Metronidazole-An Old Drug for Structure Optimization and Repurposing.

Abstract

Metronidazole, a prodrug derived from the nitroimidazole class, continues to serve as a key antimicrobial agent for managing infections caused by anaerobic bacteria, microaerophilic organisms, and protozoan parasites. Its therapeutic activity is primarily exerted under low-oxygen conditions, wherein the nitro functional group undergoes enzymatic reduction, leading to the cleavage of the imidazole ring and the generation of cytotoxic intermediates. Despite its effectiveness, the increasing prevalence of antimicrobial resistance has prompted the design of new metronidazole analogs, including ruthenium-based compounds and Schiff base derivatives. These next-generation agents exhibit broader antimicrobial coverage, alternative mechanisms of action, reduced cytotoxicity, improved efficacy against resistant strains, and potential applications beyond traditional infectious disease contexts. This review provides an in-depth analysis of metronidazole's clinical relevance, emphasizing the relationship between metabolite structure and cytotoxic effects in both human and rodent models. Additionally, it highlights recent advances in the synthesis of metronidazole derivatives and evaluates their comparative therapeutic benefits relative to the original compound.