1,2,4-Triazole: Overview, Antioxidant Activities and Toxicity

General Description

1,2,4-Triazole has garnered significant attention for their diverse pharmacological activities, including antimicrobial, antifungal, and antioxidant properties. These compounds have shown promise in combating oxidative stress-related diseases by neutralizing free radicals and mitigating their harmful effects. Various research studies have demonstrated the antioxidant activities of different 1,2,4-Triazole derivatives through assays such as ABTS, DPPH, and FRAP, highlighting their potential therapeutic applications. However, it is important to note that 1,2,4-Triazole also exhibits toxicity, particularly as an eye irritant and a reproductive toxin, emphasizing the need for caution in handling and exposure to these compounds.

Figure 1. 1,2,4-Triazole

Overview

1,2,4-Triazole, a member of the triazole family, is a five-membered heterocyclic compound characterized by three nitrogen atoms within its structure, endowing it with a high electron density. Within the triazole family, there exist two isomeric forms based on the position of the nitrogen atoms: the 1,2,3-triazole and the 1,2,4-triazole, each exhibiting two tautomeric forms. First introduced by Boldwin in 1885, the term "triazole" specifically denotes a heterocyclic ring composed of two carbon and three nitrogen atoms (C2N3H3). Since its inception, triazole and its derivatives have garnered significant attention from researchers across various fields. Literature extensively documents the diverse pharmacological activities exhibited by these derivatives, including antimicrobial, antifungal, antibacterial, antitubercular, analgesic, anti-inflammatory, anticonvulsant, antidepressant, antimalarial, antiviral, and hypoglycemic properties. Notably, some derivatives also demonstrate tranquilizing effects and hold promise as anticancer agents. In the context of cellular health, 1,2,4-Triazole derivatives have garnered attention due to their potential antioxidant properties. In the face of various threats such as viral infections, bacterial pathogens, and oxidative stress, cells are vulnerable to damage, including DNA impairment. Oxygen-free radicals, including hydroxyl radicals, hydrogen peroxide, and superoxide anions, play a pivotal role in oxidative stress and the pathogenesis of numerous diseases. Antioxidants, including 1,2,4-Triazole derivatives, serve as crucial defense mechanisms against oxidative stress by neutralizing free radicals and mitigating their harmful effects. Therefore, exploring the antioxidant potential of 1,2,4-Triazole compounds holds promise for therapeutic interventions aimed at combating oxidative stress-related diseases. ¹

Antioxidant Activities

1,2,4-Triazole is a heterocyclic compound that has been studied for its antioxidant activities in various research experiments. Dastmard et al described the antioxidant properties of 3-substituted-1,2,4-triazoles using the Colorimetric ABTS assay. One specific compound (1) exhibited significant ABTS radical scavenging activity with an IC50 of 41 µM, which was higher than that of vitamin C in most concentrations. Ivanovic et al examined the antioxidant activities of 5-substituted-1,2,4-triazole-3-thiones using the DPPH free radical scavenging assay. Two compounds (2 and 3) displayed significantly higher radical scavenging activities compared to the reference antioxidants, with IC50 values of 14.63 µM and 12.66 µM, respectively. Furthermore, 2,3-disubstituted 1,2,4-triazoles and 3,4/(4,5)-disubstituted 1,2,4-triazole-5(3)-thione compounds were evaluated for their antioxidant activities, showing moderate to excellent antioxidant activity in various assays. Other derivatives of 1,2,4-triazole, such as 4-amino-3-substituted-1,2,4-triazole-5-thione and novel phenothiazine-linked substituted benzylideneamino-1,2,4-triazole derivatives, were also found to exhibit significant antioxidant activities in in vitro assays. Triazole Schiff base derivatives and indole-based melatonin analogues substituted with triazole were tested for their antioxidant capacity, showing potential antioxidant activity in comparison to reference compounds. Finally, new 4-amino-1,2,4-triazole derivatives containing 2,6-dimethoxyphenol and their Schiff base derivatives displayed high antioxidant activities in DPPH and FRAP assays, with some compounds exhibiting better activity than reference drugs. In summary, 1,2,4-Triazole and its derivatives have demonstrated promising antioxidant activities in various in vitro assays, making them potential candidates for further research and development in the field of antioxidants. ¹

Toxicity

1,2,4-Triazole exhibits toxicity through various routes of exposure. It is documented as an eye irritant, causing redness and pain upon contact. Additionally, 1,2,4-Triazole can be absorbed through the skin and inhalation, leading to potential systemic effects. Animal studies suggest it may pose risks to human reproduction and development, qualifying as a reproductive toxin. This classification encompasses harm to reproductive function and developmental defects in offspring. Therefore, caution is advised in handling and exposure to 1,2,4-Triazole to mitigate potential adverse health effects, especially concerning reproductive health. ²

Reference

1. Pachuta-Stec A. Antioxidant Activity of 1,2,4-Triazole and its Derivatives: A Mini-Review. Mini Rev Med Chem. 2022; 22(7): 1081-1094.

2. 1,2,4-Triazole. National Center for Biotechnology Information. 2024; PubChem Compound Summary for CID 9257.

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