Comprehensive study of the possible electrotransformations of the sodium salt of 3-nitro-4-hydroxy-7-methylthio-4H-[1,2,4]triazolo[5,1-c][1,2,4]triazinide monohydrate as potential antiviral drug

Polina N. Mozharovskaia; Ivan A. Balin; Alexandra Vs. Ivoilova; Anton N. Tsmokalyuk; Roman A. Drokin; Vladimir L. Rusinov; Alla V. Ivanova; Alisa N. Kozitsina

doi:10.15826/chimtech.8969

Comprehensive study of the possible electrotransformations of the sodium salt of 3-nitro-4-hydroxy-7-methylthio-4H-[1,2,4]triazolo[5,1-c][1,2,4]triazinide monohydrate as potential antiviral drug

Polina N. Mozharovskaia, Ivan A. Balin, Alexandra Vs. Ivoilova, Anton N. Tsmokalyuk, Roman A. Drokin, Vladimir L. Rusinov, Alla V. Ivanova, Alisa N. Kozitsina

Abstract

The electrochemical transformation of nitroheterocyclic compounds plays a critical role in understanding their biological activity. Despite structural similarities among nitrotriazolotriazines, their electroreduction mechanisms remain incompletely elucidated. This study focuses on the sodium salt of 3-nitro-4-hydroxy-7-methylthio-4H-[1,2,4]triazolo[5,1-c][1,2,4]triazinide monohydrate (TZV-OH), a structural analogue of the antiviral drug Triazavirin^®(Riamilovir) – sodium salt of 3-nitro-4-oxo-7-methylthio-4H-[1,2,4]triazolo[5,1-c][1,2,4]triazinide dihydrate (TZV), and aims to investigate how structural differences affect the redox behavior of nitrotriazolotriazines. Using a combined experimental and computational approach, including cyclic voltammetry, chronoamperometry, electron paramagnetic resonance (EPR) spectroscopy, quantum chemical calculations, and preparative electrolysis with LC-HRMS analysis, we examined the electroreduction mechanism in both aqueous and aprotic media. Our findings reveal that TZV-OH undergoes a single-wave, diffusion-controlled, four-electron irreversible reduction of the nitro group, whereas TZV is reduced in two steps, complicated by a preceding chemical reaction. EPR spectroscopy confirms a higher concentration of radical intermediates for TZV-OH, supported by experiments with the DMPO spin trap and quantum chemical modeling. Mass spectrometry identified hydroxylamines, amines, and dimeric products as the primary products of the reduction process of TZV-OH. Quantum chemical calculations indicate that the formation of radical intermediates is thermodynamically more favorable for TZV-OH than for TZV, facilitating radical generation. These structural and mechanistic insights highlight the potential of TZV-OH as a superior antiviral agent. The integrated methodology outlined here serves as a predictive tool for assessing the pharmacological potential of nitrotriazolotriazines.

Keywords

nitroheterocycle compounds; EPR spectroscopy; quantum chemical calculations; electroreduction; nitro group; radical intermediates

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DOI: https://doi.org/10.15826/chimtech.8969

Copyright (c) 2025 Polina N. Mozharovskaia, Ivan A. Balin, Alexandra Vs. Ivoilova, Anton N. Tsmokalyuk, Roman A. Drokin, Vladimir L. Rusinov, Alla V. Ivanova, Alisa N. Kozitsina

This work is licensed under a Creative Commons Attribution 4.0 International License.

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