ABSTRACT
During the course of preparing anticonvulsant paeonimetabolin-I adducts, new paeonilactone-A adducts: 9-phenylthiopaeonilactone-A, 9-(o-tolylthio)paeonilactone-A, 9-(m-tolylthio)paeonilactone-A, 9-(p-tolylthio)-paeonilactone-A and 9-(2-naphthylthio)paeonilactone-A, were obtained along with expected paeonimetabolin-I adducts by anaerobic incubation of paeoniflorin from peony roots with Lactobacillus brevis in the presence of the aromatic thiols, phenylthiol, o-tolylthiol, m-tolylthiol, p-tolylthiol and 2-naphthylthiol. The structures of these compounds were determined by spectroscopic methods including two dimensional (2D) NMR.
Subject(s)
Benzoates , Bridged-Ring Compounds , Glucosides/metabolism , Lactobacillus/metabolism , Lactones/metabolism , Sulfhydryl Compounds/chemistry , Anaerobiosis , Carbohydrate Sequence , Chromatography, Thin Layer , Indicators and Reagents , Lactones/chemistry , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Monoterpenes , Paeonia/chemistry , Spectrophotometry, InfraredABSTRACT
Seventeen thiopaeonimetabolin-I adducts were obtained as mixtures of diastereoisomers after incubation of paeoniflorin with Lactobacillus brevis in the presence of various thiols. The anticonvulsant activity of the adducts was investigated in mice using the maximal subcutaneous pentylenetetrazol seizure test and sodium valproate (1.5 mmol/kg) as a positive control. Thirteen adducts showed dose-dependent prolongation of latencies of clonic and tonic convulsions. Maximal protection against convulsions was effectively demonstrated by 8-(n-hexylthio)paeonimetabolin I (8) and 8-benzoylthiopaeonimetabolin I (18) at doses of 0.125 and 0.25 mmol/kg, respectively, while 100% protection was only achieved at 0.5 mmol/kg of 8-cyclopentylthiopaeonimetabolin I and 8-(p-tolylthio)paeonimetabolin I. The principal anticonvulsant activity of the diastereoisomers of 8 and 18 was attributed to their 7S-isomers [ED50 values of 0.09 and 0.12 mmol/kg, and protective indices of 5.0 and 4.0 for 8 (7S) and 18 (7S), respectively], while the 7R counterparts [8 (7R) and 18 (7R)] showed a muscle relaxation effect.
Subject(s)
Anticonvulsants/therapeutic use , Benzoates , Bridged-Ring Compounds/therapeutic use , Glucosides/metabolism , Lactobacillus/metabolism , Seizures/drug therapy , Sulfhydryl Compounds/metabolism , Analysis of Variance , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Bridged-Ring Compounds/chemical synthesis , Bridged-Ring Compounds/chemistry , Disease Models, Animal , Male , Mice , Monoterpenes , Pentylenetetrazole , Seizures/chemically inducedABSTRACT
Paeoniflorin (1) and its derivatives having in common a cage-like pinane skeleton with hemiketal-acetal system, were evaluated for their effects on memory impairment induced by scopolamine in mice using a step-down type passive avoidance task. In the test session, 1 and its derivatives were intraperitoneally (i.p.) administered at doses of 0.002, 0.01, 0.02 and 0.2 mmol/kg, and 30 min later (15 min before the experiment), scopolamine (1 mg/kg, i.p.) was given. These compounds showed dose-dependent attenuation in a dose range of 0.002-0.02 mmol/kg and also enhancement of scopolamine-induced decrease in step-down latency. The effects of these compounds, except that of 2',3',4',5'-O-tetraacetyl-3-O-methylpaeoniflorin (8), followed a bell-shaped dose response profile. 8-Debenzoyl-6-deglucosyl-3-O-methylpaeoniflorin (6) showed no significant increase in the step-down latency at all tested doses. Maximum step-down latency was obtained by 3-O-methylpaeoniflorin (3) and 2',3,3',4',5'-penta-O-methylpaeoniflorin (7) (the minimal effective dose was 0.002 mmol/kg). Relative to 3, debenzoylation, as in 8-debenzoyl-3-O-methylpaeoniflorin (4), slightly increased the latency, while deglucosylation, as in 6-deglucosyl-3-O-methylpaeoniflorin (5), significantly reduced the prolongation of latency. Removal of both glucose and benzoyl moieties resulted in the loss of activity as seen in 6. These results revealed that, in addition to the cage-like pinane skeleton, the benzoyl and the glucosyl moieties are important structural elements of the paeoniflorin skeleton as its effects on scopolamine-induced amnesia.
