Spectrochemical, medicinal, and toxicological studies of Metronidazole and its derivatives: a quantum chemical and drug-design approach.

Nitroimidazole-based derivatives serve as fundamental components in the treatment of microbial infections. Metronidazole (MNZ), a synthetic nitroimidazole compound, is widely used as an important antimicrobial agent (AMA). Since the 1950s, MNZ has been a key drug in clinical medicine for treating a number of bacterial and protozoal diseases. It is commonly prescribed for bacterial vaginosis, amoebiasis, trichomoniasis, giardiasis, Clostridioides difficile-related diarrhoea, and anaerobic intra-abdominal infections. However, the use of MNZ as a therapeutic agent is often limited by unfavourable pharmacokinetics and side effects, including nausea, metallic taste, headache, and neurotoxicity (with long-term use). Therefore, our research explored various modified derivatives of MNZ to enhance its pharmacological activity and toxicity profiles. The geometrical characteristics of the analogues were further optimized via density functional theory (DFT) calculations via the B3LYP/6-31G+ (d, p) basis set. Molecular docking studies were conducted against bacterial thymidylate kinase and protozoal DNA, which revealed that most of the derivatives enhanced the ligand-protein binding affinities and favourable interactions at the protein active sites of both targets. Furthermore, a 100 ns molecular dynamics (MD) simulation was performed to evaluate the mode of interaction and stability of the ligand-protein complex under biological conditions. This result indicated that BNZ, SRZ, and EF5 improved the binding stability and dynamic flexibility patterns of these compounds. The pharmacological activity and safety parameters of the analogues were evaluated through ADMET and PASS analyses. Overall, the results revealed that most of the analogues possess favourable physicochemical and pharmacokinetic properties with few side effects. This research could facilitate the further development of BNZ, SRZ, and EF5 as promising candidates for next-generation AMAs, necessitating advanced preclinical evaluations. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00538-8.