Excavating precursors from the traditional Chinese herb Polygala tenuifolia and Gastrodia elata: Synthesis,anticonvulsant activity evaluation of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives

Epilepsy is a group of neurological disorders characterized by recurrent seizures that disturbs about 60 million people worldwide. In this article, a novel series of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives 1–35 were designed inspired from the traditional Chinese herb pair drugs Polygala tenuifolia and Gastrodia elata and synthesized followed by in vivo and in silico evaluation of their anticonvulsant potential. All the synthesized derivatives were biologically evaluated for their anticonvulsant potential using two acute model of seizures induced in mice, the maximal electroshock (MES) and sc-pentylenetetrazole (PTZ) models. Simultaneously, the motor impairment as a surrogate of acute neurotoxicity and in vitro screening of cytotoxicity against HepG-2 cells line were assessed through the rotarod performance test and CCK-8 assay, respectively. In addition, the physicochemical and pharmacokinetic parameters of the active compounds were determined. Our results showed that compounds 5, 7, 8, 13, 20, 25, 28, 30 and 32 exhibited preferable anticonvulsant activity in primary evaluation, with compounds 28 and 32 being the most promising anticonvulsant agents in according to results of subsequent pharmacology and toxicity evaluation. Additionally, the molecular modeling experiments predicted good binding interactions of part of the obtained active molecules with the gamma-aminobutyric acid (GABA) transferas. Therefore, it could be concluded that the synthesized derivatives 28 and 32 would represent useful lead compounds for further investigation in the development of anticonvulsant agents.     

Synthesis and evaluation of pharmacological profile of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides

In previous studies we identified several 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives displaying potent anticonvulsant effects in different animal models of epilepsy. With the aim to deepen the structure–activity relationships (SAR) for this class of compounds and identify novel anticonvulsant agents we synthesized a series of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides. The new compounds incorporate the main features of the above-mentioned anticonvulsants and a sulfonamide function capable to inhibit the enzyme carbonic anhydrase (CA, EC 4.2.1.1), which represents an attractive target in epilepsy. Pharmacological effects were evaluated in vivo against audiogenic seizures in DBA/2 mice and in vitro against several CA isoforms. Some of the new molecules showed anticonvulsant properties better than topiramate, but weak inhibitory activity and low selectivity in enzymatic assay.     

Hepatoprotective and anti-Helicobacter pylori activities of constituents from Brazilian propolis.

Propolis is a resinous hive product collected by honeybees from various plant sources. It is extensively used in food, beverage and in folk medicine for treating various ailments and reported to have broad spectrum of biological activities. The hepatoprotective activity of propolis and constituents from its MeOH extract belonging to various classes were tested on D-galactosamine (D-GalN)/tumor necrosis factor-alpha (TNF-alpha)-induced cell death in primary cultured mouse hepatocytes. The result indicated that hepatoprotective activity of alcoholic extract of tropical Brazilian propolis is mainly due to phenolic compounds including flavonoids. All the four isolated flavonoids possessed stronger inhibitory activity (IC50, < 25 microM) than silibinin (IC50, 39.6 microM) on TNF-alpha-induced cell death. The labdane-type diterpenes isolated from the MeOH extract also exhibited significant hepatoprotective activity in the same experimental model. Moreover, the labdane-type diterpenes and some of the prenylated phenolic compounds possessed antibacterial activity against Helicobacter pylori.     

Synthesis and anticonvulsant activity of a class of 2-amino 3-hydroxypropanamide and 2-aminoacetamide derivatives

Several studies have demonstrated that N-substituted amino acid derivatives exhibit weak anticonvulsant activities in vivo. In the present study, a series of amides of aminoacids structurally related to aminoacetamide have been synthesised and investigated for anticonvulsant activity. Among the molecules investigated, those containing a bicyclic (tetralinyl, indanyl) group linked to the aminoacetamide chain (40, 47 and 59) were among the most active as anticonvulsants (ED50 > 10, <100 mg/kg after oral administration) against tonic seizures in the mouse maximal electroshock, bicuculline and picrotoxin tests at doses devoid of neurotoxic activity. Altogether, these results suggest the described compounds as a class of orally available anticonvulsants. The ability of these compounds to partially block veratridine-induced aspartate efflux from rat cortical synaptosomes suggests that their anticonvulsant activity may be only partly the consequence of an interaction with neuronal voltage-dependent sodium channels. Some of the most potent compounds appear worthy of a further investigation aimed at assessing their anticonvulsant activity in other models and at elucidating the underlying mechanism of action.     

