Design, Synthesis and Evaluation of Anticonvulsant Activity of Pyridinyl-Pyrrolidones: A Pharmacophore Hybrid Approach (original) (raw)
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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-
2011
Various 2-amino-6-[3-(substituted phenyl)-5-phenyl-4,5-dihydropyrazol-1-yl]-4-(substituted phenyl)nicotinonitriles (3a-t) were designed and synthesized by clubbing two active anticonvulsant pharmacophores pyrazole and pyridine. All the synthesized compounds possessed the pharmacophoric elements essential for good anticonvulsant activity. The anticonvulsant screening was performed by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. Two compounds 3i and 3s showed significant anticonvulsant activity in both the screens with ED50 values 17.5 mg/kg and 22.6 mg/kg respectively in MES screen and 154.1 mg/kg and 242.6 mg/kg respectively in scPTZ screen. They were also found to have no acute toxic effects in mice when tested at elevated doses.
International Journal of Molecular Sciences, 2020
Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (median effective dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsa...
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.
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
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.
Synthesis, anticonvulsant and toxicity screening of newer pyrimidine semicarbazone derivatives
European Journal of Medicinal Chemistry, 2010
A number of N-(4,6-substituted diphenylpyrimidin-2-yl) semicarbazones (4aet) were synthesized and tested for their anticonvulsant activity against the two seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). All the synthesized compounds possessed the four essential pharmacophoric elements for good anticonvulsant activity. Most of the compounds displayed good anticonvulsant activity with lesser neurotoxicity. To assess the unwanted effects of the compounds on liver, estimation of enzymes and proteins was carried out.
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.