Trypanocidal structure-activity relationship for cis- and trans-methylpluviatolide.

The trypanocidal activity of racemic mixtures of cis- and trans-methylpluviatolides was evaluated in vitro against trypomastigote forms of two strains of Trypanosoma cruzi, and in the enzymatic assay of T. cruzi gGAPDH. The cytotoxicity of the compounds was assessed by the MTT method using LLC-MK2 cells. The effect of the compounds on peroxide and NO production were also investigated. The mixture of the trans stereoisomers displayed trypanocidal activity (IC50 approximately 89.3 microM). Therefore, it was separated by chiral HPLC, furnishing the (+) and (-)-enantiomers. Only the (-)-enantiomer was active against the parasite (IC50 approximately 18.7 microM). Despite being inactive, the (+)-enantiomer acted as an antagonistic competitor. Trans-methylpluviatolide displayed low toxicity for LLC-MK2 cells, with an IC50 of 6.53 mM. Furthermore, methylpluviatolide neither inhibited gGAPDH activity nor hindered peroxide and NO production at the evaluated concentrations.

Analgesic and anti-inflammatory activities evaluation of (-)-O-acetyl, (-)-O-methyl, (-)-O-dimethylethylamine cubebin and their preparation from (-)-cubebin.

The anti-inflammatory and antinociceptive effects of the acetylated (2), methylated (3) and aminated (4) derivatives of cubebin (1), obtained by its reaction with acetic anhydride, methyl iodide and dimethylethylamine chloride, respectively, were investigated, using different animal models. The compound (2) was the most effective anti-inflammatory one in the carrageenin-induced paw edema in rats and was the only one which showed dose-response correlation for this assay with r = 0.993 and Y = 64.58x + 0.22. Besides, compounds (2) and (4) were more effective than cubebin in inhibiting acetic acid-induced writhing in mice, producing dose-response correlation with doses of 10, 20 and 30 mg/kg, respectively. Regarding the hot plate and the cell migration tests in rats, none of the four tested compounds showed activity. Overall, the results showed that the acetylation and amination of cubebin were efficient in enhancing its analgesic activity, as well as its anti-inflammatory activity.

Analgesic and anti-inflammatory activities of (-)-o benzyl cubebin, a (-)-cubebin derivative, obtained by partial synthesis.

The anti-inflammatory and antinociceptive effects of the benzylated cubebin derivative, obtained by reaction of (-)-cubebin with benzyl bromide, were investigated using different animal models. The (-)-o-benzyl cubebin showed a low anti-inflammatory effect (16.2%) in relation to cubebin (57%) and indomethacin (77%) in the carrageenin-induced paw edema in rats, but on the other hand it was more effective (80%) than (-)-cubebin (41%) in inhibiting acetic acid-induced writhing in mice, producing dose-response correlation with doses of 10, 20 and 40 mg/kg, respectively. Moreover, this derivative compound did not show activity in both the hot plate and the cell migration test in rats. Overall, the results showed that the benzylation of cubebin were efficient in enhancing only its analgesic activity.

Biological activity evaluation of dibenzilbutirolactones lignans derivatives against Leishmania braziliensis

This work reports the results of the in vitro assay against extracellular forms of Leishmania (viannia) braziliensis of eleven dibenzylbutyrolactone derivatives, either isolated from plants or obtained by synthesis. From these, only two showed relative biological activity against the parasite, the raceme mixtures of methylpluviatolide: IC50 = 496 mM and (-)-6,6'- dinitrocubebin: IC50 = 510,4 μM. Thus, it can be suggested that the metabolic pathway responsible for the biological activity of these compounds against this parasite genera differs from the one related to Trypanosoma cruzi, for which these compounds were quite active. This fact highly also suggests that this class of compounds is more selective against T. cruzi. Nevertheles, other lignans derivatives should be obtained to allow the fully evaluation of this class of lignans against Leishmaniosis.

Este trabalho apresenta os resultados de ensaios in vitro contra formas extracelulares de Leishmania (viannia) braziliensis de onze derivados de dibenzilbutirolactonas isolados de plantas ou obtidos através de síntese. Destes, só dois mostraram atividade biológica relativa contra o parasita, as misturas racêmicas de methilpluviatolide,: IC50 = 496 M e (-) -6,6' - dinitrocubebin: IC50 = 510,4 M. Assim, pode-se sugerir que o caminho metabólico responsável para a atividade biológica destas combinações contra estes gêneros de parasita difere do relacionado a Trypanosoma cruzi para o qual estas combinações foram bastante ativas. Este fato também sugere fortemente que essa classe de combinações é mais seletivo contra T. cruzi. Dessa forma, deveriam ser obtidos outros derivados de lignanas para permitir a completa avaliação desta classe de substâncias contra Leishmaniose.