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Zhe-shan Quan - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Anticonvulsant Activity Evaluation of 3-alkoxy-4-(4- (hexyloxy/heptyloxy)phenyl)-4H-1,2,4 -triazole
Iranian journal of pharmaceutical research : IJPR, 2015Co-Authors: Yingquan Fang, S-b Wang, Chunling Sun, Da-chuan Liu, Zhe-shan QuanAbstract:A series of 3-alkoxy-4-(4-(hexyloxy/heptyloxy) phenyl)-4H-1,2,4-triazole was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with maximal electroshock (MES) test and rotarod tests with intraperitoneally injected mice. Among the synthesized compounds, compound 3-heptyloxy-4-(4-(hexyloxy) phenyl)-4H-1,2,4-triazole (5f) was the most active one and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED50) of 37.3 mg/Kg, median toxicity dose (TD50) of 422.5 mg/Kg, and the protective index (PI) of 11.3 which is much greater than the reference drug carbamazepine with PI value of 6.4. As well as demonstrating the anti-MES efficacy of compound 5f, its potency against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline were also established, with the results suggesting that GABA-mediated mechanisms might be involved in its anticonvulsant activity, such as enhancing of GABAergic neurotransmission or activity, activate GAD or inhibit GABA-T, and GABAA-mediated mechanisms.
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Synthesis and anticonvulsant activity evaluation of 4-(2-alkoxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones in various experimental seizure models in mice.
Drug research, 2013Co-Authors: X Cao, X-q Deng, B Shu, S-b Wang, Zhe-shan QuanAbstract:A new series of 4-(2-alkoxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones was synthesized using appropriate synthetic route. Their anticonvulsant activities were evaluated experimentally against maximal electroshock test and their neurotoxicities were evaluated under the rotarod neurotoxicity test with intraperitoneally injected mice. The results showed that all target compounds exhibited anticonvulsant activity in varying degrees against maximal electroshock test. Among them, 4-(2-octyloxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5 g) was the most promising compound with the median effective dose (ED50) of 23.7 mg/kg, the median toxicity dose (TD50) of 611.0 mg/kg, and the protective index (PI) of 25.8. Compound 5 g showed the higher safety than the standard carbamazepine (PI=6.5). As well as demonstrating the anti-MES efficacy of compound 5 g, its potency against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline were also established, with the results suggesting that GABA-mediated mechanisms might be involved in its anticonvulsant activity.
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synthesis and primary anticonvulsant activity evaluation of 6 alkyoxyl tetrazolo 5 1 a phthalazine derivatives
Drug Research, 2011Co-Authors: Xianqing Deng, Zhe-shan QuanAbstract:A new series of 6-alkyoxyl-tetrazolo[5,l- a ] phthalazine derivatives (4 a-4 o) were synthesized as potential anticonvulsant agents. Anticonvulsant activity was evaluated by the maximal electroshock (MES) test. Neurotoxicity was evaluated by the rotarod neurotoxicity test. The pharmacological results showed that 6-(4-chlorophenyoxyl) - tetrazolo [5,1- a ] phthalazine (4 m) was the most potent agent, with a median effective dose (ED 50 ) of 6.8 mg/kg and a median neurotoxic dose (TD 50 ) of 456.4 mg/kg. The protective index (PI = TD50/ED50) for compound 4 m was 67.1, which was significantly higher than that for the reference drug carbamazepine (PI = 6.4).
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Synthesis and anticonvulsant activity of 1-formamide-triazolo[4,3-a]quinoline derivatives.
Archives of pharmacal research, 2010Co-Authors: Cheng-xi Wei, Xianqing Deng, Kyu Yun Chai, Zhi-gang Sun, Zhe-shan QuanAbstract:Using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material, a series of 1-formamide-triazolo[4, 3-a]quinoline derivatives (6a-6n) was synthesized, the anticonvulsant effect and neurotoxicity of the compounds was calculated with maximal electroshock test and rotarod tests with intraperitoneally injected in KunMing mice. The results demonstrated that compound 7-(hexyloxy)-4,5-dihydro-[1,2,4] triazolo[4,3-a]quinoline-1-carboxamide (6d) was the most active one and also had the lowest toxicity. In the anti-maximal electroshock potency test, it showed median effective dose (ED50) of 30.1 mg/kg, median toxicity dose (TD50) of 286 mg/kg, and the protective index of 9.5 which is greater than the reference drug carbamazepine with the protective index value of 6.0.
