Organocatalyzed Synthesis of 5-aryl-1,2,4-triazolidine-3-thione and 1,2, 4-triazospiro-3-thione, Drug-Likeness and Anti-Microbial Studies

Background: Heterocyclic compounds emerged promising choice in drug discovery and clinical research. Among various heterocycles, 5-aryl-1,2,4-triazolidine-3-thione and 1,2,4-tri-azospiro-3-thione derivatives also showed important biological applications. Hence, organic chem-ists are striving to develop various catalytic routes for the construction of these derivatives. Method: The present work describes the eco-friendly synthesis of 5-aryl-1,2,4-triazolidine-3-thione (3a-o) and 1,2,4-triazospiro-3-thione (5p-u) via one-pot Multi-Component Reactions (MCRs) of substituted aromatic/heteroaromatic aldehyde, isatine and thiosemicarbazide in the presence of or-ganocatalysts Glutamic acid (Glu) under microwave irradiation. Additionally, the homogeneity of the selected compounds was confirmed through various spectroscopic techniques such as FT-IR, 1H- 13C-NMR, and LC-MS. Further, the drug-likeness was evaluated using SwissADME software and the anti-microbial activity of the selected derivatives were tested. Results: The reaction exhibits good tolerance towards various substituted aromatic/heteroaromatic aldehydes, isatine, and thiosemicarbazide, resulting in high yields of product isolation (86–92%). The computational ADMET properties of the prepared derivatives were evaluated for their drug-like properties, along with an assessment of Lipinski’s Rule of Five. Selected derivatives were also tested for their antimicrobial properties, showing comparable activities. Conclusion: Overall, this work describes a greener method synthesis of 5-aryl-1,2,4-triazolidine-3-thione derivatives (3a-o) and 1,2,4-triazospiro-3-thione derivatives (5p-u). The catalysts used are biodegradable, environmentally friendly organocatalysts that align with green chemistry principles. The reaction is accelerated by microwave irradiation in the presence of ethanol. The developed method is simple, allowing for easy separation of the catalyst using hot ethanol and enabling recy-cling up to three times without affecting product isolation. The developed protocol offers ad-vantages such as accessibility, cost-effectiveness, rapid reactions, mild atom economy, and elimi-nation of hazardous solvents and catalysts usage. Selected derivatives were screened for antimicro-bial activity, evaluated computationally for drug-likeness in silico, and adhered to Lipinski’s rule of five.