Screening of anxiolytic properties and analysis of structure-activity relationship of new derivatives of 6-(4-methoxy)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine under the code RD

Abstract

Introduction: Searching for new compounds with anti-anxiety activity resulting from the combination of privileged scaffolds is a promising direction in medicinal chemistry and in the development of new drugs. Anxiolytic potential and cytotoxic properties of previously synthesized molecules, containing fragments of 2,3-benzodiazepine and 1,2,4-triazole – 6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-A][2,3]benzodiazepines under the generic code RD were studied. Materials and methods: Screening for anxiolytic activity was performed on elevated plus maze (EPM) and open field (OF) test models. Structural and functional analysis of the anti-anxiety activity of the studied substances was carried out. A degree of muscle relaxant effect of the substances was assessed in the tests Grid, Wire, and Rotarod. A cytotoxicity study of RD compounds was carried out using an MTT assay on human hepatocellular carcinoma cells HepG2. Results and discussion: For a number of novel triazolo[3,4-a][2,3]benzodiazepine derivatives, a prominent anxiolytic activity was manifested in terms of EPM test. The results of OF test were consistent with the obtained data and confirmed the presence of the sought activity in the leading compounds. There was no significant effect on muscle tone for the compounds under study. It was observed that RD compounds possessed no cytotoxic properties and were safe for further studies in vivo. Conclusion: Among the new derivatives of 6-(4-methoxyphenyl)-7H-[1,2,4]triazolo[3,4-a][2,3]benzodiazepine under the code RD, substances (RD-4, 12, 13) with a high anxiolytic activity comparable to diazepam and tofisopam were found. The most promising compound is RD-4 due to its pronounced anxiolytic and low cytotoxic properties.

Consensus Ensemble Multitarget Neural Network Model of Anxiolytic Activity of Chemical Compounds and Its Use for Multitarget Pharmacophore Design

“…For two groups of synthesized andexperimentally studied novel highly active substances with laboratory codes, DAB 11-substituted 2,3,4,5-tetrahydro-11H- [1,3]diazepino[1,2a]benzimidazoles [34,35] and RD3,6-disubstituted [1,2,4]triazolo[3,4-a][2,3]benzodiazepines [36] (4 compounds in each group) using the methods described above in this article, optimized 3D models were built and ensemble docking was performed. Using the LigPlot+ v2.2 program [22], for the most energetically favorable conformation at the site of a specific target, the key points of interaction between the structure of the analyzed molecule and the amino acids of this protein were determined.…”