Novel Metronidazole Conjugates as Antimicrobial Agents.

Metronidazole (MTZ) is one of the oldest and still used anti-infective nitroimidazole group drug. Although it is effective against anaerobic bacteria, protozoa, and parasites in clinical settings, it lacks efficacy against aerobic microorganisms. Due to its efficient molecular structure and synthetic usability due to the alcohol group in its framework, medicinal chemists aimed to reach new more effective molecules such as MTZ-hybrids. In this study, 2-[(benzimidazole/benzoxazole/benzothiazol-2-yl)thio]-N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]acetamide (5a-5j) derivatives were synthesized and their antimicrobial and antifungal effects on aerobic bacteria and Candida spp. were investigated. Notably, most of newly designed conjugates displayed higher potency than MTZ itself, especially against Gram-positive strains. Furthermore, chlorinated heterocyclic moieties provided the strongest effects. Docking studies using E. coli nitroreductase (PDB: 1IDT) revealed potential interactions with the flavin mononucleotide (FMN) cofactor, suggesting that these hybrids may undergo nitro-group reduction analogous to MTZ. Additionally, pharmacokinetic predictions indicated generally favorable profiles.