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.

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.

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 New TRPV1 Antagonists as Candidates for Effective Anticonvulsant and Antinociceptive Agents

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 30
Author(s):  
Kamiński ◽  
Jakubiec ◽  
Zagaja ◽  
Andres-Mach ◽  
Mogilski ◽  
...  
Keyword(s):  
Anticonvulsant Activity ◽  
Epileptic Seizures ◽  
Maximal Electroshock ◽  
Neurogenic Pain ◽  
Mes Test ◽  
Trpv1 Receptors ◽  
Seizure Models ◽  
The Common ◽  
Drug Resistant Epilepsy ◽  
Patients With Epilepsy

Epilepsy is recognized as one of the most common neurological disorders with a high risk of drug resistance. Notably, about one-third of the patients with epilepsy are not responsive to pharmacological treatment. Thus, the search for new, more effective anticonvulsants with a novel mechanism of action is undoubtedly necessary. The most recent neurobiological studies implicate central TRPV1 receptors in the induction of epileptic seizures. Moreover, it is suggested that TRPV1 desensitization is one of the crucial mechanisms of action responsible for the anticonvulsant activity of cannabidiol (CBD), which was proven to be effective against drug-resistant epilepsy. Bearing in mind the aforementioned facts, we developed in our recent studies a series of chemically original TRPV1 antagonists. Their structures were designed as integrated hybrids that join on the common chemical template the structural fragments of anticonvulsants identified by our team in the previous studies and known TRPV1 antagonists (described in the literature). As a result, these compounds revealed potent anticonvulsant activity in the preclinical studies using the most widely employed animal seizure models, namely, the maximal electroshock (MES) test, and the psychomotor 6 Hz (32 mA and 44 mA) seizure model in mice. In addition, selected substances demonstrated potent effectiveness by decreasing pain responses in formalin-induced tonic pain, in capsaicin-induced neurogenic pain, as well as in oxaliplatin-induced neuropathic pain in mice.

scholarly journals STUDY OF THE ANTICONVULSANT ACTIVITY OF ETHANOLIC EXTRACT OF ROOT OF ACORUS CALAMUS IN ALBINO RATS

2019 ◽  
Vol 12 (1) ◽  
pp. 185
Author(s):  
Shipra Kaushik ◽  
Kalpana Gohain
Keyword(s):  
Normal Saline ◽  
Anticonvulsant Activity ◽  
Ethanolic Extract ◽  
Albino Rats ◽  
Acorus Calamus ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Onset Of Action ◽  
Electrical Shock ◽  
Seizure Models

Objective: Root of Acorus calamus has been traditionally used as an anticonvulsant. The aim of the study is to assess the anticonvulsant activity of ethanolic extract of A. calamus (EEAC) by maximal electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models on albino (Wistar strain) rats.Methods: Albino rats were taken and divided into five groups, each consisting of five rats both for MES and PTZ model. One group was used as control (normal saline 10 ml/kg), one as standard (phenytoin in MES model/diazepam in PTZ model), and three groups for the test drug (EEAC in the doses of 100, 200, and 400 mg/kg). In MES model, maximal electrical shock of 150 mA was passed for 0.2 s through earlobe electrodes after 30 min of giving the drugs and normal saline. Different stages of convulsions were noted down along with time spent by the animal in each phase of convulsions. In PTZ model, PTZ was injected 30 min after giving the drugs and normal saline, and onset of action and severity of convulsions were noted. Data were statistically analyzed by one-way analysis of variance followed by multiple Dunnett’s test.Results: EEAC dose dependently reduced the duration of tonic hind limb extension in MES model, and there was increase in latency and occurrence of convulsions in PTZ model.Conclusion: EEAC has anticonvulsant activity.