Quantitative analysis of polyphenols and antioxidant activity in four Daphne L. species

The content of biologically active phenolic compounds (total polyphenols, tannins, flavonoids, and phenolic acids) were determined using spectrophotometry in four wild Croatian species of Daphne L. in the family Thymelaeaceae (Daphne alpina, D. cneorum, D. laureola, and D. mezereum). The concentration of total flavonoids (TF) was highest in the leaves of these Daphne species (0.12?C0.51% dry herb weight, DW) whereas the content of other phenolic compounds analyzed were highest in the roots, including total polyphenols (TP; 2.71?C19.03% DW), tannins (T; 1.14?C7.39% DW), and total phenolic acids (TPA; 0.12?C0.87% DW). D. alpina contained the highest amount of polyphenols, with the exception of flavonoids, where maximum concentrations were found in D. laureola. We also examined the antioxidant activity of leaf, stem, and root extracts. All extracts analyzed demonstrated high free radical scavenging activity with the highest concentration in the leaf extracts of D. alpina. Leaf extracts of D. cneorum showed the highest antioxidant activity in a ??-carotene bleaching assay.     

Simple N,N-dimethyl phenylsulfonamides show potent anticonvulsant effect in two standard epilepsy models

Optimization of the previously reported benzothiazine analogue A led to the identification of compound 1, which showed anti-convulsant activity in two golden standard animal models of seizure, the MES and scPTZ models. Structure-activity relationship investigation of compound 1 revealed compounds 2, 6 and 19 as attractive anti-epileptic drug (AED) candidates with potent anticonvulsant effect in both the MES and scPTZ models. As these compounds are structurally different from existing AEDs, determination of their mechanism of actions could provide clues to understanding current therapy-resistant seizures. Moreover, these simple phenylsulfoneamide compounds could be good starting points for searching broad spectrum AEDs by such in vivo screening.     

Determination of bioactive compounds in fermented soybean products using GC/MS and further investigation of correlation of their bioactivities

The active ingredients and bioactivities (anti-oxidant, anti-tyrosinase, anti-proliferative and estrogenic activities) of soybean and soybean products (Cheonggukjang, Meju, Makjang, Doenjang and soy sauce) produced by different fermentation processes were compared. There were high correlations between active ingredients and bioactivities. Free phenolic acids extracted from soybean products were identified and quantified by gas chromatography/mass spectrometry (GC/MS). Overall, the components and activities in fermented soybean products were different than those in soybeans. Total phenolic content (TPC), protein content (PC) and anti-oxidant activity increased as fermentation time increased. TPC and PC showed strong negative correlations with anti-oxidant activity. Doenjang and soy sauce, two long-term fermented products, showed lower total flavonoid content (TFC) and estrogenic activities than short-term fermented soybean products. This might be explained by the decomposition and hydrolysis of flavonoids due to the long fermentation time and high temperature. Strong anti-proliferative activity against cancer cell lines, which was highly correlated with TFC, was found in Meju and Cheonggukjang. Soybean and all fermented products except Meju exhibited effective tyrosinase inhibitory activities. Fermented products showed stronger estrogenic activity than soybeans, which was highly correlated with syringic acid.     

