Synthesis and Evaluation of Anticonvulsant Activities of 4-Phenylpiperidin- 2-one Derivatives

2020 ◽  
Vol 17 (6) ◽  
pp. 713-724
Author(s):  
Shi-Ben Wang ◽  
Hui Liu ◽  
Guang-Yong Li ◽  
Kang Lei ◽  
Xiao-Jing Li ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Anticonvulsant Activity ◽  
Experimental Methods ◽  
Aminobutyric Acid ◽  
Maximal Electroshock ◽  
Rotarod Test ◽  
In Silico Studies ◽  
Anticonvulsant Activities ◽  
Potential Use

Background: Although Antiepileptic Drugs (AEDs) acting on various targets have been applied in the clinic, the efficacy and tolerance of AEDs in the treatment of epilepsy have not significantly improved. Therefore, there is an urgent need to develop some novel chemical moieties with a better safety profile and greater efficacy. We designed and synthesized twenty-seven 4- phenylpiperidin-2-one derivatives. This study aimed to investigate the potential use of a series of 4- phenylpiperidin-2-one derivatives as anticonvulsant drugs. Methods: Two experimental methods, Maximal Electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, neurotoxicity (NT) was tested using the rotarod test. Results: Compound 7-[4-(trifluoromethyl)phenyl]-6,7-dihydrothieno[3,2-b]pyridin-5-(4H)-one (11; MES, ED50 = 23.7 mg/kg, PI > 33.7; PTZ, ED50 = 78.1 mg/kg, PI > 10.0) showed the best anticonvulsant activity. The results of in vivo γ-aminobutyric Acid (GABA) estimation showed that compound 11 may have an effect on the GABA system. Compound 11 showed significant interactions with residues at the benzodiazepine (BZD)-binding site on GABAA receptors. Most target compounds have favorable blood brain barrier (BBB) permeability and oral bioavailability in predictions using silico molecular properties. Conclusion: According to the in vivo and in silico studies, compound 11 stand out as potential anticonvulsant agents for further studies.

Synthesis and Evaluation of N-substituted (Z)-5-(Benzo[d][1,3]dioxol-5- ylmethylene)-2-Thioxothiazolidin-4-one Derivatives and 5-Substituted- Thioxothiazolidindione Derivatives as Potent Anticonvulsant Agents

2020 ◽  
Vol 18 (10) ◽  
pp. 798-807
Author(s):  
Shiyang Dong ◽  
Yanhua Liu ◽  
Jun Xu ◽  
Yue Hu ◽  
Limin Huang ◽  
...  
Keyword(s):  
Anticonvulsant Activity ◽  
Structural Modification ◽  
Docking Study ◽  
Maximal Electroshock ◽  
Molecular Docking Study ◽  
Rotarod Test ◽  
Protective Index ◽  
Channel Inhibition ◽  
Anticonvulsant Activities

Background: Epilepsy is a serious and common neurological disorder threatening the health of humans. Despite enormous progress in epileptic research, the anti-epileptic drugs present many limitations. These limitations prompted the development of more safer and effective AEDs. Methods: series of N-substituted (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)- 2-thioxothiazolidin-4- one derivatives and 5-substituted-thioxothiazolidindione derivatives were designed, synthesized and tested for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ). Neurotoxicity was determined by the rotarod test. Results: Among them, the most potent 4e displayed high protection against MES-induced seizures with an ED50 value of 9.7 mg/kg and TD50 value of 263.3 mg/kg, which provided 4e with a high protective index (TD50/ED50) of 27.1 comparable to reference antiepileptic drugs. 4e clearly inhibits the NaV1.1 channel in vitro. The molecular docking study was conducted to exploit the results. Conclusion: Stiripentol is a good lead compound for further structural modification. Compound 4e was synthesized, which displayed remarkable anticonvulsant activities, and the NaV1.1 channel inhibition was involved in the mechanism of action of 4e.

