Design and comparative anticonvulsant activity assessment of CNS-active alkyl-carbamoyl imidazole derivatives

A novel series of carbamoyl derivatives of alkylimidazole has been designed and their anticonvulsant activity was comparatively evaluated in the mice- and rats-maximal-electroshock (MES), subcutaneous-metrazol (scMet) seizure tests and the mice-6 Hz psychomotor (6 Hz) models. The ten new designed molecules contain in their chemical structure imidazole, alkyl side-chain and carbamate as three potential active moieties.In spite of the close structural features of the carbamoyl imidazole derivatives only compounds 7, 8, 13 and 16 were active at the MES test with ED₅₀ values ranging from 12 to 20 mg/kg coupled with high protective index (PI = TD₅₀/ED₅₀) values of 4.1–7.3 after ip administration to rats. A similar phenomenon was observed in mice where compounds 7, 8, 9, 12 had MES-ED₅₀ values of 14–26 mg/kg. Compounds 7 and 13 also demonstrated anticonvulsant activity in the 6 Hz model with ED₅₀ values of 32 and 44 mg/kg, respectively. As the most active entities, compounds 7, 8 followed by 13 and 16, thus offer an optimal efficacy–safety profile and consequently, might be promising candidates for development as new antiepileptics.     

Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-substituted thiazolidin-3ylamino)ethyl)benzamide derivatives as anticonvulsant agents

Herewith, we report the design and synthesis of a series of N-(2-oxo-2((4-oxo-2-substituted thiazolidin-3yl)amino)ethyl) benzamide derivatives 7(a–j) under microwave irradiation, based on four component pharmacophoric model to get structural prerequisite indispensable for anticonvulsant activity. The synthesized derivatives were investigated in maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (sc-PTZ) induced seizure and neurotoxicity screening. All the test compounds were administered at a dose of 30, 100 and 300 mg/kg body weight at the time interval of 0.5 h and 4 h. The compounds were also evaluated for behavioral activity and toxicity study. The compound 7h was found to be most active in MES model. The anticonvulsant screening data shows that 65% of the compounds were found active against MES model when compared to 35% sc-PTZ model. The computational parameter such as docking study, log P determination and ADME prediction were performed to exploit the results.     

Synthesis and anti-hyperglycemic activity of hesperidin derivatives

A series of hesperidin derivatives were prepared and identified by IR, ¹H NMR, and MS spectra. These compounds were evaluated in vitro and in vivo based on α-glucosidase inhibition, glucose consumption of HepG2 cells, and blood glucose level in streptozotocin-induced diabetic mice. The results revealed that all the compounds exhibited anti-hyperglycemic activities. The inhibition at 10^?3 M of compounds 3 and 7a on α-glucosidase were 55.02% and 53.34%, respectively, as compared to 54.80% by acarbose. Treated by compound 3 and the reference drug metformin, glucose consumption of HepG2 cell were 1.78 and 2.11 mM, respectively. After the streptozotocin-induced diabetic mice were oral administrated with compound 3 at 100 mg kg^?1 d^?1 for 10 days, the blood glucose level of 3 treated mice (13.23 mM, P <0.05) showed significant difference when compared to model control (23.03 mM). Thus, compound 3 exhibited promising anti-hyperglycemic activity.     

Synthesis,and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids

This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED₅₀ = 32.08 mg/kg, MES test) and 9 (ED₅₀ = 40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action.     

Response of native grasses and Cicer arietinum to soil polluted with mining wastes: Implications for the management of land adjacent to mine sites