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Synthesis and anticonvulsant activity of a new 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine
European journal of medicinal chemistry, 2010Co-Authors: Li-ping Guan, Xianqing Deng, Xin Sui, Ying-chun Quan, Zhe-shan QuanAbstract:A series of 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine derivatives were synthesized. In initial screening and quantitative evaluation, compound 2r was among the most active agents, exhibiting in the same time the lowest toxicity. In the anti-maximal electroshock test, it showed median effective dose (ED50) of 17.3 mg/kg and median toxicity dose (TD50) of 380.3 mg/kg, and the protective index (PI) of 22.0, which is much better than PI of the reference drugs. In a subsequent test, compound 2r had median hypnotic dose (HD50) of 746.6 mg/kg, thus demonstrating much better margin of safety compared to reference drugs. Compound 2r also showed oral activity against MES-induced seizures and lower oral neurotoxicity. For explanation of the putative mechanism of action, compound 2r was tested in chemical induced models.
Li-ping Guan - One of the best experts on this subject based on the ideXlab platform.
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Structure-based design, synthesis, and anticonvulsant activity of isatin-1- N -phenylacetamide derivatives
Medicinal Chemistry Research, 2013Co-Authors: Chao Xie, Li-ping Guan, Li-ming Tang, Cheng-yan Pan, Si-hong WangAbstract:In an effort to develop the potent anticonvulsant agents, a series of novel isatin-1-N-phenylacetamide derivatives was synthesized and screened for their in vivo anticonvulsant activity against maximal electroshock test and evaluated for their neurotoxicity by the rotarod test at the same dose levels. Ten compounds exhibited the anticonvulsant activity. 2-(5-Methyl-2,3-dioxoindolin-1-yl)-N-phenylacetamide (4b) was found to be the most potent compound of the series with an ED50 of 91.3 mg/kg, TD50 of >1,000 mg/kg, a higher protective index (PI = TD50/ED50, >11) was gained than the reference drug phenobarbital and carbamazepine. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.
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Design, synthesis and anticonvulsant activity evaluation of 7-substituted-[1,2,4]-triazolo[4,3-f]pyrimidine derivatives.
Medicinal chemistry (Shariqah (United Arab Emirates)), 2012Co-Authors: Li-ping Guan, Xin Sui, Yue Chang, Zheng-shun Yan, Guozhong TongAbstract:In this study, a novel series of 7-substituted-[1,2,4]triazolo[4,3-f]pyrimidine derivatives was synthesized as potential anticonvulsant agents. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test, and their neurotoxicities were evaluated by the rotarod neurotoxicity test. The pharmacological results showed that the compound 3i (7-(4-chlorophenoxy)-[1,2,4]triazolo[4,3-f]pyrimidine) was among the most active agent with median effective dose (ED50) value of 34.7 mg/kg, median toxicity dose (TD50) of 262.9 mg/kg, and providing a protective index (PI=TD50 /ED50) value of 7.6. The compound 3i also showed oral activity against MES-induced seizures and lower oral neurotoxicity. The compound 3i demonstrated antagonistic activity against seizures induced by PTZ, ISN, 3-MP and thiosemicarbazide.
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Synthesis and anticonvulsant activity of a new 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine
European journal of medicinal chemistry, 2010Co-Authors: Li-ping Guan, Xianqing Deng, Xin Sui, Ying-chun Quan, Zhe-shan QuanAbstract:A series of 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine derivatives were synthesized. In initial screening and quantitative evaluation, compound 2r was among the most active agents, exhibiting in the same time the lowest toxicity. In the anti-maximal electroshock test, it showed median effective dose (ED50) of 17.3 mg/kg and median toxicity dose (TD50) of 380.3 mg/kg, and the protective index (PI) of 22.0, which is much better than PI of the reference drugs. In a subsequent test, compound 2r had median hypnotic dose (HD50) of 746.6 mg/kg, thus demonstrating much better margin of safety compared to reference drugs. Compound 2r also showed oral activity against MES-induced seizures and lower oral neurotoxicity. For explanation of the putative mechanism of action, compound 2r was tested in chemical induced models.
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Synthesis of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles as potential anticonvulsant agents.
