Evaluation of the pharmacological potential of N-((5-phenyl-6,11-dihydro-[1,2,4]triazolo[1’,5’:1,6]pyrido[3,4-b]indol-2-yl)methyl)benzamides

Abstract

The rational design of new biologically active compounds is based on the use of effective structural fragments, capable of ensuring high biosimilarity, favorable pharmacokinetic properties and an appropriate safety profile. Among them, 1,2,4-triazole and indole cores occupy a special place, being widely represented in pharmacologically active molecules due to their ability to participate in various types of molecular interactions. The combination of 1,2,4-triazole and indole fragments within a single molecule promotes the creation of conjugated systems with potentially multifunctional activity, thereby expanding the opportunities for the discovery of new therapeutic agents. Early-stage computer-based prediction of toxicological and pharmacokinetic properties remains a key strategy for optimizing the screening process. The application of in silico methods allows timely assessment of the safety, ADME profile and biological potential of compounds prior to experimental investigations.

Aim. This study aimed to perform an in silico assessment of the toxicological properties, ADME parameters, and molecular docking profiles of newly designed compounds belonging to the N-((5-phenyl-6,11-dihydro-[1,2,4]triazolo-[1’,5’:1,6]pyrido[3,4-b]indol-2-yl)methyl)benzamide series, in order to substantiate their synthesis and guide further experimental validation.

Materials and methods. Molecular structure design for in silico studies was guided by a critical analysis of the scientific literature and fundamental principles of organic chemistry, allowing the rational incorporation of established pharmacophoric elements into compact molecular frameworks. Safety profiles and potential toxicological risks were predicted using the TEST (Toxicity Estimation Software Tool) platform. Physicochemical properties and pharmacokinetic behaviors were evaluated through the SwissADME online resource. Advanced molecular docking techniques were employed to identify potential binding sites with model enzymes and to characterize the energetic and spatial features of ligand-target interactions. Ligand structures were generated using MarvinSketch 6.3.0, HyperChem 8, and AutoDock Tools 1.5.6, while protein targets were prepared with Discovery Studio 4.0 and AutoDock Tools 1.5.6. Docking simulations were conducted with AutoDock Vina, enabling accurate modeling of ligand-protein binding based on energetic and steric complementarity. This integrative in silico approach facilitated the early-stage evaluation of biological potential and safety profiles prior to experimental validation.

Results. The investigated N-((5-phenyl-6,11-dihydro-[1,2,4]triazolo-[1’,5’:1,6]pyrido[3,4-b]indol-2-yl)methyl)benzamide derivatives exhibited statistically significant moderate to low toxicity towards aquatic organisms (Daphnia magna, Pimephales promelas) and lacked mutagenic potential. The predicted oral toxicity values (LD₅₀) in rats ranged from 470 mg/kg to 990 mg/kg, indicating a relatively safe profile for the compounds. Pharmacokinetic analysis revealed high aromaticity, a low degree of carbon bond saturation, and variable water solubility among the studied compounds. The most favorable properties were observed for 2-bromo-4-fluoro-N-((5-phenyl-6,11-dihydro-[1,2,4]triazolo[1’,5’:1,6]pyrido[3,4-b]-indol-2-yl)methyl)benzamide, 2-bromo-N-((5-phenyl-6,11-dihydro-[1,2,4]triazolo-[1’,5’:1,6]pyrido[3,4-b]indol-2-yl)methyl)benzamide, 4-fluoro-N-((5-phenyl-6,11-dihydro-[1,2,4]triazolo[1’,5’:1,6]pyrido[3,4-b]indol-2-yl)methyl)benzamide and N-((5-phenyl-6,11-dihydro-[1,2,4]triazolo[1’,5’:1,6]pyrido[3,4-b]indol-2-yl)methyl)-thiophene-2-carboxamide. These compounds were identified as the most promising candidates for further synthesis and biological evaluation.

Conclusions. Computer modeling demonstrated that a series of designed N-((5-phenyl-6,11-dihydro-[1,2,4]triazolo[1’,5’:1,6]pyrido[3,4-b]indol-2-yl)methyl)-benzamide derivatives is characterized by a relatively safe toxicological profile, absence of mutagenic potential and favorable pharmacokinetic properties. Based on comprehensive in silico evaluation, four compounds exhibiting the most promising characteristics in terms of safety and potential bioactivity are recommended for further experimental studies.