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 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 AND ANTICONVULSANT ACTIVITY (CHEMO SHOCK) OF N-1(SUBSTITUTED-N-4[(4-OXO-3-PHENYL-3, 4-DIHYDRO-QUINAZOLINE-2-YLMETHYL) SEMICARBAZONES

2017 ◽  
Vol 10 (4) ◽  
pp. 359 ◽  
Author(s):  
Meena K Yadav ◽  
Laxmi Tripathi ◽  
Diptendu Goswami
Keyword(s):  
Glutamate Receptor ◽  
Elemental Analysis ◽  
Anticonvulsant Activity ◽  
Chemical Structure ◽  
Shock Model ◽  
Analysis Techniques ◽  
H Nmr ◽  
Electronic Environment ◽  
Seizure Models ◽  
Anticonvulsant Activities

Objective: This work is designed at finding new structure leads with potential anticonvulsant activities of 4(3H)-quinazolinone pharmacophore scaffold.Methods: A new series of 4(3H)-quinazolinone pharmacophore was designed with substituted moieties possesses different electronic environment in the hope of developing potent and safe new effective compounds. In such fashion, in this paper, we report the synthesis and anticonvulsant activity (Chemo shock) of N-1(substituted-N-4[(4-oxo-3-phenyl-3, 4-dihydro-quinazoline-2-ylmethyl) semicarbazones 3A-d (1-7), 3B-d (1-7), 3C-d (1-7), their chemical structure were characterized using IR,  H-H NMR, and elemental analysis techniques. Their anticonvulsant activity was evaluated using chemicals strychnine, thiosemicarbazide and 4-aminopyridine induced seizure models at a dose of 30, 100, 300 mg/kg unto 2 hrs tests in mice. The rotarod assay was performed in mice to evaluate the neurotoxicity of the compounds. 1Results: Compounds 3C (d-4), 3B (d-4), and 3A (d-4) were observed to be most feasible to act against glutamate receptor for anticonvulsant activity.Conclusions: The results obtained revealed that numbers of novel quinazolinone semicarbazone derivatives are effective in chemical to induce (chemo shock) model and showing good anticonvulsant activity.Keywords: Quinazolinone, Semicarbazones, Strychnine, Thiosemicarbazide, 4-aminopyridine, Anticonvulsant activity, Chemo shock.

scholarly journals STUDY OF THE ANTICONVULSANT ACTIVITY OF ETHANOLIC EXTRACT OF ROOT OF ACORUS CALAMUS IN ALBINO RATS

2019 ◽  
Vol 12 (1) ◽  
pp. 185
Author(s):  
Shipra Kaushik ◽  
Kalpana Gohain
Keyword(s):  
Normal Saline ◽  
Anticonvulsant Activity ◽  
Ethanolic Extract ◽  
Albino Rats ◽  
Acorus Calamus ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Onset Of Action ◽  
Electrical Shock ◽  
Seizure Models

Objective: Root of Acorus calamus has been traditionally used as an anticonvulsant. The aim of the study is to assess the anticonvulsant activity of ethanolic extract of A. calamus (EEAC) by maximal electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models on albino (Wistar strain) rats.Methods: Albino rats were taken and divided into five groups, each consisting of five rats both for MES and PTZ model. One group was used as control (normal saline 10 ml/kg), one as standard (phenytoin in MES model/diazepam in PTZ model), and three groups for the test drug (EEAC in the doses of 100, 200, and 400 mg/kg). In MES model, maximal electrical shock of 150 mA was passed for 0.2 s through earlobe electrodes after 30 min of giving the drugs and normal saline. Different stages of convulsions were noted down along with time spent by the animal in each phase of convulsions. In PTZ model, PTZ was injected 30 min after giving the drugs and normal saline, and onset of action and severity of convulsions were noted. Data were statistically analyzed by one-way analysis of variance followed by multiple Dunnett’s test.Results: EEAC dose dependently reduced the duration of tonic hind limb extension in MES model, and there was increase in latency and occurrence of convulsions in PTZ model.Conclusion: EEAC has anticonvulsant activity.

scholarly journals COMPARATIVE STUDY OF ANTICONVULSANT EFFECT OF THE LEAVES OF SAPINDUS EMARGINATUS AND ACORUS CALAMUS IN EXPERIMENTALLY INDUCED ANIMAL MODELS OF EPILEPSY