Mine tailings are an environmental problem in Southern Spain because wind and water erosion of bare surfaces results in the dispersal of toxic metals over nearby urban or agricultural areas. Revegetation with tolerant native species may reduce this risk. We grew two grasses, Lygeum spartum and Piptatherum miliaceum, and the crop species Cicer arietinum (chickpea) under controlled conditions in pots containing a mine tailings mixed into non-polluted soil to give treatments of 0%, 25%, 50%, 75% and 100% mine tailings. We tested a neutral (pH 7.4) mine tailings which contained high concentrations of Cd, Cu, Pb and Zn. Water-extractable metal concentrations increased in proportion to the amount of tailings added. The biomass of the two grasses decreased in proportion to the rate of neutral mine-tailing addition, while the biomass of C. arietinum only decreased in relation to the control treatment. Neutron radiography revealed that root development of C. arietinum was perturbed in soil amended with the neutral tailings compared to those of the control treatment, despite a lack of toxicity symptoms in the shoots. In all treatments and for all metals, the plants accumulated higher concentrations in the roots than in shoots. The highest concentrations occurred in the roots of P. miliaceum (2500 mg kg^?1 Pb, 146 mg kg^?1 Cd, 185 mg kg^?1 Cu, 2700 mg kg^?1 Zn). C. arietinum seeds had normal concentrations of Zn (70–90 mg kg^?1) and Cu (6–9 mg kg^?1). However, the Cd concentration in this species was ～1 mg kg^?1 in the seeds and 14.5 mg kg^?1 in shoots. Consumption of these plant species by cattle and wild fauna may present a risk of toxic metals entering the food chain.     

Facile synthesis of new imidazo[1,2-a]pyridines carrying 1,2,3-triazoles via click chemistry and their antiepileptic studies

The present article reports the synthesis and anticonvulsant studies of new 2-arylimidazo[1,2-a]pyridines carrying suitably substituted 1,2,3-triazoles as well as their intermediates. The structures of newly synthesized compounds were confirmed by various spectroscopic techniques. The anticonvulsant study was carried out by MES and scPTZ screening methods, while their toxicity study was performed following Rotarod method. The active compounds showed enhanced seizure control in scPTZ method when compared with that of MES method. Compounds 3f, 4c, 4f, 5k, 5p and 5w carrying active pharmacophores exhibited complete protection against seizure and their results were comparable with standard drug diazepam. Majority of new compounds were found to be non-toxic, while few of them showed toxicity at 100 mg/kg. The c log P values of target compounds are in the range of 3.5–5.3, which confirm their lipophilic nature.     

Chemotherapy of leishmaniasis. Part XII: Design,synthesis and bioevaluation of novel triazole integrated phenyl heteroterpenoids as antileishmanial agents

A novel series of triazole integrated phenyl heteroterpenoids have been synthesized and screened for their in vitro activity against intracellular amastigote form of Leishmania donovani. Among all tested compounds, compound 3a was found to be the most active with IC₅₀ 6.4 μM and better selectivity index (SI) 18 as compared to reference drugs, miltefosine and miconazole. When evaluated in vivo in L. donovani/hamster model, 3a has exhibited 79 ± 11% inhibition of parasite multiplication at 50 mg kg^?1 × 5 days on day 7 post treatment.     

Biodegradation of Tapis blended crude oil in marine sediment by a consortium of symbiotic bacteria

Biodegradation rate and the high molecular weight hydrocarbons are among the important concerns for bioremediation of crude oil. Inoculation of a non-oil-degrading bacterium as supplementary bacteria increased oil biodegradation from 57.1% to 63.0% after 10 days of incubation. Both the oil-degrading bacteria and the non-oil-degrading bacteria were isolated from Malaysian marine environment. Based on the 16S rDNA sequences, the oil-degrading bacteria was identified as Pseudomonas pseudoalcaligenes (99% similarity) while the non-oil-degrading bacterium was Erythrobacter citreus (99% similarity). E. citreus does not grow on crude oil enriched medium under present experimental condition but it withstands 5000 mg kg^?1 Tapis blended crude oil in sediment. Under optimal condition, the oil-degrading bacterium; P. pseudoalcaligenes, alone utilized 583.3 ± 3.8 mg kg^?1 (57.1%) at the rate of 3.97 × 10^?10 mg kg^?1 cell^?1 day^?1 Tapis blended crude oil from 1000 mg kg^?1 oil-contaminated sediment. Inoculation of E. citreus as the supplementary bacteria to P. pseudoalcaligenes enhanced biodegradation. The bacterial consortium degraded 675.8 ± 18.5 mg kg^?1 (63.0%) Tapis blended crude oil from the 1000 mg kg^?1 oil-contaminated sediment. Biodegradation rate of the bacterial consortium increased significantly to 4.59 × 10^?10 mg kg^?1 cell^?1 day^?1 (p = 0.02). Improvement of the oil degradation by the bacterial consortium was due to the synergetic reaction among the bacterial inoculants. There are two implications: (1) E. citreus may have a role in removing self-growth-inhibiting compounds of P. pseudoalcaligens. (2) P. pseudoalcaligenes degraded Tapis blended crude oil while E. citreus competes for the partially degraded hydrocarbons by P. pseudoalcaligenes. P. pseudoalcaligenes forced to breakdown more hydrocarbons to sustain its metabolic requirement. The bacterial consortium degraded 78.7% of (C₁₂–C₃₄) total aliphatic hydrocarbons (TAHs) and 74.1% of the 16 USEPA prioritized polycyclic aromatic hydrocarbons.     