Design, Synthesis and Biological Activity of Some 4, 5-Disubstituted-2, 4- Dihydro-3H-1, 2, 4- Triazole-3-Thione Derivatives

2019 ◽  
Vol 19 (3) ◽  
pp. 197-205 ◽  
Author(s):  
Krishan Kumar Verma ◽  
Umesh Kumar Singh ◽  
Jainendra Jain
Keyword(s):  
Biological Activity ◽  
1H Nmr ◽  
Anticonvulsant Activity ◽  
Maximal Electroshock ◽  
Gamma Amino Butyric Acid ◽  
Rotarod Test ◽  
Design Synthesis ◽  
Amino Butyric Acid ◽  
Mes Test ◽  
Autodock 4.2

Background: In the present study, 4, 5-disubstituted triazol-3-thione derivatives were synthesized and evaluated for anticonvulsant activity along with neurotoxicity determination. Materials and Methods: The synthesized compounds were characterized using FTIR, 1H-NMR and MS. The anticonvulsant activity was assessed by Maximal Electroshock (MES) test and subcutaneous Pentylenetetrazole (scPTZ) tests and neurotoxicity was assessed by rotarod test. Docking was also performed to study the interactions of compounds with LYS329 residue of gamma amino butyric acid aminotransferase (GABA-AT) using Autodock 4.2 software. Results: The compounds 7a and 9a with significant pharmacological activity were also found to interact with LYS329 residue of GABA-AT by H-bond with a docking score of -5.92 kcal/mol (Ki = 41.99 μM) and -5.87 kcal/mol (Ki = 49.83 μM) respectively. Conclusion: Most of the compounds were found to be active in MES test but only seven showed protection in scPTZ test.

scholarly journals Scrapie-Induced Defects in Learning and Memory of Transgenic Mice Expressing Anchorless Prion Protein Are Associated with Alterations in the Gamma Aminobutyric Acid-Ergic Pathway

2008 ◽  
Vol 82 (20) ◽  
pp. 9890-9899 ◽  
Author(s):  
Matthew J. Trifilo ◽  
Manuel Sanchez-Alavez ◽  
Laura Solforosi ◽  
Joie Bernard-Trifilo ◽  
Stefan Kunz ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Learning And Memory ◽  
Prion Protein ◽  
Gabaa Receptors ◽  
Memory Loss ◽  
Long Term Potentiation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Scrapie Agent

ABSTRACT After infection with RML murine scrapie agent, transgenic (tg) mice expressing prion protein (PrP) without its glycophosphatidylinositol (GPI) membrane anchor (GPI−/− PrP tg mice) continue to make abundant amounts of the abnormally folded disease-associated PrPres but have a normal life span. In contrast, all age-, sex-, and genetically matched mice with a GPI-anchored PrP become moribund and die due to a chronic progressive neurodegenerative disease by 160 days after RML scrapie agent infection. We report here that infected GPI−/− PrP tg mice, although free from progressive neurodegenerative disease of the cerebellum and extrapyramidal and pyramidal systems, nevertheless suffer defects in learning and memory, long-term potentiation, and neuronal excitability. Such dysfunction increases over time and is associated with an increase in gamma aminobutyric acid (GABA) inhibition but not loss of excitatory glutamate/N-methyl-d-aspartic acid. Enhanced deposition of abnormally folded infectious PrP (PrPsc or PrPres) in the central nervous system (CNS) localizes with GABAA receptors. This occurs with minimal evidence of CNS spongiosis or apoptosis of neurons. The use of monoclonal antibodies reveals an association of PrPres with GABAA receptors. Thus, the clinical defects of learning and memory loss in vivo in GPI−/− PrP tg mice infected with scrapie agent may likely involve the GABAergic pathway.

