Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent.

A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10 µM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11ß-HSD1. In this model, compound 1 binds into the catalytic site of 11ß-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+).

Spasmolytic activity of Artemisia copa aqueous extract and isolated compounds.

Artemisia copa Phil. (Compositae) is used in popular medicine as a digestive and for gastric pains. The effects of A. copa aqueous extract and its isolated compounds were evaluated on isolated rat jejunum. The extract inhibited non-competitively the cumulative concentration-response curves induced by acetylcholine and CaCl2. The tonic jejunum contractions induced by 80 mM KCl were inhibited by A. copa. Relaxant effects of A. copa on the tonic contraction induced by 25 mM KCl, [EC50: 0.94 mg mL(-1) (0.64-1.39)], was not inhibited by glibenclamide, TEA, l-NAME or methylene blue. Chrysoeriol, spinacetin and luteolin (30 µg mL(-1)), produced an antagonism on the CaCl2 concentration-response curve, showing an inhibition of the maximum contractions (70.0% ± 5.0%, 49.1% ± 4.5% and 77.0% ± 3.5% of E max, respectively), whereas tricin did not inhibit when the same concentration was used. A. copa exerts spasmolytic activity by blocking calcium channels and three isolated compounds could be, at least partly, responsible for the effect.

Psychopharmacological effects of Artemisia copa aqueous extract in mice.

OBJECTIVE: To evaluate the aqueous extract from aerial parts of Artemisia copa Phil. (Asteraceae) administered orallyfor its psychopharmacological activities in several experimental models. METHODS: The extract was administered p.o. in Swiss albino mice and tested on pentobarbital-induced hypnosis, locomotor activity, exploration in the hole-board, anxiolytic like profile evaluated in the marble-burying test and anticonvulsant activity on convulsions induced by pentylenetetrazol. RESULTS: Artemisia copa at doses up to 1.5 g/kg produced a dose-dependent sleep induction and potentiation of sub-hypnotic and hypnotic doses of pentobarbital. The extract also produced a dose-dependent increase and decrease in the spontaneous motor activity (0.5-1.5 g/kg, respectively), no disruption or a decrease on exploratory (hole-board) behavioral profiles (0.5-1.5 g/kg respectively) and a dose-related anxiolytic-like activity as indicated by increases in the percentage of marbles they left uncovered in the marble-burying test at doses (0.5 g/kg) that do not disrupt the motor activity. In addition, the extract (1.5 g/kg) produced a significant increase in the latency time and a decrease in the duration of seizures and mortality induced by PTZ 75 mg/kg in mice. CONCLUSION: These results suggest that the aqueous extract of Artemisia copa may contain sedative principles with potential anxiolytic and anticonvulsant activities.

Evaluation of antinociceptive, antinflammatory activities and phytochemical analysis of aerial parts of Urtica urens L.

The antinociceptive and antiinflammatory activities of the ethanol extract of the aerial part of Urtica urens were determined by experimental animal models. U. urens extract was found to possess significant antinociceptive activity in chemically induced mouse pain models (ED50 39.3 mg/kg: 17.2-74.5 mg/kg) in the writhing test and 62.8% inhibition of the licking time in the late phase of the formalin test at a dose of 500 mg/kg p.o. and antiinflammatory activity on carrageenan-induced rat hind paw edema (41.5% inhibition at a dose of 300 mg/kg i.p.). The extract displayed activity neither in the thermal model of pain nor in the topical inflammation model. The major component of the extract was determined as chlorogenic acid (670 mg/1000 g dry weight) and could be partly responsible for this activity.

Neuropharmacological activity of Eupatorium buniifolium aqueous extract in mice.

The aim of this study was to evaluate the neuropharmacological profile of the Eupatorium buniifolium aqueous extract (EB) in mice. EB at doses up to 1.5 g/kg p.o. of the lyophilized material produced a dose dependent sleep induction and potentiation of sub-hypnotic and hypnotic doses of pentobarbital, respectively. However, EB neither modified the spontaneous motor activity nor produced a myorelaxant effect. Moreover, EB 1.5 g/kg in a nose-poke habituation task, produced a disruption of the normal patterns of habituation, and in a step-down inhibitory avoidance task, induced an amnesic effect similar to diazepam. These results suggest that the activity of EB may be a CNS-depressant.

Flavonoids from Artemisia copa with anti-inflammatory activity.

Bioactivity-guided fractionation of the dichloromethane and ethanol extracts from the aerial parts of Artemisia copa led to the isolation of the flavonoids spinacetin, jaceosidin, axillarin, penduletin, tricin and chrysoeriol. These compounds were studied for possible inhibitory activity on the generation of inflammatory mediators in a cell line of mouse macrophages (RAW 264.7) stimulated with lipopolysaccharide. Spinacetin and jaceosidin weakly inhibited nitric oxide production whereas all flavonoids reduced prostaglandin E2 levels to different extents. The most active flavonoid was jaceosidin that inhibited cyclooxygenase-2 activity in a concentration-dependent manner with an IC50 value of 2.8 microM. In addition, the other flavonoids partially inhibited synovial phospholipase A2 activity. These mechanisms may provide a basis for explaining the anti-inflammatory activity of this plant.

Metabolites from endophytes of the medicinal plant Erythrina crista-galli.

Erythrina crista-galli (Fabaceae) is used in Argentinean ethnopharmacology as anti-inflammatory medication, narcotic, desinfectant, and for the treatment of wounds. The common name of the tree is "ceibo" or coral tree. The dominating endophytes in E. crista-galli all belong to the genus Phomopsis as identified by microscopic features and the analysis of their ITS sequences. To investigate a possible contribution of Phomopsis spp. to the metabolites found in the plant, twelve different isolates were cultivated in different media. Besides several new metabolites a number of known compounds were detected: mellein, nectriapyrone, 4-hydroxymellein, scytalone, tyrosol, clavatol, mevinic acid, and mevalonolactone.