2021 ◽  
pp. 36-39
Author(s):  
PRIYADARSHINI SHOUGRAKPAM ◽  
ABHISHEK BHATTACHARJEE ◽  
NGANGOM GUNINDRO ◽  
SANJENBAM RITA
Keyword(s):  
Anticonvulsant Activity ◽  
Clonic Seizure ◽  
Acorus Calamus ◽  
Anticonvulsant Effect ◽  
Maximal Electroshock ◽  
Group V ◽  
Gum Acacia ◽  
Group I ◽  
Seizure Models ◽  
Animal Models Of Epilepsy

Objective: To compare anticonvulsant activity of methanol extracts of Sapindus emarginatus (MESE) and Acorus calamus (MEAC) in experimental seizure models in mice. Methods: Hind limb tonic extension (HLTE) in Maximal electroshock (MES) seizure and clonic seizure in Pentylenetetrazol (PTZ) seizure models were assessed. Group I (control) mice received 1% gum acacia in distilled water (1 ml/100 g). Topiramate (50 mg/kg) was administered in group II (standard) animals. Group III and IV mice were treated with 200 and 400 mg/kg of MESE, respectively. Mice in group V and VI were given MEAC at the dose of 200 and 400 mg/kg, respectively. Drugs were given orally suspended in 1% gum acacia suspension (1 ml/100 g) for 7 d. Next day after 1 h of drug administration, the seizure was induced for evaluation. Results: Anticonvulsant property of both extracts was confirmed by reduction (p<0.001) in HLTE phase in MES model; delayed onset of the clonic seizure (p<0.001) and its shortened phase (p<0.001) in PTZ model when compared with the control. MESE-200 mg/kg produced significantly longer (p<0.001) HLTE phase with lower protection (40.34%) among the different doses of the extracts. Clonic seizure onsets and durations in PTZ model were comparable among the different extract-treated groups; however, mortality was higher (66.6%) with MESE-200 mg/kg. Conclusion: Anticonvulsant activity of MESE and MEAC was evident; however, MESE at the dose of 200 mg/kg was less effective.

Screening of Some Novel 4, 5 Disubstituted 1, 2, 4-Triazole-3-thiones for Anticonvulsant Activity

2020 ◽  
Vol 20 (1) ◽  
pp. 41-48 ◽  
Author(s):  
Krishan K. Verma ◽  
Umesh K. Singh ◽  
Jainendra Jain
Keyword(s):  
Drug Administration ◽  
Anticonvulsant Activity ◽  
Motor Coordination ◽  
Docking Study ◽  
Maximal Electroshock ◽  
Gamma Amino Butyric Acid ◽  
Molecular Docking Study ◽  
Amino Butyric Acid ◽  
Mes Test ◽  
Autodock 4.2

Objective: In the present study, we synthesized fifteen 4, 5-disubstituted 1, 2, 4-triazol- 3-thione derivatives and evaluated for anticonvulsant activity with neurotoxicity determination. Method: The synthesized compounds were characterized using FTIR, 1H-NMR and MS. The molecular docking study 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. The anticonvulsant activity was assessed by maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) tests. The neurotoxicity was assessed by rotarod ataxia test. Results: In MES test, compounds 5a, 8a and 9a were found active at 100 mg/kg and five compounds were found active at 300 mg/kg dose after 1 hr of administration. After 4 hr of drug administration, only two compounds 8a and 9a exhibited protection at 100 mg/kg. In scPTZ test, three compounds 2a, 6a and 8a were found active at 100 mg/kg and 7a was active at 300 mg/kg after 1 hr of test drug administration. Most of the compounds were found active in MES test with 8a and 9a being the most active among all. In docking study, 2a was found to be best compound based on the binding energy of -6.5 kcal/mol and estimated inhibition constant of 17.2 µM. Conclusion: Majority of synthesized compounds were found active in MES test, whereas only few were found to possess anti scPTZ activity. Among all compounds, only 14a caused motor coordination impairment in rotarod ataxia test at 300 mg/kg 1 hr duration.

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