΔG = -8.4 kcal/mol), whereas compounds 7 and 9 were identified as the best binders to E. coli peptide deformylase (ΔG = -7.1 kcal/mol). In the case of ALK, compound 8 exhibited the highest binding affinity (ΔG = -9.0 kcal/mol).

Conclusions. The analyzed compounds may be considered as promising scaffolds for further in vitro and in vivo studies, particularly as potential multitarget pharmacological agents. The most relevant candidates for experimental validation are compounds 2, 5–8 and 10, as they combine a favorable pharmacokinetic balance with high predicted binding affinity toward several biological targets.