Derivados semissintéticos a partir dos limonoides isolados das sementes da andiroba (Carapa guianensis –Meliaceae) e sua atividade antimalárica contra Plasmodium spp

Abstract

With the resistance of the protozoan of the genus Plasmodium falciparaum and Plas- modium vivax to the base treatment of the derivatives of artemisinin and chloroquine, respectively, arises the need for the implementation of new anti-malarial drugs. Ac- cording to works carried out by LAPAAM/INPA, they reveal potential anti-malarial ac- tivity of limonoids isolated from residual seed biomass and oil from Andiroba (Carapa spp). This work aims to isolate limonoids from Andiroba seeds and to perform semi - synthetic modifications in order to investigate their anti-malarial activities in vitro against P. vivax and P. falciparum. The extraction of limonoids started with the collec- tion of C. guianensis seeds and residual biomass, followed by the implementation of chromatographic techniques, such as extraction, liquid-liquid partition, chromato- graphic partition and HPLC partition. The semi-synthetic products purified from the benzoylation, butyrylating, penethionylation, heptanoylation and NaBH4 reduction re- actions of the gedunin type of limonoids were characterized structurally by Ultra-Fast Fluid Chromatograph High Resolution spectroscopy (UFLC / HRMS-ESI) and uni and / or two-dimensional Nuclear Magnetic Resonance. The present work isolated four li- monoids: 6α-hydroxyigedunine (34), 7-deacetyl-7-oxygedunin (9), 6α-acetoxyglycine (10) and 6α-acetylazaradione (33) and obtained thirteen semi-synthetic substances. The substances 6α-acetoxygedunin and its semi-synthetic derivative 6α-hy- droxydesacetylgedunin (10.1) showed potential activity against P. vivax strain. Among the three semisynthetic substances tested in the in vitro antimalarial assays against Plasmodium falciparum K1 strain, 6-epi-gedunin derivatives (9.1.1, IC50 1.76 μM) and gedunin (9.2.1, IC50 2.49) were considered the most active and all substances used in this thesis presented low toxicity in normal cells with viability greater than 50% in the concentration of 50 μg/mL.