Archives of pharmacal research, 2009Co-Authors: Cheng-xi Wei, Li-ping Guan, Kyu Yun Chai, Jing-hao Jia, Zhe-shan QuanAbstract:A series of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles were synthesized. The anticonvulsant effect and neurotoxicity of the compounds (intraperitoneally) were evaluated with the maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests in mice. 2-Phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3g) was the most active and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED50) of 29.5 mg/kg, a median toxicity dose (TD50) of 285 mg/kg, and a protective index (PI) of 9.7, which is greater than the reference drug, carbamazepine, which has a PI of 6.4.
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Design, synthesis and anticonvulsant activity evaluation of 7-substituted-4H-[1,2,4]triazino[3,4-a]phthalazin-4-one derivatives
Journal of the Brazilian Chemical Society, 2009Co-Authors: Xian-yu Sun, Li-ping Guan, Lei Zhang, Cheng-xi Wei, Hu-ri Piao, Zhe-shan QuanAbstract:In this study, a novel series of 7-substituted-4H-[1,2,4]triazino[3,4-a]phthalazin-4-one derivatives was synthesized as potential anticonvulsant agents. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test, and their neurotoxicities were evaluated by the rotarod neurotoxicity test. The pharmacological results showed that 7-hexyloxy-4H-[1,2,4]triazino[3,4-a]phthalazin-4-one 4e was the most potent with median effective dose (ED50) value of 6.6 mg kg-1, median toxicity dose (TD50) of 39.4 mg kg-1, providing a protective index (PI=TD50 /ED50) value of 6.0.
Zengtao Wang - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Evaluation of 5-(o-Tolyl)-1H-tetrazole Derivatives as Potent Anticonvulsant Agents.
Archiv Der Pharmazie, 2017Co-Authors: Shiyang Dong, Huayu Wang, Zhongli Zhang, Tiantian Wang, Kun Qian, Zengtao WangAbstract:A series of 5-(o-tolyl)-1H-tetrazole derivatives were synthesized and evaluated for their anticonvulsant activities. 1-(2-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed important anticonvulsant activity against the MES-induced seizures, as well as lower neurotoxicity with an ED50 value of 12.7 mg/kg and a TD50 value of over 500 mg/kg after intraperitoneal injection into mice, providing 3h with a high protective index (TD50 /ED50 ) of over 39.4. The achieved results prove that the distinctive compounds could be valuable as a model for future development, adaptation, and investigation to construct more active analogues.
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Design and Synthesis of 5-Substituted Benzo[d][1,3]dioxole Derivatives as Potent Anticonvulsant Agents.
Archiv der Pharmazie, 2017Co-Authors: Shiyang Dong, Tiantian Wang, Yi Jin, Xiaodong Chen, Zengtao WangAbstract:A series of 5-substituted benzo[d][1,3]dioxole derivatives was designed, synthesized, and tested for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. Neurotoxicity was determined by rotarod test. In the preliminary screening, six compounds, 3a, 3c, 3d, and 4d–f, showed promising anticonvulsant activities in the MES model, and compounds 4c and 4d exhibited full protection against seizures at doses of 300 mg/kg in the scPTZ model. Among the synthesized compounds, 3c as the most active compound showed high protection against the MES-induced seizures with an ED50 value of 9.8 mg/kg and a TD50 value of 229.4 mg/kg after intraperitoneal injection into mice, thus providing compound 3c with a high protective index (TD50/ED50) of 23.4 comparable to those of reference antiepileptic drugs.
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Design, synthesis and evaluation of 5-substituted 1- H -tetrazoles as potent anticonvulsant agents
Archives of pharmacal research, 2016Co-Authors: Ai-mei Liao, Tiantian Wang, Bangrong Cai, Yi Jin, Seung-hoon Cheon, Changju Chun, Zengtao WangAbstract:A series of 5-substituted 1-H-tetrazoles were designed and synthesized as potent anticonvulsant agents. Their preliminary anticonvulsant activities were evaluated using maximal electroshock and subcutaneous pentylenetetrazole (scPTZ) seizure tests. Neurotoxicity was determined using rotarod test. The results indicated that the compound 2j in scPTZ model exhibited the ED50 values of 83.3 mg/kg, superior to the standard drug ethosuximide with the maximum activity. In addition, compound 2k showed the most potent activity in MES model with ED50 value of 9.6 mg/kg and TD50 value of 189.5 mg/kg after intraperitoneal injection in mice, and displayed a high protective index (TD50/ED50) of 19.7 compared to reference antiepileptic drugs.
