Avaliação da atividade antimalárica e citotóxica de compostos derivados de 1,2,3- triazóis em modelo murino

Abstract

Malaria remains one of the most worrying infectious diseases in the world, affecting mainly tropical areas with high rates of mortality among children under 5 years and pregnant woman. Estimated that 2015 occurred 212 million new cases of malaria, and 429 000 deaths. About 90% of malaria cases are estimated to have occurred in the WHO African Region. The increase of the number of multidrug- resistant Plasmodium strains becoming less effective the treatment currently available for malaria. Therefore, the development of new drugs with different mechanisms of action is necessary to overcome parasites resistance. Triazole derivatives are reported to exhibit several biological activities such as analgesic, antibacterial, fungicidal, anti-inflammatory, antihypertensive, antiviral and antitumor. 1,2,3-triazole, in general, are stable under acidic and basic environments and form hydrogen bonds with biomolecular targets. Thus, triazoles provide a moiety which is promising from the perspective of synthetic strategy, and can also be advantageous biologically. This study aims to evaluate the antimalarial activity of derivatives of 1,2,3-triazoles. Preliminary pharmacokinetics studies of the compounds have been made based on the Lipinski Rule of Five using the Molsoft program. All derivatives have demonstrated good pharmacokinetic properties to be evaluated in vivo. To evaluate in vitro cytotoxicity was used primary cultures of murine peritoneal macrophages. Cell viability was determined by MTT assay. Toxicity in vitro was also determined by hemolysis assay against human erythrocytes. Some compounds showed relatively toxic when evaluated by MTT assay but in hemolysis test most compounds showed no toxicity against RBCs. In vivo antimalarial activity of ten compounds were evaluated using mice infected with Plasmodium berghei NK65. The compounds were tested at 10mg/kg using the 4-day suppressive test described by Peters (modified) and blood smears were used to obtain the inhibition of parasite multiplication. All 9 compounds evaluated exhibited antimalarial activity, reaching percentages of suppression above 30% until 9 days post-infection. Compounds (1), (4), (5) and (6) showed promising activities, with parasitaemia suppression greater than 50% in most cases. All of these compounds have in common the presence of a 10-carbon chain attached to the 1-position of the triazole ring, which may be related to the better activity of the compounds. Molecular docking studies were performed to determine whether the pLDH enzyme was the action target of the derivatives and showed that further studies should be performed to determine the action target. These results suggest that the molecules should require further researches, with the aim of provide new antimalarials.