ABSTRACT
In order to improve the previously observed antichagasic activity of Cu(II) complexes containing 2-chlorobenzhydrazide (2-CH), we report herein the synthesis and anti-Trypanosoma cruzi activity of novel copper complexes containing 2-methoxybenzhydrazide (2-MH), 4-methoxybenzhydrazide (4-MH) and three α-diimine ligands, namely, 1,10-phenanthroline (phen), 2,2-bipyridine (bipy) and 4-4'-dimethoxy-2-2'-bipyridine (dmb). Two of these complexes showed higher in vitro anti-Trypanosoma cruzi activity when compared to benznidazole, the main drug used in Chagas disease treatment. One of them, the copper complex with 4-MH and dmb, [Cu(4-MH)(dmb)(ClO4)2], exhibited a higher selectivity index than that recommended for preclinical studies. Considering this observation, complex [Cu(4-MH)(dmb)(ClO4)2] was selected for preliminary in vivo assays, which verified that this compound was able to reduce parasitemia by 64% at the peak of infection. Further investigations were performed on all compounds. The Cu(II) complexes bind to ct-DNA with Kb values in the range of 103-104 M-1, with [Cu(4-MH)(dmb)(ClO4)2] showing the highest Kb value (1.45 × 104 M-1). Molecular docking simulations predicted that [Cu(4-MH)(dmb)(ClO4)2] binds in the minor groove of the double helix of ct-DNA and forms one hydrogen bond.
Subject(s)
Chagas Disease/drug therapy , Copper/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Chagas Disease/parasitology , Coordination Complexes , Female , Hydrazines/chemical synthesis , Hydrazines/pharmacology , Hydrogen Bonding , Ligands , Mice , Mice, Inbred BALB C , Molecular Docking Simulation , Nitroimidazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Trypanocidal Agents/chemical synthesisABSTRACT
The aim of this study was to obtain an electrochemical device between the electrostatic interaction of the electropolymerized porphyrin {CoTPyP[RuCl3(dppb)]4}, where TPyP = 5,10,15, 20-tetrapyridilphorphyrin and dppb = 1,4-bis(diphenylphosphino)butane, and gold nanoparticles (AuNPsn-), to be used as a voltammetric sensor to determine catechol (CC). The modified electrode, labelled as [(CoTPRu4)n8+-BE]/AuNPsn- {where BE = bare electrode = glassy carbon electrode (GCE) or indium tin oxide (ITO)}, was made layer-by-layer. Initially, a cationic polymeric film was generated by electropolymerization of the {CoTPyP[RuCl3(dppb)]4} onto the surface of the bare electrode to produce an intermediary electrode [(CoTPRu4)n8+-BE]. Making the final electronic device also involves coating the electrode [(CoTPRu4)n8+-BE] using a colloidal suspension of AuNPsn- by electrostatic interaction between the species. Therefore, a bilayer labelled as [(CoTPRu4)n8+-BE]/AuNPsn- was produced and used as an electrochemical sensor for CC determination. The electrochemical behaviour of CC was investigated using cyclic voltammetry at [(CoTPRu4)n8+-GCE]/AuNPsn- electrode. Compared to the GCE, the [(CoTPRu4)n8+-GCE]/AuNPsn- showed higher electrocatalytic activity towards the oxidation of CC. Under the optimized conditions, the calibration curves for CC were 21-1357 µmol l-1 with a high sensitivity of 108 µA µmol l-1 cm-2. The detection limit was 1.4 µmol l-1.