Cheng-xi Wei - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Anticonvulsant Activity of 9-Alkoxy-6,7-dihydro-2H-benzo[c][1,2,4]triazolo[4,3-a]azepin-3[5H]-ones
Synthetic Communications, 2012Co-Authors: F-y Piao, Cheng-xi Wei, W-b Zhang, W Zhang, R-b Han, Ri-shan JiangAbstract:Abstract A series of novel 9-alkoxy-6,7-dihydro-2H-benzo[c][1,2,4]triazolo[4,3-a]azepin-3(5H)-one derivatives was designed and synthesized starting from 2,3,4,5-tetrahydro-7-hydroxy-1H-2-benzazepin-1-one. The structures of these compounds were confirmed by mass, 1H NMR infrared spectra, and elemental analysis. Their anticonvulsant activity was evaluated by maximal electroshock (MES) test, and their neurotoxic effects were determined by the rotarod neurotoxicity test. The results shown that 3k was the most active compound with median effective dose (ED50) of 27.3 mg/kg, median toxicity dose (TD50) of 118.3 mg/kg, and protective index (PI) of 4.3. Possible structure–activity relationship is discussed.
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Synthesis and anticonvulsant activity of 1-formamide-triazolo[4,3-a]quinoline derivatives.
Archives of pharmacal research, 2010Co-Authors: Cheng-xi Wei, Xianqing Deng, Kyu Yun Chai, Zhi-gang Sun, Zhe-shan QuanAbstract:Using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material, a series of 1-formamide-triazolo[4, 3-a]quinoline derivatives (6a-6n) was synthesized, the anticonvulsant effect and neurotoxicity of the compounds was calculated with maximal electroshock test and rotarod tests with intraperitoneally injected in KunMing mice. The results demonstrated that compound 7-(hexyloxy)-4,5-dihydro-[1,2,4] triazolo[4,3-a]quinoline-1-carboxamide (6d) was the most active one and also had the lowest toxicity. In the anti-maximal electroshock potency test, it showed median effective dose (ED50) of 30.1 mg/kg, median toxicity dose (TD50) of 286 mg/kg, and the protective index of 9.5 which is greater than the reference drug carbamazepine with the protective index value of 6.0.
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Synthesis of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles as potential anticonvulsant agents.
Archives of pharmacal research, 2009Co-Authors: Cheng-xi Wei, Li-ping Guan, Kyu Yun Chai, Jing-hao Jia, Zhe-shan QuanAbstract:A series of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles were synthesized. The anticonvulsant effect and neurotoxicity of the compounds (intraperitoneally) were evaluated with the maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests in mice. 2-Phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3g) was the most active and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED50) of 29.5 mg/kg, a median toxicity dose (TD50) of 285 mg/kg, and a protective index (PI) of 9.7, which is greater than the reference drug, carbamazepine, which has a PI of 6.4.
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Design, synthesis and anticonvulsant activity evaluation of 7-substituted-4H-[1,2,4]triazino[3,4-a]phthalazin-4-one derivatives
Journal of the Brazilian Chemical Society, 2009Co-Authors: Xian-yu Sun, Li-ping Guan, Lei Zhang, Cheng-xi Wei, Hu-ri Piao, Zhe-shan QuanAbstract:In this study, a novel series of 7-substituted-4H-[1,2,4]triazino[3,4-a]phthalazin-4-one derivatives was synthesized as potential anticonvulsant agents. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test, and their neurotoxicities were evaluated by the rotarod neurotoxicity test. The pharmacological results showed that 7-hexyloxy-4H-[1,2,4]triazino[3,4-a]phthalazin-4-one 4e was the most potent with median effective dose (ED50) value of 6.6 mg kg-1, median toxicity dose (TD50) of 39.4 mg kg-1, providing a protective index (PI=TD50 /ED50) value of 6.0.
Boris Yagen - One of the best experts on this subject based on the ideXlab platform.
