RESUMO
This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Edema/tratamento farmacológico , Peritonite/tratamento farmacológico , Inibidores da Agregação Plaquetária/farmacologia , Úlcera/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Carragenina , Celecoxib/química , Celecoxib/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Lignanas/química , Lignanas/farmacologia , Masculino , Camundongos , Estrutura Molecular , Peritonite/induzido quimicamente , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Úlcera/induzido quimicamenteRESUMO
Introduction: species of the family Cyperaceae are commonly used by the population to treat gastric disorders.However, there are a few ethnopharmacological studies about this family Lagenocarpus rigidus (Kunth) Ness, Cyperaceae, is one of the most widespread swamp species. Objective: evaluate the gastric activity of L. rigidus and its chemical characterization. Methods: ethanolic extract of L. rigidus (ELR) leaves prepared by percolation was subjected to total polyphenol and flavonoid quantification, as well as HPLC quantification of some flavonoids. Angiotensin converting enzyme (ACE) inhibition was determined by colorimetric assays.The gastric effects of ELR were tested in male Wistar rats (n = 6 each group) treated with different doses (600, 60 and 6 mg/kg i.p.) ELR.Gastric lesions were induced by administration of indomethacin (30 mg/kg s.c.).The number of ulcers and the index of mucosal damage (IMD) were determined taking into account the color, edema and bleeding of gastric lesions, the number of petechiae, and the number and size of the ulcers. Statistical analysis of data was performed with one-way ANOVA followed by Tukey's test; significance was p < 0.05. Results: ELR inhibited the ACE (68.5±18.1%) at a concentration of 100 mg/mL.Oral administration of ELR (6, 60 and 600 mg/kg) showed protective activity against indomethacin-induced gastric injury. Total polyphenols in ELR were 157.7 ± 5.8 mg pirogalol/mg equivalent flavonoids and 66.9 ± 3.1 µg equivalent quercetin/mg. Conclusion: L. rigidus protects against acute gastric damage induced by indomethacin in an independent dose manner.
Introducción: las especies de la familia Cyperaceae popularmente se utilizan para tratar trastornos gástricos. Sin embargo, hay pocos estudios etnofarmacológicos sobre esta familia. Lagenocarpus rigidus (Kunth) Ness, Cyperaceae, es una de las especies más grandes de población en pantano. Objetivo: evaluar la actividad gástrica de L. rigidus, junto a su caracterización química. Métodos: el extracto etanólico de hojas de L. rigidus (ELR), preparado por percolación fue objeto de cuantificación de polifenoles y flavonoides totales, cuantificación por HPLC de algunos flavonoides. La inhibición de la enzima convertidora de angiotensina (ECA) se realizó por ensayos colorimétricos. Los efectos gástricos de ELR se llevó a cabo en ratas Wistar macho (n = 6, cada grupo), el tratamiento con diferentes dosis (600, 60 y 6 mg/kg ip) de ELR. Las lesiones gástricas se indujeron mediante la administración de indometacina (30 mg/kg sc). El número de úlceras y signos de puntuación del índice de lesión de las mucosas (IMD) se evaluó teniendo en cuenta el color, edema y hemorragia de las lesiones gástricas, el número de petequias, y el número y tamaño de las úlceras. El análisis estadístico de los datos se realizó mediante ANOVA 1 vía, seguido por el test de Tukey y significación fue de p < 0,05. Resultados: ELR inhiben la ACE (68,5 ± 18,1 %) a una concentración de 100 mg/mL. La administración oral de ELR (6, 60 y 600 mg/kg) mostró un efecto protector gástrico contra inducido por indometacina. Los polifenoles totales de ELR fue 157,7 ± 5,8 mg equivalente de pirogalol/mg de flavonoides y 66,9 ± 3,1 μg equivalentes de quercetina/mg. Conclusiones: L. rigidus protege contra el daño gástrico agudo inducido por la indometacina en una organización independiente de la dosis.
RESUMO
Ethanolic extract of Annona muricata L., Annonaceae, leaf (AML) was used to investigate its antinociceptive and anti-ulcerogenic activities and the involvement of the mechanism of ethanolic leaves extract of AML in various animal models. Antinociceptive activity of AML extract was done using acetic acid-induced abdominal writhing in mice, formalin test in rats and hot plate test in mice. Furthermore, the anti-ulcerogenic effect of AML extract was studied in ethanol-induced ulcer model in rats, ethanol-induced gastric lesions in L-NAME-pre-treated rats as well as ethanol-induced gastric lesions in NEM-pre-treated rats test model to determine its mechanism. AML exhibited significant and dose-dependent antinociceptive activity. It also significantly decreased the ulcerative lesion produced by ethanol in rats in a dose-dependent manner. Pre-treatment with N-ethymaleimide, a thiol blocker, including mucosal nonprotein sulfhydryl groups, reduced the anti-ulcerogenic effect of AML extract in the same ulcer model, suggesting that AML extract may have active substances such as tannins, flavanoids and triterpenes that increase the mucosal nonprotein sulfhydryl group content.