Synthesis and anticonvulsant activity of some 2-(2-{1-[substituted phenyl]ethylidene}hydrazinyl)-4-(4-methoxy-phenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile (original) (raw)
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INTERNATIONAL JOURNAL OF RESEARCH IN AYURVEDA & PHARMACY, 2014
Diethyl-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate (1A) and Diethyl-4-(4-hydroxyphenyl)-2, 6-dimethyl-1, 4dihydropyridine-3, 5dicarboxylate (1A') were synthesized by the condensation of ethyl acetoacetate with formaldehyde and para hydroxy benzaldehyde for 1A and 1A' respectively. From these intermediates, novel derivatives of 2, 6-dimethyl-N 3 ,N 5-diphenyl-1,4-dihydropyridine-3,5-dicarbohydrazide (2A-2D') were prepared in the presence of methanol and respective phenyl hydrazine. In view of the biological activities possessed by 1,4-dihydropyridines, synthesized compounds were subjected to in vivo anticonvulsant and sedative activities. Anticonvulsant activity was evaluated using Maximal electroshock (MES) induced convulsion method and Pentylenetetrazole (PTZ) induced convulsion method. Sedative activity was assessed by two models namely, locomotor activity using actophotometer in mice and anxiolytic activity using the elevated plus maze in rats. Phenytoin and diazepam were taken as standards for anticonvulsant activity, Chlorpromazine and diazepam were used as standards for sedative activity. Dimethyl sulfoxide (DMSO) was used as control; activity of synthesized drugs was compared with that of standards. All the newly synthesized derivatives exhibited significant anticonvulsant activity and considerably low sedative activity.
Bioorganic & Medicinal Chemistry Letters, 2006
Twenty-two new N-phenyl-2-(4-phenylpiperazin-1-yl)acetamide derivatives have been synthesized and evaluated for their anticonvulsant activity in animal models of epilepsy. These molecules have been designed as analogs of previously obtained anticonvulsant active pyrrolidine-2,5-diones in which heterocyclic imide ring has been changed into chain amide bound. The final compounds were synthesized in the alkylation reaction of the corresponding amines with the previously obtained alkylating reagents 2-chloro-1-(3-chlorophenyl)ethanone (1) or 2-chloro-1-[3-(trifluoromethyl)phenyl]ethanone (2). Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole screens in mice and/or rats. Several compounds were tested additionally in the psychomotor seizures (6-Hz model). The acute neurological toxicity was determined applying the rotarod test. The results of pharmacological studies showed activity exclusively in the MES seizures especially for 3-(trifluoromethyl)anilide derivatives, whereas majority of 3-chloroanilide analogs were inactive. It should be emphasize that several molecules showed also activity in the 6-Hz screen which is an animal model of human partial and therapy-resistant epilepsy. In the in vitro studies, the most potent derivative 20 was observed as moderate binder to the neuronal voltage-sensitive sodium channels (site 2). The SAR studies for anticonvulsant activity confirmed the crucial role of pyrrolidine-2,5-dione core fragment for anticonvulsant activity.
Bioorganic Medicinal Chemistry Letters, 2006
Twenty-two new N-phenyl-2-(4-phenylpiperazin-1-yl)acetamide derivatives have been synthesized and evaluated for their anticonvulsant activity in animal models of epilepsy. These molecules have been designed as analogs of previously obtained anticonvulsant active pyrrolidine-2,5-diones in which heterocyclic imide ring has been changed into chain amide bound. The final compounds were synthesized in the alkylation reaction of the corresponding amines with the previously obtained alkylating reagents 2-chloro-1-(3-chlorophenyl)ethanone (1) or 2-chloro-1-[3-(trifluoromethyl)phenyl]ethanone (2). Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole screens in mice and/or rats. Several compounds were tested additionally in the psychomotor seizures (6-Hz model). The acute neurological toxicity was determined applying the rotarod test. The results of pharmacological studies showed activity exclusively in the MES seizures especially for 3-(trifluoromethyl)anilide derivatives, whereas majority of 3-chloroanilide analogs were inactive. It should be emphasize that several molecules showed also activity in the 6-Hz screen which is an animal model of human partial and therapy-resistant epilepsy. In the in vitro studies, the most potent derivative 20 was observed as moderate binder to the neuronal voltage-sensitive sodium channels (site 2). The SAR studies for anticonvulsant activity confirmed the crucial role of pyrrolidine-2,5-dione core fragment for anticonvulsant activity.
International journal of basic and clinical pharmacology, 2017
Since the processes of synthesis of drug compounds, methods of their purification, drying and grinding have a ABSTRACT Background: We have synthesized three 5-R-1-aryl-1,5-dihydro-4Нpyrazole(3,4-d)pyrimidine-4-one derivatives that previously have demonstrated powerful anticonvulsant activity. A great number of physicochemical factors are known to influence on bioavailability and stability of active pharmaceutical ingredients. Therefore the purpose of research was to determine the effect of purification technology and dispersibility of 5-R-1-aryl-1, 5-dihydro-4Нpyrazole (3,4-d) pyrimidine-4-one derivatives on their anticonvulsant activity. Methods: The anticonvulsant effect of this compounds was studied in a model of pentylenetetrazole-induced seizure in mice. Results: The results obtained revealed the optimal solvent for recrystallization of compounds to be isopropanol: compounds, purified by recrystallization from isopropanol, had higher solubility in water and tween; also, they had a tendency to increase anticonvulsant activity. It was found that there is a significant dependence of the latter on compound's dispersion-the smaller the size of crystals the higher anticonvulsant activity. Conclusions: The dependence of anticonvulsant activity of compounds on the degree of dispersion was proved: the smaller particle size the higher anticonvulsant activity. This can be explained by fast dissolution of finedispersed substances, thus increasing the bioavailability if the compounds studied.