Novel 3-Substituted-2, 3-Dihydro-2-Thioxoquinazolin-4-(1H)-one derivative as Anticonvulsants: Synthesis, Molecular Docking and Pharmacological Screening

2020 ◽  
Vol 17 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Nimisha jain ◽  
Pradeep Kumar Singour
Keyword(s):  
Molecular Docking ◽  
Anticonvulsant Activity ◽  
Type A ◽  
Docking Study ◽  
Aminobutyric Acid ◽  
World Health ◽  
Maximal Electroshock ◽  
Gamma Aminobutyric Acid ◽  
Molecular Docking Study ◽  
Acid Type

Background: According to the World Health Organization, 50 million people worldwide are suffering from epilepsy, making it one of the most common neurological diseases globally. 2,3 disubstituted quinazolinone-4-one derivatives endowed with various pharmacological activity, particularly having anticonvulsant action. Objectives: The aim of this study was to synthesize 3-Substituted-2,3-Dihydro-2-thioxoquinazolin- 4-(1H)-one derivative and evaluate for anticonvulsant activity and neurotoxicity in order to find an efficient, compound with lesser side effects. Methods: A novel series of 3-[4-(2-amino-5, 6-dihydro-4(substituted phenyl)-4H-1, 3-oxazin /thiazin-6yl) phenyl]-2, 3-dihyro-2-thioxoquinazolin-4(1H)-one derivatives (4a-4p) were synthesized. The structures of the synthesized compounds were assigned on the basis of spectral data (UV, IR, 1HNMR, 13CNMR and MS) and performed anticonvulsant activity against maximal electroshock test and Subcutaneous Pentylenetetrazole model. Neurotoxicity was assessed using a rotarod apparatus test. The molecular docking study was performed to assess their binding affinities towards Gamma-Aminobutyric Acid type A receptor. A quantitative estimate of drug-likeness was also performed, which calculates the molecular properties and screen the molecules based on drug-likeness rules. Results: Compounds 4b, 4e, 4j and 4m have shown the highest anticonvulsant activity against tonic seizure with decreased mean duration of tonic hind leg extension of 8.31, 7.35, 8.61 and 8.99 s, respectively in maximal electroshock model and increased onset time clonic convulsion duration of 94.45, 96.65, 93.51 and 91.86 s in Subcutaneous Pentylenetetrazole model. Molecular docking study revealed a better binding affinity with Gamma-Aminobutyric Acid type A receptor. Conclusion: The compound 4b and 4e emerged out as the pilot molecule with a better anticonvulsant activity without any neurotoxicity. The obtained results showed that compounds 4b and 4e could be useful as a template for future design, optimization, and investigation to produce more active analogs.

scholarly journals Involvement of GABAA Receptors in the Anxiolytic-Like Effect of Hydroxycitronellal

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Jéssica C. Andrade ◽  
Álefe B. Monteiro ◽  
Humberto H. N. Andrade ◽  
Thallita K. S. N. Gonzaga ◽  
Pablo R. Silva ◽  
...  
Keyword(s):  
Open Field ◽  
Mechanism Of Action ◽  
Gabaa Receptors ◽  
In Silico ◽  
Elevated Plus Maze ◽  
Field Tests ◽  
Plus Maze ◽  
In Silico Studies ◽  
Sedative Effects

Hydroxycitronellal (HC) is a monoterpene present in essential oils of aromatic plants of different species, obtained from semisynthesis of citronellal, and is widely used as a fragrance in cosmetics. The objective of this work was to evaluate the possible anxiolytic-like activity of HC and its possible mechanism of action using in vivo and in silico methodologies. Swiss male mice (Mus musculus) were treated with HC (12.5, 25, and 50 mg/kg, i.p.) and subjected to the rota rod, elevated plus maze, and open field tests. No significant impairments were observed in the rota rod tests for the motor activity of the animals treated with HC at 12.5, 25, and 50 mg/kg, i.p., indicating no myo-relaxing or sedative effects. In the elevated plus maze, HC (in the three doses) induced significant increases in the percentage of entries (respectively, 34.8%, 33.8%, and 38.6%) and in the length of stay (respectively, 49.9%, 56.1%, and 57.0%) in the open arms of the EPM, as well as the number of crossings in the open field tests. The mechanism of action of the compound’s anxiolytic-like activity can be attributed to the involvement of GABAA receptors, and this interaction was observed in in vivo and in silico studies. For HC, the results suggest anxiolytic-like effects, possibly via modulation of the GABAergic system. The use of natural products to treat anxiety can become an alternative to existing synthetic products.

