Structure–Activity Relationship and Antioxidant Potential Of 1,2,4-Triazole-5-Thione Derivatives: Correlation with Physicochemical Properties and in Silico Docking Studies

Abstract

A novel series of 3,4-disubstituted-1,2,4-triazole-5-thione derivatives (3a–3ab) was investigated for their antioxidant potential using the DPPH radical scavenging assay, and the results were interpreted through structure–activity relationship (SAR), physicochemical correlation, and molecular docking studies. The synthesized compounds exhibited a wide range of antioxidant activities, with bromo-substituted derivatives showing the highest activity, particularly compound 3h (80% inhibition, IC₅₀ = 6 µg/mL) and 3k (76% inhibition, IC₅₀ = 8 µg/mL). The overall SAR trend followed Br > Cl > F > OCH₃ > H, while positional effects in methoxy-substituted derivatives were observed as para > meta > ortho. Additionally, phenyl substitution at the R₁ position significantly enhanced activity due to improved resonance stabilization and hydrophobic interactions. Physicochemical analysis revealed that compounds with balanced lipophilicity and optimal polarity exhibited superior antioxidant performance. Molecular docking studies supported the experimental findings, demonstrating that highly active compounds showed lower binding energy and stronger interaction profiles, including hydrogen bonding, π–π stacking, and hydrophobic interactions. The triazole-5-thione core was identified as a key pharmacophoric unit responsible for radical scavenging activity. Overall, the study establishes a strong correlation between molecular structure, physicochemical properties, and antioxidant activity, identifying brominated, phenyl-containing derivatives as promising lead compounds for further development.