Design, Synthesis, and Antimicrobial Evaluation of Novel Triazole-Acetamide-Linked Thiadiazole Hybrids

INTRODUCTION: Infections caused by multidrug-resistant bacteria and fungi pose an increasing global threat, underscoring the urgent need for new drugs with novel structures and mechanisms of action. METHODS: A new series of triazole-thiadiazole hybrid derivatives (7a-7i) was designed, synthesized, and structurally characterized using 1H NMR and 13C NMR spectroscopy. The antimicrobial efficacy of the synthesized compounds was evaluated in vitro against a panel of clinically significant, resistant bacterial and fungal strains. RESULTS: Compound 7a demonstrated the highest potency against E. coli with a MIC of 3.90 μg/mL, followed by compound 7b (7.81 μg/mL) and compound 7e (31.25 μg/mL). Antifungal screening revealed moderate activity against the resistant strains C. krusei ATCC 6258 and C. albicans ATCC 24433. Compound 7a inhibited C. krusei with an MIC of 62.5 μg/mL, while compounds 7e and 7h exhibited MIC values of 125 μg/mL against both fungal strains. DISCUSSION: Preliminary Structure-Activity Relationship (SAR) analysis suggests that small, hydrophobic alkylamine substituents significantly enhance antimicrobial activity. In silico ADMET profiling supported the biological findings, indicating that all compounds fall within acceptable drug-likeness criteria. Among them, compound 7b emerged as the most promising lead, exhibiting high oral absorption, good solubility, and permeability, and the lowest predicted cardiotoxicity risk. CONCLUSION: These results suggest that triazole-thiadiazole hybrids, particularly compound 7b, represent a promising scaffold for the development of new antimicrobial agents.