Síntese e avaliação das atividades ansiolítica e antioxidante de complexos benzodiazepínicos de paládio(II) e platina(II)

Abstract

The planning of drug candidate compounds is an important strategy of Medicinal Chemistry for the discovery of alternative sources in the treatment of several pathologies, such as anxiety disorders (TA). Problems related to TA affect thousands of people worldwide and benzodiazepines stand out as drugs of first choice for treatment. These facts inspired the elaboration of this research work, with the following objectives: to synthesize palladium(II) and platinum(II) complexes containing benzodiazepine ligands – Diazepam (DZP), Bromazepam (BMZ), Alprazolam (APZ) –, in order to evaluate how their biological activities are combating anxiety and oxidative stress. Seventeen metal complexes have been synthesized, most of them organometallic derived from benzodiazepine compounds with yields considered moderate to good. Some of the complexes were obtained from other benzodiazepine complexes, generally dimeric, employing reactions such as substitution and addition of ligands and insertion of alkynes in complexes containing Pd-C bond. Using these strategies, compounds with two bioactive ligands (hybrids) were prepared. For example, Pd(II) complexes were prepared from the [(DZP)PdOAc]2 dimer containing, in addition to the benzodiazepine pharmacophoric group, the ligands derived from isonicotinic (AI) and nicotinic (AN) acids. The isolated metal complexes were well characterized by spectroscopic techniques, except those modified by reactions of insertion of alkynes in the metal-carbon bond, which although pure need further characterization for the proper determination of their structure. Tests to verify the antioxidant capacity of the obtained complexes demonstrated promising results, with emphasis on the [(BMZ)PdCl2] complex. It is worth mentioning that studies to assess the antioxidant activity of these compounds are important, since in cases of TA high levels of oxidative stress may be associated. The anxiolytic evaluation studies of the [(DZP)PdCl]2 complex showed an anxiolytic effect at a dose of 0.15 mg/kg (0.176 µmol/kg), for the elevated plus maze test (EPM), not promoting changes in the locomotor activity and no amnesic effect at this administered dose. Finally, the results obtained in the EPM demonstrate that the anxiolytic-like effect promoted by the complex is mediated via the GABAA receptor.