Antioxidant properties and phenolic profiling by UPLC-QTOF-MS of Ajwah,Safawy and Sukkari cultivars of date palm

Date palm (P. dactylifera) plays a vital role in ethnomedicinal practices in several parts of the world. There are over 2000 cultivars of date palm that differ in chemical composition and extent of bioactivity. The present study was undertaken to comparatively evaluate the antioxidant potential of three cultivars of date palm (Ajwah, Safawy and Sukkari) from Saudi Arabia and analyze their phenolic constituents in order to draw a rationale for their activity. Antioxidant activities of the date cultivars were evaluated by different quantitative methods including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging assay, total antioxidant capacity, reducing power, total phenolic (TPC), flavonoid (TFC) and tannin content (TTC), while qualitative phenolic composition was determined using ultra performance liquid chromatography coupled to quadropole time of flight mass spectrometry (UPLC-QTOF-MS). All the three date extracts showed good DPPH radical scavenging (IC₅₀ 103–177 μg/mL) and hydroxyl radical scavenging (IC₅₀ 1.1–1.55 mg/mL) activity and total antioxidant capacity (IC₅₀ 87–192 μg/mL). The reducing power was also comparable to that of ascorbic acid, used as standard in above experiments. All the three samples contain significant amount of major antioxidant components (phenolic, flavonoid and tannin) that successfully correlates with the results of radical scavenging assays. UPLC-QTOF-MS revealed a total of 22 compounds in these date cultivars classified into common phenolics, flavonoids, sterols and phytoestrogens. Significant variation in the degree of antioxidant activity of these three date cultivars can be attributed to the difference in the content and composition of phenolic compounds.     

Primary and secondary metabolism of winter wheat under cold hardening and treatment with antioxidants

The content of saccharides and phenolic compounds (including flavonoids and lignin) and the activity of L-phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) were determined in leaves and tillering nodes of winter wheat Triticum aestivum L.) cultivars Inna and Moskovskaya 39, differing in the level of frost resistance. These parameters were determined in three groups of plants—control, hardened, and treated with synthetic antioxidants (ambiol and amerol 2000). Cold hardening increased accumulation of primary and secondary metabolites in tissues but decreased the enzyme activity. Treatment with antioxidants also increased the content of saccharides and phenolic compounds (primarily flavonoids) and PAL activity. These changes were more pronounced in cultivar Inna, which is less frost resistant than Moskovskaya 39.     

Anticonvulsant, antidepressant-like activity of Abelmoschus manihot ethanol extract and its potential active components in vivo

Depression is the most common psychiatric comorbidity in patients with epilepsy. Searching for antiepileptic (anticonvulsant) and antidepressant-like medicines from natural products is very important for the treatment of this disease. The flower of Abelmoschus manihot (Linn.) Medicus has been reported to have neuroprotective effect against cerebral ischemia injury. In order to further explore the activity of Abelmoschus manihot on the central nervous system, the anticonvulsant and antidepressant-like effects of Abelmoschus manihot ethanol extract (AMEE) as well as its potential active components in vivo was investigated in the present study. It was found that AMEE could protect mice against PTZ-induced clonic convulsions and mortality. AMEE could also decrease immobility time in the FST in mice. Furthermore, the potential active components of AMEE in rat brain were identified by ultra performance liquid chromatography-mass spectrometer (UPLC-MS). Five parent components including isoquercitrin, hyperoside, hibifolin, quercetin-3′-O-glucoside, quercetin and three metabolites were detected in rat brain after administration of AMEE. In conclusion, eight flavonoids were identified in rat brain after administration of AMEE; meanwhile, these flavonoids might represent the potential bioactive components of AMEE and contribute to its anticonvulsant and antidepressant-like activity in vivo.     

Antidepressant effect and pharmacological evaluation of standardized extract of flavonoids from Byrsonima crassifolia

Byrsonima crassifolia (Malpighiaceae) has been used in traditional medicine for the treatment of some mental-related diseases; however, its specific neuropharmacological activities remain to be defined. The present study evaluates the anxiolytic, anticonvulsant, antidepressant, sedative effects produced by the extracts of Byrsonima crassifolia, and their influence on motor activity in ICR mice. Additionally, we determine the acute toxicity profiles of the Byrsonima crassifolia extracts and the presence of neuroactive constituents. Our results show that the methanolic extract of Byrsonima crassifolia produces a significant (P < 0.05) antidepressant effect in the forced swimming test in mice at 500 mg/kg dose. However, it does not possess anxiolytic, sedative, or anticonvulsant properties, and does not cause a reduction of mice locomotion (P > 0.05). Although the main compound of the methanolic extract was identified as quercetin 3-O-xyloside (12 mg/kg), our findings suggest that flavonoids, such as rutin (4.4 mg/kg), quercetin (1.4 mg/kg) and hesperidin (0.7 mg/kg), may be involved in the antidepressant effects. To the best of our knowledge, the present study constitutes the first report on the presence of the flavonoids with neuropharmacological activity rutin and hesperidin in Byrsonima crassifolia. In conclusion, the present results showed that the methanolic extract standardized on flavonoids content of Byrsonima crassifolia possesses potential antidepressant-like effects in the FST in mice, and could be considered as relatively safe toxicologically with no deaths of mice when orally administered at 2000 mg/kg.     

