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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

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

Author(s): Nimisha Jain and Pradeep Kumar Singour*

Volume 17, Issue 2, 2020

Page: [199 - 213] Pages: 15

DOI: 10.2174/1570180816666190222155404

Price: $65


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.

Objectives: 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.

Keywords: Anticonvulsant, molecular docking, GABA, MES, quinazolin-4(3H)-ones, scPTZ, seizures.

Graphical Abstract
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