RESUMO
We investigated the immunomodulatory, antiparasitic and cardioprotective effects of a sesquiterpene lactone (SL) administered alone or combined with benznidazole (Bz), in a murine model of Chagas' disease by in vitro and in vivo assays. Antiparasitic and cytotoxic potential of tagitinin C (SL) and Bz were tested in vitro against T. cruzi epimastigotes and cardiomyocytes. Swiss mice challenged with T. cruzi were also treated for 20â¯days with tagitinin C (10â¯mg/kg) alone and combined with Bz (100â¯mg/kg). Tagitinin C exhibited a higher antiparasitic (IC50: 1.15⯵M) and cytotoxic (CC50 at 6.54⯵M) potential than Bz (IC50: 35.81⯵M and CC50: 713.5⯵M, respectively). When combined, these drugs presented an addictive interaction, determining complete suppression of parasitemia and parasitological cure in all infected mice (100%) compared to those receiving Bz alone (70%). Anti-T. cruzi immunoglobulin G, and pro-inflammatory cytokines IFN-γ and TNF-α levels were reduced in animals treated with tagitinin C combined with Bz, while IL-10 production was unaffected. Heart inflammation was undetectable in 90% of the animals receiving this combination, while only 50% of the animals receiving Bz alone showed no evidence of myocarditis. Together, our findings indicated that the combination of tagitinin C and Bz exerts potent antiparasitic, immunomodulatory and cardioprotective effects. Due to the remarkable suppression of parasitemia and high parasitological cure, this combination was superior to Bz monotherapy, indicating a high potential for the treatment of Chagas's disease.
Assuntos
Antiparasitários/farmacologia , Cardiotônicos/farmacocinética , Fatores Imunológicos/farmacologia , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Cardiotônicos/farmacologia , Linhagem Celular , Doença de Chagas/tratamento farmacológico , Doença de Chagas/metabolismo , Doença de Chagas/parasitologia , Citocinas/metabolismo , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/parasitologia , Camundongos , Miocardite/metabolismo , Miocardite/parasitologia , Nitroimidazóis/farmacologia , Parasitemia/tratamento farmacológico , Parasitemia/metabolismo , Parasitemia/parasitologia , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
New Mannich base-type eugenol derivatives were synthesized and evaluated for their anticandidal activity using a broth microdilution assay. Among the synthesized compounds, 4-allyl-2-methoxy-6-(morpholin-4-ylmethyl) phenyl benzoate (7) and 4-{5-allyl-2-[(4-chlorobenzoyl)oxy]-3-methoxybenzyl}morpholin-4-ium chloride (8) were found to be the most effective antifungal compounds with low IC50 values, some of them well below those of reference drug fluconazole. The most significant IC50 values were those of 7 against C. glabrata (1.23 µm), C. albicans and C. krusei (both 0.63 µm). Additionally, the synthesized compounds were evaluated for their in vitro cytotoxic effects on human mononuclear cells. As result, the cytotoxic activity of eugenol in eukaryotic cells decreased with the introduction of the morpholinyl group. Given these findings, we point out compounds 7 and 8 as the most promising derivatives because they showed potency values greater than those of eugenol and fluconazole and they also presented high selectivity indexes.
Assuntos
Antifúngicos , Candida/crescimento & desenvolvimento , Candidíase/tratamento farmacológico , Citotoxinas , Eugenol/farmacologia , Leucócitos Mononucleares/metabolismo , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Eugenol/química , Humanos , Leucócitos Mononucleares/citologiaRESUMO
This work describes the atropisomeric relationships of 3-methyl-5-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-1-phenyl-1H-pyrazol-4-amine (2d), which belongs to series 4-aminobipyrazole derivatives designed as anti-inflammatory agents. The (1)H nuclear magnetic resonance spectra obtained in the presence of a chiral lanthanide shift salt associated to chiral high-performance liquid chromatography analysis, X-ray diffraction, and molecular modeling tools confirmed that ortho bis-functionalized bipyrazole 2d exists as a mixture of aR,aS-atropisomers. These results provide useful information to understand the pharmacological profile of this derivative and of other 4-aminobipyrazole analogs.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Pirazóis/química , Pirazóis/síntese química , Anti-Inflamatórios/farmacologia , Cromatografia Líquida de Alta Pressão , Simulação por Computador , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Ligação Proteica/efeitos dos fármacos , Pirazóis/farmacologia , EstereoisomerismoRESUMO
We have investigated the in vitro inhibition of papain, trypsin, and cathepsins B and G by five benzophenone-type compounds, three natural ones isolated from Garcinia brasiliensis and two synthetic derivatives. The activities of pentaprenylated trihydroxy-substituted benzophenone guttiferone A (1) on all assayed enzymes were approximately 2-69 folds higher than that manifested by mono-hydroxylated tetraprenylated and triprenylated compounds epiclusianone (2) and garciniaphenone (3), respectively, the other natural benzophenones that also inhibited significantly the four enzymes. Differently, the synthetic derivatives 2,2',4-trihydroxybenzophenone (4) and diphenylmethanone (5) have inhibited weakly the studied proteases. Furthermore, compound 1 has bonded preferentially to cathepsin G, once its IC(50) value (2.7+/-0.1 microM) on such peptidase is quite similar to that of the classical inhibitor of serine proteases, chymostatin (2.1+/-0.1 microM). Interesting structure-activity relationships (SARs) were confirmed by flexible docking simulations, likewise the potential usefulness of natural compound 1 as antitumoral drug is strengthened by our results concerning the antiproteolytic activity.
Assuntos
Benzofenonas/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Serina Proteinase/farmacologia , Benzofenonas/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/química , Cinética , Modelos Moleculares , Estrutura Molecular , Inibidores de Serina Proteinase/química , Análise Espectral/métodosRESUMO
This article reports the structural elucidation by IR, UV and MS spectroscopic data along with 1H and 13C NMR chemical shift assignments of two benzophenones isolated from the fruit pericarp of Garcinia brasiliensis Mart. (Clusiaceae): garciniaphenone, (1R,5S,7S)-3-benzoyl-4-hydroxy-6,6-dimethyl-5,7-di(3-methyl-2-butenyl)bicyclo[3.3.1]non-3-ene-2,9-dione, a novel triprenylated benzophenone; and 7-epi-clusianone, a tetraprenylated benzophenone that has already been extracted from another species of the same family. Furthermore, the keto-enol tautomeric equilibrium at solution-state was described for these compounds by 1D and 2D NMR spectral methods and one attempt to rationalize the different ratios between the noted tautomers was based on stereochemical features.