Host-hemiparasite transfer of the C-glucosyl xanthone mangiferin between Mangifera indica and Dendrophthoe falcata

Abstract

To test the hypothesis that higher antioxidant potential of hemiparasitic plants is due to sequestration of phenolic compounds from the host plants, samples of Dendrophthoe falcata, a hemiparasite collected from different hosts, were investigated for total phenolics, total flavonoids and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging activity. The hosts significantly influenced the phenolic content of the hemiparasite. However, similar influence was not detected on radical scavenging activity and no correlation was found in the phenolics and free radical scavenging activities. Further investigation on transfer of constituents revealed that D. falcata sample obtained from a host, Mangifera indica, contained mangiferin, a C-glucosyl xanthone, and some unidentified flavonoids as confirmed by HPTLC flavonoid patterns. The data indicated that the hosts significantly affected total phenolics and total flavonoids in a hemiparasite. This is the first report of transfer of mangiferin from M. indica to a hemiparasite. The present report points towards the need of further investigations on the possible role of transferred phenolics either as mediators of host defense, host defense compounds utilized as cues of identification of the host by the hemiparasite or compounds taken up by the parasites to support their defense against rejection by the hosts.     

Design,synthesis, in vivo,and in silico evaluation of new coumarin-1,2,4-oxadiazole hybrids as anticonvulsant agents

A novel series of coumarin-1,2,4-oxadiazole hybrids were designed, synthesized, and evaluated as anticonvulsant agents. The title compounds were easily synthesized from reaction of appropriate coumarins and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazole derivatives. In vivo anticonvulsant activity of the synthesized compounds were determined using pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures confirming that they were more effective against MES test than PTZ test. It should be noted that compounds 3b, 3c, and 3e showed the best activity in MES model which possessed drug-like properties with no neurotoxicity. Anticonvulsant activity of the most potent compound 3b was remarkably reduced after treatment with flumazenil which confirmed the participation of a benzodiazepine mechanism in the anticonvulsant activity. Also, docking study of compound 3b in the BZD-binding site of GABA_A receptor confirmed possible binding of 3b to the BZD receptors.     

Influence of cranberry phenolics on glucan synthesis by glucosyltransferases and Streptococcus mutans acidogenicity

AIMS: To investigate the influence of several phenolic compounds isolated from cranberry fruit (Vaccinium macrocarpon) on some of the virulence properties of Streptococcus mutans associated with glucan synthesis and acidogenicity. METHODS AND RESULTS: Individual phenolic acids, flavonols and proanthocyanidins were isolated by semi-preparative high-performance liquid chromatography from fresh cranberry fruit. Flavonols and proanthocyanidins (at 500 micromol l(-1)) moderately inhibited the activity of surface-adsorbed glucosyltransferases (GTFs) B and C and F-ATPases (15-35% inhibition; P < 0.05), and also disrupted acid production by S. mutans cells without affecting bacterial viability. Phenolic acids displayed minimal biological effects. Quercetin-3-arabinofuranoside, myricetin and procyanidin A2 displayed the most inhibition of S. mutans virulence traits; a combination of these compounds displayed enhanced effects. CONCLUSIONS: Specific flavonoids from cranberries exhibit statistically significant but moderate biological activity against S. mutans. The biological activity of cranberry extracts may be a result from the complex mixture of flavonoids rather than a single active compound. SIGNIFICANCE AND IMPACT OF STUDY: This is the first study to identify the bioactive constituents in cranberry against an oral bacterium using highly purified isolated compounds. The combined effects of specific flavonols and proanthocyanidins from cranberry on GTFs activity, acid production and acid tolerance of S. mutans make them attractive compounds to fully explore for their anti-biofilm and cariostatic properties.     