Arsenic reduced scale-insect infestation on arsenic hyperaccumulator Pteris vittata L.

Arsenic hyperaccumulation by Pteris vittata L. (Chinese brake fern) may serve as a defense mechanism against herbivore attack. This study examined the effects of arsenic exposure (0, 5, 15 and 30 mg kg^?1) on scale insect (Saissetia neglecta) infestation of P. vittata. Scale insects were counted as a percentage fallen from the plant to the total number of insects after 1 week of As-treatment. The arsenic concentrations in the fronds ranged from 5.40 to 812 mg kg^?1. Greater arsenic concentrations resulted in higher percentage of fallen-scale insects (17.2–55.0%). Lower arsenic concentrations (≤5 mg kg^?1) showed significantly lower effect on the population compared to 15–30 mg kg^?1 (p < 0.05). Arsenic content in the fallen-scale insects was as high as 194 mg kg^?1, which indicated that arsenic has been ingested by the scale insects via plant sap. This study is consistent with the hypothesis that arsenic may help P. vittata defend against herbivore's attack.     

Selenium induced anticonvulsant effect: A potential role of prostaglandin E1 receptor activation linked mechanism

ProjectSelenium deficiency has been associated with enhanced propensity of seizures in man and laboratory animals. Therefore, the present study has been designed to investigate the anti-convulsant effect of sodium selenite and seleno-dl-methionine on pentylenetetrazole induced seizures in mice and the role of prostaglandin receptor activation in the proposed anticonvulsant effect of sodium selenite.ProcedureSodium selenite (1, 3 and 10 mg kg^?1, i.p.) and seleno-dl-methionine (0.3, 1 and 3 mg kg^?1, i.p.) was used to evaluate the potential effect on pentylenetetrazole induced seizures in mice. Pentylenetetrazole induced seizures were assessed in terms of onset time of straub's tail phenomenon, jerky movements of the whole body and convulsions. Additionally, an isobolographic study design was used to examine the interaction between sodium selenite and celecoxib (a cyclooxygenase-2 inhibitor). Sodium selenite and seleno-dl-methionine significantly attenuated pentylenetetrazole induced seizures in mice.ResultsPrior administration of misoprostol (a selective agonist of prostaglandin E₁ receptors) markedly attenuated the anticonvulsant effect of sodium selenite as well as seleno-dl-methionine in mice. However, the administration of misoprostol per se did not produce any behavioral changes. Further, sodium selenite was observed to exert a synergistic interaction with celecoxib.ConclusionsSelenium induced reduction in seizure like behavior might be ascribed to the activation of a prostaglandin E₁ receptor activation linked mechanism. It is further proposed that sodium selenite exerts a synergistic anti-convulsant effect with celecoxib indicating the therapeutic usefulness of combining the two agents to treat epilepsy.     

Toward scrubbing the bay: Nutrient removal using small algal turf scrubbers on Chesapeake Bay tributaries

