Metal-metronidazole derivatives as potential antitrichomonal agents on Trichomonas vaginalis

Metronidazole (MTZ) remains the main treatment for Trichomonas vaginalis infections; however, increasing resistance has driven the search for more effective therapeutic alternatives. In this study, we prepared and characterized three metal-based metronidazole complexes: [Zn(MTZ)₂Cl₂], [Cu(MTZ)₂μ-Cl(H₂O)]₂Cl₂, and [Cu(MTZ)(PPh₃)₂(NO₃)]‧ H₂O, (MTZ = metronidazole; PPh₃ = triphenylphosphine). Single-crystal X-ray diffraction confirmed the coordination of MTZ by the N-imidazole and auxiliary ligands of the metal centers. The [Zn(MTZ)₂Cl₂] complex demonstrated significant antiproliferative activity against T. vaginalis, with an IC₅₀ of 1.7 μM after 24 h, surpassing that of free MTZ. Similar potency was observed for copper-MTZ complexes. Ultrastructural analyses via scanning and transmission electron microscopy revealed membrane blebbing, cytoplasmic vacuolization, and hydrogenosomal disorganization, morphological hallmarks of apoptosis-like cell death. These findings were further supported by TUNEL and Annexin V assays, indicating DNA fragmentation and phosphatidylserine exposure. Cytotoxicity assays using HMVII human cells showed low toxicity for MTZ, [Zn(MTZ)₂Cl₂], and [Cu(MTZ)₂μ-Cl (H₂O)]₂Cl₂ (CC₅₀ > 100 μM), whereas the [Cu(MTZ)(PPh₃)₂NO₃]‧H₂O complex was markedly cytotoxic (CC₅₀ = 3.35 μM). The results suggest that MTZ-based zinc and copper complexes enhance antiparasitic efficacy with acceptable safety profiles. These findings provide a promising foundation for developing novel treatments for drug-resistant trichomoniasis.