Synthesis and Pharmacological Evaluation of New Indolyl-oxadiazoles as Anticonvulsant Agents

2009 ◽  
Vol 2 (3) ◽  
pp. 661-666
Author(s):  
Harish Rajak ◽  
Ravichandran Veerasamy ◽  
Arun Kumar Gupta ◽  
Murli Dhar Kharya ◽  
Pradeep Mishra
Keyword(s):  
1H Nmr ◽  
13C Nmr ◽  
Anticonvulsant Activity ◽  
Anticonvulsant Drug ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Anticonvulsant Agents ◽  
Pharmacological Evaluation ◽  
Anticonvulsant Activities

The search for better anticonvulsant drug and the importance of 2,5-disubstituted 1,3,4-oxadiazoles and indole as anticonvulsant pharmacophores, prompted us to design, synthesize and evaluate a series of differently substituted 1,3,4-oxadiazoles for their potential anticonvulsant activity. The structures of the compounds were elucidated by elemental and spectral (IR, 1H NMR, 13C NMR and MS) analyses. Most of the test compounds demonstrated appreciable anticonvulsant activities in maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models.

scholarly journals Synthesis, in silico Studies, and Anticonvulsant Activity of 1,3,4-Oxadiazole Derivatives

2021 ◽  
Vol 18 (23) ◽  
pp. 701
Author(s):  
Banylla Felicity Dkhar Gatphoh ◽  
Natasha Naval Aggarwal ◽  
Merugumolu Vijay Kumar ◽  
Bistuvalli Chandrashekharappa Revanasiddappa
Keyword(s):  
Ammonium Nitrate ◽  
In Silico ◽  
Anticonvulsant Activity ◽  
In Silico Analysis ◽  
Aromatic Aldehydes ◽  
Maximal Electroshock ◽  
Oxadiazole Derivatives ◽  
New Compounds ◽  
Silico Analysis

The title compounds 1,3,4-oxadiazole derivatives (C1-5) were synthesized by the cyclization of 4-hydroxy benzhydrazide (1) with various substituted aromatic aldehydes (2) in the presence of ceric ammonium nitrate. The structures of the newly synthesized compounds were established based on FT-IR, 1H-NMR, and Mass spectral data. In silico analysis was carried out using the Schrodinger 2018-3 suite device Maestro and docked to the binding site of the Human GABAA receptor (PDB ID:4COF). The toxicity of the compounds was predicted using the LAZAR (Lazy structure-activity relationship) program. The invivo anticonvulsant study was performed by means of a maximal electroshock test and pentylenetetrazole (PTZ)-induced seizures. Compounds C4&C5 showed the highest docking score of −5.676 and −5.277, respectively, and compounds C4&C5 showed the most increased in vivo anticonvulsant activity when compared with the reference drugs in both the PTZ and MES test methods. HIGHLIGHTS A new series of 1,3,4-oxadiazoles (C1-C5) were synthesized by reacting aromatic aldehydes and 4-hydroxy benzhydrazide using cerric ammonium nitrate as (CAT) catalyst and characterized by spectral data All the new compounds were subjected for In-silico analysis and docked to Human GABAA receptor (PDB ID:4COF) In-vivo anticonvulsant activity was carried out for all the new compounds by using maximal electroshock (MES) and pentylenetetrazole (PTZ) models Some of the tested compounds C4&C5 displayed promising anticonvulsant activity GRAPHICAL ABSTRACT

Novel 3-{4-[2-Amino-4-(Substitutedphenyl)-2H-[1, 3] Oxazin/Thiazin-6-Yl} -2-Phenyl-3H-Quinazolin-4-One Derivatives as Enhancer of GABA Mediated Inhibition: Synthesis, Molecular Modeling and Pharmacological Studies