Subject(s)
Amnesia/drug therapy , Benzoates , Bridged-Ring Compounds , Drugs, Chinese Herbal , Glucosides/therapeutic use , Amnesia/chemically induced , Animals , Avoidance Learning , Glucosides/chemistry , Male , Mice , Mice, Inbred ICR , Monoterpenes , Scopolamine , Structure-Activity RelationshipABSTRACT
Seventeen thiopaeonimetabolin-I adducts were obtained as mixtures of diastereoisomers after incubation of paeoniflorin with Lactobacillus brevis in the presence of various thiols. Four compounds, 8-(n-hexylthio)- (8), 8-cyclopentylthio-, 8-(p-tolyl)thio- and 8-benzoylthio- (18) paeonimetabolins, showed 100% protection against pentylenetetrazole-induced convulsions at doses of 0.125, 0.25, or 0.50 mmol/kg, relative to valproic acid (100% protection at 1.5 mmol/kg). For 8 and 18, the principle anticonvulsant activity resided in the (7S)-isomers while (7R)-isomers showed muscle relaxation effects.
Subject(s)
Anticonvulsants/chemical synthesis , Benzoates , Bridged-Ring Compounds , Glucosides/chemistry , Lactobacillus/metabolism , Plants, Medicinal , Sulfhydryl Compounds/chemistry , Animals , Anticonvulsants/therapeutic use , Dose-Response Relationship, Drug , Male , Mice , Monoterpenes , Pentylenetetrazole , Seizures/chemically induced , Seizures/drug therapy , Stereoisomerism , Structure-Activity Relationship , Valproic Acid/therapeutic useABSTRACT
The pyrimido[1,2-alpha]benzimidazole derivatives compounds 1-8 were synthesized through cyclocondensation of 2-aminobenzimidazole with the appropriate benzsubstituted benzoylacetone by fusion at 150-170 degrees C for 5 h. Quaternary salts compounds 9-22 were obtained by quaternization of compounds 1-8 with dimethyl or diethyl sulfate and subsequent isolation as the relatively insoluble perchlorate salts. Assignment and confirmation of the structures of the newly synthesized compounds were based upon elemental microanalyses and other spectral evidence.
Subject(s)
Benzimidazoles/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Pyrimidines/chemical synthesis , Benzimidazoles/chemistry , Heterocyclic Compounds/chemistry , Pyrimidines/chemistryABSTRACT
3-[2-[p-(Un)substituted phenyl]imidazo [2,1-b]benzothiazol-3- yl]propionic acid derivatives (2a--e) were prepared via the interaction of the corresponding 2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazoles (1a--e) with acrylic acid in the presence of acetic anhydride and acetic acid. Esterification of 2a--e produced methyl esters (3a--e). Upon the interaction of 3a with m-chloroperbenzoic acid, the S-dioxide (4a) was obtained. Compound 5a was prepared from 4a by alkaline hydrolysis. Vilsmeier formylation for 1a--e produced novel [2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazol-3- yl]formaldehyde derivatives (6a--e). Derivatives 6a--e reacted with ethyl bromoacetate to give ethyl 3-hydroxy-3-[2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazol- 3-yl]propionate esters (7a--e). Compound dl-7a was resolved with l-(+)-tartaric acid. Compounds 2a--e showed weak or no activity in the carrageein-induced paw edema assay. Compound 4a significantly inhibited the leakage of pontamine-sky blue dye into the peritoneal cavity of mice, in the capillary permeability inhibition assay. Compound 5a inhibited the writhing by 62% in the acetic acid-induced writhing assay.