Restoration of the Chesapeake Bay poses significant challenges because of increasing population pressure, conversion of farmland to urban/suburban development, and the expense of infrastructure needed to achieve significant and sustained nutrient reductions from agricultural and urban sources. One radical approach for removing non-point source nutrients before they reach the bay is to deploy large-scale algal turf scrubbers along its tributaries. The objective of this study was to determine rates of nutrient removal and algal fatty acid production using small ATS units located along three Chesapeake Bay rivers. Small-scale ATS units (each containing 1 m² growing area) were operated for 5–10 months from April 2007 to April 2008 on three western shore tributaries of the Chesapeake Bay in Maryland: the Bush River, the Patapsco River and the Patuxent River. Total nitrogen (TN) and total phosphorus (TP) removal rates at the Patuxent site fluctuated considerably but averaged 250 mg TN, 45 mg TP m^?2 day^?1 from May to October 2007, then decreased to 16 mg TN, 3 mg TP m^?2 day^?1 from December 2007 to February 2008. Nutrient removal rates at the Bush river site also fluctuated but averaged only 85 mg TN, 10 mg TP m^?2 day^?1 from May to June 2007, before decreasing to <10 mg TN, <1 mg TP m^?2 day^?1 from July to September 2007. The Patapsco River unit began operation in August 2007, reached its maximum removal values of 150 mg TN, 18 mg TP m^?2 day^?1 from mid-October to late-November 2007, then decreased to values of 45 mg TN, 4 mg TP m^?2 day^?1 from November 15, 2007 to mid-April 2008. In the best case (Patuxent site from May to October 2007), daily removal rates of 250 mg N and 45 mg P m^?2 are equivalent to removal rates of 380 kg N and 70 kg P ha^?1 over a 150-day season in Maryland. Fatty acid (FA) content of the harvested material was consistently low (0.3–0.6% of dry weight) and varied little between sites. Mean algal FA production rates (23–54 mg FA m^?2 day^?1) are equivalent to rates of 34–81 kg FA ha^?1 year^?1 based on a 150-day operational season in Maryland.     

Recycling of agro-industrial sludge through vermitechnology

This work illustrates the feasibility of vermitechnology to stabilize sludge from an agro-industry. To achieve the goal, industrial sludge (IS) was mixed with three different bulky agents, i.e. cow dung (CD), biogas plant slurry (BGS) and wheat straw (WS), in different ratios to produce nine different feed mixtures for earthworm Eisenia fetida. Vermicomposting bedding material was analyzed for its different physic-chemical parameters after 15 weeks of experimentations. In all waste mixtures, a decrease in pH, organic C and C:N ratio, but increase in total N, available P, exchangeable K, exchangeable Ca and trace elements (Mg, Fe and Zn) was recorded. IS (40%) + CD (60%) and IS (40%) + BGS (60%) vermibeds showed the highest mineralization rate and earthworm growth patterns during vermicomposting process. Vermicompost contains (dry weight basis) a considerable range of plant available forms of P (17.5–28.9 g kg^?1), K (13.8–21.4 g kg^?1), Ca (41.1–63.4 g kg^?1), Mg (262.4–348.3 mg kg^?1), Fe (559.8–513.0 mg kg^?1) and Zn (363.1–253.6 mg kg^?1). Earthworm growth parameters, i.e. biomass gain, total cocoon production, individual growth rate (mg wt. worm^?1 day^?1), natality rate, total fecundity were optimum in bedding containing 20–40% industrial sludge. C:N ratio of worm-processed material was within the agronomic acceptable or favorable limit (<15–20). The results clearly suggested that vermitechnology can be a potential technology to convert industrial sludges into vermifertilizer for sustainable land restoration practices.     

Chemotherapy of leishmaniasis. Part XI: Synthesis and bioevaluation of novel isoxazole containing heteroretinoid and its amide derivatives

Novel isoxazole containing heteroretinoid (4) and its amide derivatives (5a–j) have been synthesized and evaluated for their in vivo antileishmanial activity against Leishmania donovani in hamsters. Compounds 3, 5a, 5d, 5k and 5l inhibited 70–76% parasite growth at 50 mg kg^?1 × 5 days. The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent.     

Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety

A series of new xanthone derivatives with piperazine moiety [1–7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT_1A, 5-HT₆ and 5-HT_7b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT_1A receptors (K_i = 24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.     

Synthesis,vasorelaxant activity and antihypertensive effect of benzo[d]imidazole derivatives

A series of 1H-benzo[d]imidazole analogues of Pimobendan, substituted at position 5 with either –CF₃ or –NO₂, were synthesized using a short synthetic route. All the nitro derivatives were potent, and exhibited a concentration- and partial endothelium-dependent vasorelaxant effects, with EC₅₀s <5 μM. 2-Methoxy-4-[5-nitro-1H-benzo[d]imidazol-2-yl]phenol (compound 13) was the most potent derivative of the series, showing an EC₅₀ value of 1.81 μM and E_max of 91.7% for ex vivo relaxant response in intact aortic rings, resulting in a 2.5-fold higher activity compared to Pimobendan. The closely related 5-CF₃ analogue (compound 8), was 19 times less potent than 13. The antihypertensive activity of compound 13 was evaluated at doses of 25, 50 and 100 mg kg^?1, using spontaneously hypertensive rats (SHR), showing a statistically significant dose-dependent effect.     

