The combination of the indole fragment, which demonstrates activity due to its aromatic structure, with the 1,2,4-triazole nucleus, which is characterised by chemical stability and the ability to form hydrogen bonds, creates a promising basis for the development of new therapeutic agents with improved properties. The active implementation of various modifications of indole and 1,2,4-triazole frameworks is aimed at optimizing the pharmacokinetic and pharmacodynamic characteristics of medicinal products. Due to their unique structural features and a wide range of biological activities, these compounds remain an attractive area of research for the development of innovative pharmaceuticals.

The aim of this work has been to preliminarily evaluate the potential of indole-containing 1,2,4-triazole derivatives as a basis for the development of biologically active substances.

Materials and methods. The selection of structures for in silico studies has been based on the results of the scientific literature analysis and the basic principles of organic chemistry, which allowed us to integrate known pharmacophore fragments in the condensed state rationally. To determine the safety and potential toxic effects of the studied compounds, in silico methods have been applied using the TEST (Toxicity Estimation Software Tool) software developed by the US Environmental Protection Agency. The online resource SwissADME has been used to analyse the physicochemical properties and pharmacokinetic parameters of the studied compounds. The molecular docking method, based on computational algorithms, has been used to predict and study interactions, including the identification of potential binding sites, estimation of energy parameters and spatial configuration of molecules. MarvinSketch 6.3.0, Hyper Chem 8, and AutoDock Tools-1.5.6 were used for creating ligand models. The enzymes had been prepared for analysis using Discovery Studio 4.0 and AutoDock Tools-1.5.6. Molecular docking was performed using Vina software, which provides modelling and evaluation of interactions between ligand and three-dimensional protein structure, considering their energy and spatial compatibility.

Results. The most favourable safety profile of in silico studies has been shown by 6,11-dihydro[1,2,4]triazolo[4’,3’:1,6]pyrido[3,4-b]-5-carboxylic acid. Instead, its iso-propyl and n-butyl esters require special attention due to their high level of toxicity and potential danger to the ecosystem and genetic integrity of organisms. Butyl-6,11-dihydro[1,2,4]triazolo[4’,3’:1,6]pyrido[3,4-b]-5-carboxylate demonstrates the widest range of interactions with lanosterol 14α-demethylase, peptide deformylase, cyclooxygenase-2 and, accordingly, a high potential for influence on these enzymes. On the other hand, ethyl-6,11-dihydro[1,2,4]triazolo[4’,3’:1,6]pyrido[3,4-b]-5-carboxylate is highly likely to affect the anaplastic lymphoma kinase. Similarly, 6,11-dihydro[1,2,4]triazolo[4’,3’:1,6]pyrido-[3,4-b]-5-carboxylic acid demonstrates a significant potential for binding to the mentioned kinase. All the structures submitted for the study demonstrate a high level of drug-like properties. Their ability to overcome all the filters associated with pharmacokinetic parameters, together with their high predicted bioavailability, indicates their suitability for oral dosage form development.

Conclusions. According to the results of the study, it has been found that 6,11-dihydro[1,2,4]triazolo[4’,3’:1,6]pyrido[3,4-b]-5-carboxylic acid and its esters demonstrate positive pharmacological potential for the creation of a biologically active substance.