Design,synthesis, in vivo and in silico evaluation of phenacyl triazole hydrazones as new anticonvulsant agents

A series of phenacyl triazole hydrazones 3 have been designed based on the hybridization of (arylalkly)triazole and aroyl hydrazone scaffolds as new anticonvulsant agents. The target compounds 3 were easily synthesized from appropriate phenacyl triazoles and aryl acid hydrazides and characterized by IR, NMR and Mass spectroscopy. The in vivo anticonvulsant evaluation of synthesized compounds by using MES and PTZ tests revealed that they are more effective in MES model respect to PTZ test. All compounds showed 33–100% protection against MES-induced seizures at the dose of 100 mg/kg. However, the isonicotinic acid hydrazide derivative 3h showed the best profile of activity in both models. Molecular docking studies of compound 3h with different targets (NMDA, AMPA, GABA_A and sodium channel), postulated that the compound acts mainly via GABA_A receptors. In silico molecular properties predictions indicated that all compounds have favourable oral bioavailability and BBB permeability.     

Variation in antioxidant properties and phenolics concentration in different organs of wild growing and greenhouse cultivated Castilleja tenuiflora Benth.

The content of total phenolic compounds and flavonoids was determined in methanol extracts of root, stem, leaves, and inflorescences from wild growing and greenhouse cultivated plants of Castilleja tenuiflora. The antioxidant activity in each extract was evaluated using three in vitro models: scavenging of free radicals with 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS), and reducing power by the phosphomolybdenum assay. Both, antioxidant activity and phytochemicals content were influenced significantly (P < 0.05) by the source of the plant material and the organ. Cultivated plants had the highest content of phenolic compounds (37.95 mg gallic acid equiv. g^?1 dry weight, P < 0.05) and the strongest antioxidant activity. Total phenolic compounds content correlated significantly with the antioxidant activity for all studied plant material and organs (P < 0.05). TLC profile using DPPH as a detection reagent indicated that the phenylethanoids verbascoside and isoverbascoside are the main contributors to the free-radical scavenging of C. tenuiflora. Cultivated plants of C. tenuiflora are an alternative source of natural antioxidants to wild growing plants. The antioxidant properties of C. tenuiflora may be associated with its traditional use to treat conditions consistent with radical-related diseases (e.g. inflammation, tumors).     

Content of different groups of phenolic compounds in microshoots of Juglans regia cultivars and studies on antioxidant activity

Phenolic and other compounds were extracted from micropropagated axillary shoots (microshoots) of the walnut (Juglans regia L.) cultivars ‘Chandler’, ‘Howard’, ‘Kerman’, ‘Sunland’, and ‘Z₆₃’. Among cultivars, microshoots showed differences in phenolic compounds, phenolic acids, flavonoids, and proanthocyanidins. All cultivars contained the phenolics acids chlorogenic acid, gallic acid, p-coumaric acid; the naphthoquinone juglone; and the flavonoid quercetin. The phenolic acids syringic acid and vanillin were present only in microshoots of ‘Howard’. Microshoot extracts had different antioxidant activity with ‘Kerman’ the highest and ‘Chandler’ the lowest in each of three antioxidant assays: the phosphomolybdenum assay (PPM), reducing power assay, and 2,2-diphenyl-1-picrylhydrazyl-scavenging effect. There was a strong linear relationship between total phenolic compound content of microshoots and increasing antioxidant activity.     

The chemical constituents and economic plants of the Euphorbiaceae

The chemical constituents and economic plants of the Euphorbiaceae. A chemical review of the different classes of compounds which have been isolated from the Euphorbiaceae (other than the diterpenoids) is given. This includes triterpenoids and related compounds (sterols, alcohols and hydrocarbons), phenolic compounds (flavonoids, lignans, coumarins, tannins, phenanthrenes, quinones, phenolic acids, etc.), alkaloids, cyanogenic glucosides and glucosinolates. A summary of the industrial and medicinal uses of members of the Euphorbiaceae is provided.