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Design and pharmacological activity of glycinamide and N-methoxy amide derivatives of analogs and constitutional isomers of valproic acid
Epilepsy & behavior : E&B, 2011Co-Authors: Neta Pessah, Boris Yagen, Naama Hen, Jakob A. Shimshoni, Bogdan J. Wlodarczyk, Richard H. Finnell, Meir BialerAbstract:Abstract A series of glycinamide conjugates and N-methoxy amide derivatives of valproic acid (VPA) analogs and constitutional isomers were synthesized and evaluated for anticonvulsant activity. Of all compounds synthesized and tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following anticonvulsant tests: maximal electroshock, subcutaneous metrazol, and 6-Hz (32-mA) seizure tests. In mice, the ED50 values of N-methoxy-VCD were 142 mg/kg (maximal electroshock test), 70 mg/kg (subcutaneous metrazol test), and 35 mg/kg (6-Hz test), and its neurotoxicity TD50 was 118 mg/kg. In rats, the ED50 of N-methoxy-VCD in the subcutaneous metrazol test was 36 mg/kg and its protective index (PI = TD50/ED50) was > 5.5. In the rat pilocarpine-induced status epilepticus model, N-methoxy-VCD demonstrated full protection at 200 mg/kg, without any neurotoxicity. N-Methoxy-VCD was tested for its ability to induce teratogenicity in a mouse strain susceptible to VPA-induced teratogenicity and was found to be nonteratogenic, although it caused some resorptions. Nevertheless, a safety margin was still maintained between the ED50 values of N-methoxy-VCD in the mouse subcutaneous metrazol test and the doses that caused the resorptions. On the basis of these results, N-methoxy-VCD is a good candidate for further evaluation as a new anticonvulsant and central nervous system drug.
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syntheses and evaluation of anticonvulsant profile and teratogenicity of novel amide derivatives of branched aliphatic carboxylic acids with 4 aminobenzensulfonamide
Journal of Medicinal Chemistry, 2010Co-Authors: Meir Bialer, Bogdan J. Wlodarczyk, Richard H. Finnell, Boris YagenAbstract:Despite the availability of 14 new antiepileptic drugs (AEDs), about 30% of epileptic patients are not seizure-free. Consequently there is substantial need to develop new effective AEDs. A novel class of aromatic amides composed of phenylacetic acid or branched aliphatic carboxylic acids, with five to nine carbons in their carboxylic moiety, and aminobenzenesulfonamide were synthesized and evaluated in the anticonvulsant rat-maximal electroshock (MES) and subcutaneous metrazol seizure (scMet) tests. Fourteen of the synthesized amides had an anticonvulsant ED50 of <50 mg/kg in the rat-MES test. The amides 2-methyl-N-(4-sulfamoylphenyl)butyramide (10), 2-ethyl-N-(4-sulfamoylphenyl)butyramide (11), and 3,3-dimethyl-N-(4-sulfamoylphenyl)butyramide (15) were the most potent compounds possessing MES-ED50 values of 7.6, 9.9, and 9.4 mg/kg and remarkable protective index (PI = TD50/ED50) values of 65.7, 50.5, and 53.2, respectively. These potent sulfanylamides caused neural tube defects only at doses markedly exc...
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Tetramethylcyclopropyl Analogue of a Leading Antiepileptic Drug, Valproic Acid. Synthesis and Evaluation of Anticonvulsant Activity of Its Amide Derivatives
Journal of medicinal chemistry, 2004Co-Authors: Eyal Sobol, Meir Bialer, Boris YagenAbstract:Although valproic acid (VPA) is an extensively used antiepileptic drug for treatment of various kinds of epilepsies, it has been proven to possess two life-threatening side effects: hepatotoxicity and teratogenicity. Amide and urea derivatives of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) were prepared to discover lead compounds with clinical potential. In the amide and alkylamide series of TMCA derivatives, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (21) was one of the most active compounds, having the subcutaneous metrazol test (scMet) ED50 values of 35 mg/kg in rats and 74 mg/kg in mice. In the maximal electroshock-induced seizure test (MES), this compound had ED50 values of 108 mg/kg in rats and 115 mg/kg in mice. Compound 21 was 18.5 and 4.5 times more potent than VPA in the corresponding rat tests. The most active compound in the series of urea derivatives was 2,2,3,3-tetramethylcyclopropanecarbonylurea (25), possessing MES ED50 values of 29 mg/kg in rats and 90 mg/kg in mice. In the scMet test this compound had ED50 values of 92 mg/kg in rats and 125 mg/kg in mice. The median toxic dose (TD50) in rats was 538 mg/kg, providing compound 25 with a wide safety margin and a protective index (TD50/ED50) of 18.5 in the MES test, which is about 12 times greater than that of VPA. Compounds 21 and 25 have the potential for development as novel potent and safe central nervous system active drugs with a broad spectrum of antiepileptic activity.
