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

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.

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.

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.

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.

These results suggest that triazole-thiadiazole hybrids, particularly compound 7b, represent a promising scaffold for the development of new antimicrobial agents.