2020 ◽  
Vol 17 (2) ◽  
pp. 199-213
Author(s):  
Nimisha Jain ◽  
Pradeep Kumar Singour
Keyword(s):  
Anticonvulsant Activity ◽  
Oral Absorption ◽  
Maximal Electroshock ◽  
Moderate Activity ◽  
Significant Activity ◽  
Molecular Docking Study ◽  
Tonic Seizure ◽  
Seizure Models ◽  
Anticonvulsant Activities ◽  
Quinazolinone Derivatives

Background: According to WHO, the 50 million people worldwide are suffering from epilepsy, making it one of the most common neurological diseases globally. Epilepsy is often characterized by neurobiological, cognitive, psychological and behavioral changes and that may enhance the susceptibility to seizures and affect the quality of life. Objective: The aim of the present work was to develop 2, 3 disubstituted 4-(3H)-quinazolinone derivatives in order to find an effective and highly lipophilic compound with lesser side effects and to evaluate them for anticonvulsant and neurotoxic activity. Methods: A novel series of 3-4-[2-amino-4-(substitutedphenyl)-2H-[1.3] oxazin/thiazin-6-yl 2- phenyl-3H-quinazolin-4-one derivatives were synthesized and evaluated for their anticonvulsant activity. The structures of the compound have been confirmed by spectral analysis. The molecular docking study was performed for finding the binding affinity with GABAA receptor in order to rationalize their anticonvulsant activities in a qualitative way. Quantitative estimate of drug-likeness was also performed which calculate the molecular properties and screen the molecules based on drug-likeness rules. Anticonvulsant activities of synthesized compounds were done by using (Maximal electroshock) MES induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in Wistar rats of either sex. None of the compounds demonstrated any sign of neurotoxicity. Results: Compounds 3-4-[2-amino-4-(fluorophenyl)-2H- [1, 3] oxazin-6-yl 2-phenyl-3H quinazolin-4-one (5i) and 3-4-[2-amino-4-(fluorophenyl)-2H- [1, 3] thiazin -6-yl 2-phenyl-3H quinazolin-4-one (5n) have shown significant activity against tonic seizure by the MES model and clonic seizure by scPTZ induced seizure model. Conclusion: These ten novels synthesized compounds had significant anticonvulsant activity. As a result, the compound (5i) and (5n) emerged out as the pilot molecule with a better anticonvulsant activity without any neurotoxicity, while the other compounds have moderate activity. QED analysis of compounds (5i) and (5n) also indicated that these compounds will have good oral absorption. The proposed work is to make efforts towards the development and identification of novel molecules as anticonvulsant agents by the synthesis of some novel quinazolinone derivatives with improved biological activity.

Anticonvulsant properties of amino-oxyacetic acid

1961 ◽  
Vol 201 (5) ◽  
pp. 833-837 ◽  
Author(s):  
J. P. Da Vanzo ◽  
M. E. Greig ◽  
M. A. Cronin
Keyword(s):  
Anticonvulsant Activity ◽  
Aminobutyric Acid ◽  
Methionine Sulfoximine ◽  
Pentobarbital Sodium ◽  
The Brain ◽  
Fasted Rats ◽  
Optimal Protection ◽  
Oxyacetic Acid

Amino-oxyacetic acid (AOAA), a compound which inhibits γ-aminobutyric-α-ketoglutaric transaminase in vitro and causes accumulations of γ-aminobutyric acid (GABA) in vivo, has anticonvulsant activity against convulsions caused by thiosemicarbazide in rats, mice, and cats and against methionine sulfoximine convulsions in cats. Pentobarbital sodium and trimethadione were slightly active in protecting against thiosemicarbazide-induced convulsions whereas chlorpromazine and methadone were inactive. Pyridoxal, ethanol (in fasted rats), and paraldehyde showed anticonvulsant activity in thiosemicarbazide convulsions. The anticonvulsant activity of AOAA did not appear to be due to increased GABA levels in the brain for the following reasons: a) maximum GABA levels occurred 6–8 hr after administration of AOAA. Optimal protection against thiosemicarbazide, however, was afforded during the first 3 hr after administration and it had fallen off markedly at 6 hr. b) Hydroxylamine, which has been reported to raise GABA levels, had no anticonvulsant activity on thiosemicarbazide.

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