Planejamento e síntese de novos derivados da associação molecular benzonidazol e metronidazol

Abstract

Chagas disease is caused by protozoan Trypanosoma cruzi, still has high contagion rates in present days, especially in the Amazon region. After contamination, the infective cycle of Chagas disease has two phases: acute and chronic. The acute phase is, in majority of cases, asymptomatic and efficiently treated, however the chronic phase is symptomatic and has proved not efficient treatment. There is only one available medicine, the generic benznidazole or Rochagan®, distributed free of charge, and it must be administered for 60 days, approximately. However, benznidazole has low efficiency, being effective only on acute phase (asymptomatic). Besides that, the medicine use to cause severe side effects in clinical patients, producing in many times the treatment rejection. The molecular modeling has become an important tool on new drugs design, using the DFT method to evaluate of the new potent molecules. Thereby, the main goal of this work was to design new derivatives by using molecular modifications of benznidazole and metronidazole aiming to reduce their redox capacity. With this purpose, a theoretical study was performed of two benznidazole derivatives through molecular association and chain increase. From the theoretical study, this molecular association between benznidazole and metronidazole molecules can develop a less toxic new derivative of than benznidazole. Both designed derivatives were synthesized on laboratory using the classics methodologies of electrophilic and nucleophilic substitution, esterification, alkylation and nitration. According to their HOMO, LUMO, ionization potential, and electron affinity values, it was possible observe that the nibendazole 1 and nibendazole 2 compounds have a lower redox capacity when compared to benznidazole. The GAP values showed that the derivatives are less reactive than benznidazole. The HOMO and LUMO graphics, showed that the nitroimidazoles rings have high electron-withdrawing capacity as well as benzyl group has high electron-donating capacity. These properties change in accordance to methyl moiety or nitrogen positions on azolic ring of derivatives compounds.