Síntese e avaliação da atividade tripanocida de análogos de gibbilimbol

Abstract

Chagas Disease (CD) is caused by the protozoan Trypanosoma cruzi and, according to WHO, this disease is considered one of the most important neglect diseases among the others, once it affects all around the world more than 6 millions of people of which 2.2 million are located in southern America, mostly in Brazil and Argentina. Besides the inefficacy of the therapeutic and the scarce alternatives for chemotherapy available, the cytotoxicity and the side effects of the two used drugs, benznidazole and nifurtimox, affects negatively the adherence to the treatment. Thus, it is extremely necessary to make efforts to develop new drug candidates with trypanocidal activity and low toxicity for Chagas Disease. One strategy that has had shown potential is exploring natural products as therapy or as inspiration to create new chemical entities, due to its great biological potential, less toxicity compared to the synthetic ones, and exclusive mechanisms of action in the biological environment. Regarding this, gibbilimbols A-D are natural products belonging to the class of alkylphenols, isolated for the first time from Piper gibbilimbum (Piperaceae), with huge medicinal potential, since it has shown anticancer, antioxidant and antiparasitic activities, including trypanocidal and leishmanicidal, with gibbilimbol B being the most active against epimastigote form of T. cruzi. Due to these qualities of gibbilimbols for new drug prototypes, which also was verified using computational studies on swssADME platform, this present work describes the synthesis of seventeen gibbilimbol B analogues of which thirteen are novel, six amides and seven esters, both with unsaturation on carbon 4’ of the side chain. These new analogues were characterized by FT-IR and 1H and 13C NMR and have the trypanocidal activity accessed against the epimastigote form of the parasite. The amides showed the best results against the parasite when R = t-butyl and chlorine. The esters with unsaturated side chain did not impress by its trypanocidal activity, but they showed the best cytotoxic profile of all compounds. The esters with a saturated side chain showed the best results with the substituents nitro and methyl.