Design, Synthesis, Antimicrobial Evaluation and Molecular Docking of New Pyrrolidinone–1,2,4‐ Mercapto Triazole Hybrids Fused as Multifunctional Therapeutic Agents

Abstract

ABSTRACT The increasing emergence of multidrug‐resistant bacteria has made the discovery of novel antimicrobial agents an urgent challenge. This study addresses this critical need by applying a well‐established synthetic pathway to design a new series of hybrid molecules that combine two bioactive pharmacophores: 1,2,4‐mercapto‐triazole and pyrrolidone. While the synthetic approach is classical, the originality of this work lies in its targeted application, these hybrid compounds are rationally designed as promising candidates for next‐generation antimicrobials, specifically aimed at overcoming current resistance mechanisms. An efficient synthetic strategy was achieved starting from itaconic acid, which was further functionalized through a reaction with thiocarbohydrazide to incorporate the 1,2,4‐mercapto‐triazole. The antimicrobial activity was assessed against a panel of Gram‐positive and Gram‐negative bacterial strains. Among the synthesized derivatives, compounds 5a, 3b, and 3h exhibited superior bacterial inhibition compared to reference antibiotics. Molecular docking suggested potential binding to the active site of dihydropteroate synthase (DHPS), a key enzyme in folate biosynthesis, via stable hydrogen bonds. While this supports DHPS as a plausible target, the observed whole‐cell activity may also involve additional mechanisms, paving the way for rational optimization. These findings highlight the potential of 1,2,4‐mercapto‐triazole–pyrrolidone hybrids as promising candidates for next‐generation antimicrobial agents capable of overcoming current resistance mechanisms.