Beef cattle pasture to wetland reconversion: Impact on soil organic carbon and phosphorus dynamics

There is a major need to understand the historical condition and chemical/biological functions of the ecosystems following a conversion of wetlands to agricultural functions. To better understand the dynamics of soil total organic carbon (TOC) and phosphorus (P) during beef cattle pastures to wetland reconversion, soil core samples were collected from the beef cattle pasture and from the natural wetland at Plant City, FL, during five summer seasons (2002–2007). The levels of TOC and soil P were significantly affected by changing land use and hydrology. Draining natural wetlands to grazed pastures resulted in very pronounced reduction of TOC from 180.1 to 5.4 g g^?1. Cumulative concentrations of total phosphorus (TP) in soils (1134 mg kg^?1) under drained condition are two to three times lower than those in soils (2752 mg kg^?1) under flooded condition over the periods of land use reconversion. There was a declining trend (r = 0.82**; p ≤ 0.01) in total soil P from natural wetland (763 mg kg^?1) to altered pastures (340 mg kg^?1), largely as organic-bound P (natural wetland, 48%; grazed pastures, 44%; altered pastures, 29%). These results are important in establishing baseline information on soil properties in pasture and wetland prior to restoring and reconverting pasture back to wetland conditions. The results further suggest that changes in soil properties due to changing land use and hydrologic conditions (drying and re-wetting) could be long lasting.     

Lead,zinc, cadmium hyperaccumulation and growth stimulation in Arabis paniculata Franch

Metal hyperaccumulation is of great interest in recent years because of its potential application for phytoremediation of heavy metal contaminated soils. In this study, a field survey and a hydroponic experiment were conducted to study the accumulation characteristics of lead (Pb), zinc (Zn) and cadmium (Cd) in Arabis paniculata Franch., which was found in Yunnan Province, China. The field survey showed that the wild population of A. paniculata was hyper-tolerant to extremely high concentrations of Pb, Zn and Cd, and could accumulate in shoots an average level of 2300 mg kg^?1 dry weight (DW) Pb, 20,800 mg kg^?1 Zn and 434 mg kg^?1 Cd, with their translocation factors (TFs) all above one. Under the hydroponic culture, stimulatory effects of Pb, Zn and Cd on shoot dry biomass were noted from 24 to 193 μM Pb, 9 to 178 μM Cd and all Zn supply levels in nutrient solution, while the effects were not obvious in the roots. Chlorophyll concentrations in Pb, Zn and Cd treatments showed an inverted U-shaped pattern, consistent with the change of plant biomass. Pb, Zn and Cd concentrations in the shoots and roots increased sharply with increasing Pb, Zn and Cd supply levels. They reached > 1000 mg kg^?1 Pb, 10,000 mg kg^?1 Zn and 100 mg kg^?1 Cd DW in the 24 μM Pb, 1223 μM Zn and 9 μM Cd treatment, respectively, in which the plants grew healthy and did not show any symptoms of phytotoxicity. The TFs of Zn were basically higher than one and the amount of Zn taken by shoots ranged from 78.7 to 90.4% of the total Zn. However, the TFs of Pb and Cd were well below one, and 55.0–67.5% of total Pb and 57.8–83.5% of total Cd was accumulated in the shoots. These results indicate that A. paniculata has a strong ability to tolerate and hyperaccumulate Pb, Zn and Cd. Meanwhile, suitable levels of Pb, Zn and Cd could stimulate the biomass production and chlorophyll concentrations of A. paniculata. Thus, it provides a new plant material for understanding the mechanisms of stimulatory effect and co-hyperaccumulation of multiple heavy metals.     

