Estudo químico e farmacológico do gênero Byrsonima (Malpighiaceae) para o desenvolvimento de novos anti-inflamatórios e antimicrobianos

Abstract

Five Amazonian Byrsonima species, B. crispa, B. duckeana, B. garcibarrigae, B. incarnata and B. japurensis, were selected to investigate the anti-inflammatory and antimicrobial properties of its extracts and semi-synthetic substances. The ability of aqueous extracts from the stem bark to act synergistically through inhibition of cyclooxygenase-2 (COX-2), lipoxygenase (LOX), inducible nitric oxide synthase (iNOS) and / or antioxidant activity was investigated by in vitro, in silico and in vivo models. In turn, the hexane extracts were rich in α and β-amyrin triterpenes, which were obtained in high quantity and high purity by a simple and cheap method developed in this work. These triterpenes were used in the semisynthesis of 24 derivatives, of which 18 were evaluated for their antimicrobial properties. The aqueous extracts contained phenolic compounds and flavonoids, resulting in a high antioxidant capacity in the DPPH•, ABTS●+ and superoxide tests and in the bacterial lipopolysaccharide activated macrophage assay, i.e. an in vitro model of inflammatory response. They also showed good enzymatic inhibition capacity and their phenolic components showed a good affinity for COX-2, LOX and iNOS in the in-silico evaluation, suggesting an interesting synergistic effect. B. japurensis, only species used in folk medicine, showed more potent anti-inflammatory and analgesic activities in in vivo models, possibly by the specific combination of some phenolic compounds that are well absorbed by the oral route. Of the 18 derivatives developed with the triterpenes α and β-amirin, five showed activity against Trypanosoma cruzi, T. brucei, Leishmania infantum, Candida albicans, Staphylococcus aureus and Escherichia coli, with different degrees of potency and specificity. Possibly, they act by interaction with lipid components of the cell membrane and also by inhibition of 14α-demethylase (CYP51), for which all the compounds presented different degrees of affinity in the in-silico evaluation. The method developed to obtain the inclusion complexes with sulfobutyl ether-β-cyclodextrin can be further optimized and used in modulating the selectivity and toxicity of these active substances, which is a strategy already reported in the literature for different drugs. In conclusion, this study was able to demonstrate that the five species of Byrsonima may be promising sources of new medicines. In particular, B. japurensis would serve as a promising model for a new multitarget medicine to treat inflammation. The hexane extracts provided interesting chemical skeletons that can be converted into very promising substances for the antimicrobial arsenal, in a simple, inexpensive and highly reproducible way.