Bioorganic & Medicinal Chemistry Letters, 2011
Twenty-two new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. Several compounds were tested additionally in the 6-Hz psychomotor seizure model. The neurotoxicity was determined applying the rotarod test. Excluding one compound, all other molecules were found to be effective in at least one seizure model. The most active were 1-
Archiv der Pharmazie, 2012
Various 1-[6-(4-substituted phenyl)-3-cyano-4-(substituted phenyl)-pyridin-2-yl]-5-oxopyrrolidine-3carboxylic acids (3a-t) were designed and synthesized by clubbing pyrrolidinones and pyridines, the two active anticonvulsant pharmacophores. All the synthesized compounds fulfilled the requirements of suggested pharmacophoric model for anticonvulsant activity. Their in vivo anticonvulsant evaluation was performed by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. The minimal motor impairment was assessed by rotorod test and the estimation of various liver enzymes was performed to check the magnitude of liver toxicity posed by the synthesized compounds. Compounds 3d and 3k displayed comparable anticonvulsant activity to the standard drugs with ED 50 values of 13.4 and 18.6 mg/kg in electroshock screen, repectively. The compounds 3d and 3k were also found to have encouraging anticonvulsant activity (ED 50 ¼ 86.1 and 271.6 mg/kg, respectively) in scPTZ screen. Interestingly, they did not show any sign of motor impairment at the maximum dose administered and were not toxic to the liver.
In the present investigation, we described herein the molecular properties prediction by Molinspiration (2008) and synthesized a series of 17 2-(substituted benzylidene/ethylidene)-N-(substituted phenyl)hydrazinecarboxamide analogues. All the title compounds (4aq) followed the Lipinski ''Rule of Five.'' The synthesized compounds were characterised by elemental analyses and spectral data followed by anticonvulsant activity according to the Antiepileptic Drug Development Programme Protocol. 2-(4-Hydroxybenzylidene)-N-(2-chlorophenyl)hydrazinecarboxamide (4j) was found to be the most active compound of the series showing protection at 4.0 h at a dose of 100 mg/kg against maximal electroshock seizure test and 50 % (2/4, 0.25, 1-2 h) and 100 % (4/4, 0.5 h) protection in 6 Hz psychomotor seizure test without showing any neurotoxicity. N-(2-chlorophenyl)hydrazine carboxamide (3b) showed 100 % (4/4, 0.25-2 h) and 66.6 % (2/3, 4 h) protection in 6 Hz psychomotor seizure test.
Acta Poloniae …, 2009
A series of 3,5-(substituted)oxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(substituted)pyridines (1a-j) were synthesized by Hantzsch method for pyridine synthesis. Treatment with chloroacetyl chloride produced N-(2-chloroacetyl)-3,5-(substituted)oxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(substituted)pyridines (2a-e), which on further treatment with sulfanilamide resulted in 3,5-(substituted)oxycarbonyl-1,4-dihydro-2,6dimethyl-N-[2-(4-sulfamoylphenylamino)-acetyl]-4-(substituted)pyridines (3a-e). The structures has been established on the basis of spectral (IR, 1 H-NMR, mass) and elemental analysis. Compounds 1a-j and 3a-e (5 mg/kg and 10 mg/kg) were evaluated for their anticonvulsant effect against pentylenetetrazole-induced convulsions with diazepam (4 mg/kg) as the reference. Compounds 3a-e exhibited significant (p < 0.01) anticonvulsant activity compared to the control.
Scripta Scientifica Pharmaceutica, 2016
The high psychotropic activity of pyrimidine derivatives attracts attention and leads to the creation of new pyrimidine drugs which affect the central nervous system. As psychotropic agents, a special attention deserve azolopyrimidine derivatives, including pyrazolopyrimidines. Thus, the compounds with antiepileptic, anticonvulsant, sedative, anxiolytic activity (1,2), ligands of benzodiazepine site of GABA receptors (3) were found among the pyrazolopyrimidine derivatives. This research aimed at synthesizing the Nsubstituted derivatives of 1-(4-methoxyphenyl)-1,5dihydro-4Н-pyrazolo[3,4-d]pyrimidin-4-one. The choice of substituent in the first position of pyrazolopyrimidine system was conditioned by the proved influence of the 4-metoxyphenyl radical in affecting the anticonvulsant activity of substances (4,5,6). To establish the prospects of synthesis and an optimization of further pharmacological screening, we performed a prediction of the biological activity that was planned for the synthesis of compounds using a PASS computer program. N-Substituted derivatives of 1-(4-methoxyphenyl)-1,5-dihydro-4Нpyrazolo[3,4-d]pyrimidine-4-one were selected for a synthesis. Marked psychotropic activities such as antiepileptic, anxiolytic, antidepressant, antineurotic, and convulsant activities (Ra≥0.50) were predicted for these compounds. The initial compound-1-(4-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4d]pyrimidine-4-one 4 was obtained within two stages. The first stage included the synthesis of intermediate-ethyl 5-amino-1-(4-methoxyphenyl)-1Hpyrazole-4-carboxylate 3 by an interaction with the