Evaluation of phosphorus distribution and bioavailability in sediments of a subtropical wetland reserve in southeast China

The phosphorus (P) fractions and bioavailable P in the sediments from the Quanzhou Bay Estuarine Wetland Nature Reserve were investigated using chemical extraction methods for the first time to study the distribution and bioavailability of P in the reserve sediments. A hypothesis was presented suggesting that the bioavailable P in the sediments could be evaluated using the P fractions. The total phosphorus (TP), inorganic phosphorus (IP), organic phosphorus (OP), non-apatite phosphorus (NAIP), and apatite phosphorus (AP) contents in the sediments were in the ranges of 303.87–761.59 mg kg⁻¹, 201.22–577.66 mg kg⁻¹, 75.83–179.16 mg kg⁻¹, 28.86–277.90 mg kg⁻¹, and 127.36–289.94 mg kg⁻¹, respectively. The water soluble phosphorus (WSP), readily desorbable phosphorus (RDP), algal available phosphorus (AAP), and NaHCO₃ extractable phosphorus (Olsen-P) contents in the sediments were in the ranges of 0.58–357.17 mg kg⁻¹, 80.77–586.75 mg kg⁻¹, 1.09–24.12 mg kg⁻¹, and 54.96–676.82 mg kg⁻¹, respectively. The correlation analysis results showed that the NAIP was the major component of the bioavailable P and that the impact of the AP on the bioavailable phosphorus may be minimal. Due to the low TP content in the sediments of the Quanzhou Bay Estuarine Wetland Nature Reserve, the potential pollution risks of P in the sediments may not be very high. The results also show that the bioavailable P concentrations in the sediments of the Quanzhou Bay Estuarine Wetland Nature Reserve could not be evaluated by measuring the P fractions and that the hypothesis was untenable.     

Inhibitory effects of taurine and oat fiber on intestinal endotoxin release in rats

Numerous studies have demonstrated that endotoxin plays an important role in the development and progression of hepatic cirrhosis. However, there is no effective remedy for the prevention and treatment of intestinal endotoxemia. Taurine has been reported to have beneficial effects on endotoxemia. Oats have been shown to absorb intestinal toxins and increase excretion of intestinal toxins. The present study was to investigate whether a combination of taurine and oat has an additive inhibitory effect on endotoxin release in a rat liver ischemia/reperfusion model. Our results showed that the combination of taurine (300 mg kg^?1 d^?1) and oat fiber (15 g kg^?1 d^?1) significantly reduced endotoxin levels in the portal vein by 36.3% when compared to the control group (0.168 ± 0.035 Eu/ml in the treatment group vs 0.264 ± 0.058 Eu/ml in the control group, P < 0.01). The treatment of taurine (300 mg kg^?1 d^?1) and oat fiber (15 g kg^?1 d^?1) induced 21.5% and 18.4% reduction in endotoxin levels, respectively, when compared to the control group (P < 0.05). We conclude that the combination of taurine and oat fiber achieved an additive inhibitory effect on intestinal endotoxin release, which might be an effective approach for the treatment of intestinal endotoxemia.     

Chlorophenoxy aminoalkyl derivatives as histamine H3R ligands and antiseizure agents

A series of twenty new chlorophenoxyalkylamine derivatives (9–28) was synthesized and evaluated on their binding properties at the human histamine H₃ receptor (hH₃R). The spacer alkyl chain contained five to seven carbon atoms. The highest affinities have shown the 4-chloro substituted derivatives 10 and 25 (K_i = 133 and 128 nM, respectively) classified as antagonists in cAMP accumulation assay (EC₅₀ = 72 and 75 nM, respectively). Synthesized compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Two compounds (4-chloro substituted derivatives: 20 and 26) were the most promising and showed in the MES seizure model in rats (after ip administration) ED₅₀ values of 14 mg/kg and 13.18 mg/kg, respectively. Protective indexes (PI = TD₅₀/ED₅₀) were 3.2 for 20 and 3.8 for 26. Moreover, molecular modeling and docking studies were undertaken to explain affinity at hH₃R of target compounds, and the experimentally and in silico estimation of properties like lipophilicity and metabolism was performed. Antiproliferative effects have been also investigated in vitro for selected compounds (10 and 25). These compounds neither possessed significant antiproliferative and antitumor activity, nor modulated CYP3A4 activity up to concentration of 10 μM.