Azolo[5,1‐c][1,2,4]triazines and Azoloazapurines: Synthesis, Antimicrobial activity and in silico Studies

Abstract

The present work reports on the synthesis of series of azolo[5,1‐c][1,2,4]triazines and derivatives of azoloazapurines. The synthesized compounds were tested in vitro for antibacterial activity against N. gonorrhoeae and antimycotic activity against Trichophyton interdigitale, Epidermophyton floccosum, Microsporum canis and Candida albicans. It was found that 10 compounds of the series of 3‐nitroazolo[5,1‐c][1,2,4]triazine‐4‐amines 4 exhibit high antibacterial activity (MIC≤15 μg/ml), but do not exhibit antimycotic activity. For compounds active against N. gonorrhoeae, a biological target was predicted from the pharmacophore search method and homologous modeling was carried out for it. The results of molecular docking using the constructed model of dihydrofolate reductase have a good correlation with in vitro tests. Refined docking showed the similarity of the leading compounds positions in the protein active site. The formation of stable non‐covalent bonds of the nitro group with the amino acid residues Lys34/Lys55 makes a major contribution to the orienting effect of ligands.

Development of A. solani β-tubulin models and comparison of docking results for benzo[d]azoles derivatives as potential antifungal agents

“…To create a homologous model of fungal β-tubulin, the amino acid sequence of A. solani (GenBank: HQ413317.1), obtained from the National Center for Biotechnology Information (NCBI) databases, was used [34]. Furthermore, we used two approaches to create the three-dimensional structure of βtubulin: 1) the Prime program [17] and the structure of the D-chain pdb id:5CA1 as a template -the A. solani I model; 2) the SWISS-MODEL service [23,24] and the structure 295 of a fragment of the crystal structure of human microtubules (pdb id: 7UNG [35]) -model of A. solani II. Despite the fact that the primary structures of proteins are identical, the spatial arrangement of atoms of amino acid residues are different.…”

“…Previously, using this software package, we performed Induced Fit Docking (IFD) between 2-acyl(thioacyl)aminobenzimidazoles and a number of fungal β-tubulins [18]. The purpose of this work was to perform a virtual screening of potentially antifungal benzazoles with a homologous model of β-tubulin from the microscopic fungus Alternaria solani with using freely distributed programs we selected (KNIME [19], DataWarrior [20], AutoDock Vina [16], AutoDockTools [21], OpenBabel [22] and SWISS-MODEL service [23,24]). At the same time, it was important to compare the screening results obtained during docking with two homologous protein models: the one obtained in the SWISS-MODEL service and the model obtained using a commercial Prime software.…”

Synthesis and DFT analysis of non-covalent interactions in crystal structures of 6-R-2-alkoxy-, 2,3-di-, and 2,2,3-tri-tert-butylpyrrolo[1,2-b][1,2,4]triazines

“…Azolotriazines are particularly interesting in terms of their diverse chemical transformations and the bioisosteric nature [ 7 ]. The quantitative and qualitative structural analysis of known azolo[1,2,4]triazines, along with molecular modeling, has been successfully used to identify the most privileged scaffolds for further drug design [ 8 – 10 ]. These developments resulted in the production of the 4-aminopyrrolo[2,1- f ][1,2,4]triazine remdesivir, which is active against a number of viruses including Ebola virus and coronaviruses [ 11 ].…”