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Microwave Assisted Synthesis and Molecular Docking Studies of Some 4- (3H)-quinazolinone Derivatives as Inhibitors of Human Gamma- Aminobutyric Acid Receptor, the GABA (A)R-BETA3 Homopentamer

[ Vol. 17 , Issue. 5 ]

Author(s):

Rakesh Devidas Amrutkar* and Mahendra Sing Ranawat   Pages 453 - 461 ( 9 )

Abstract:


Background: Quinazolines and quinazolinones constitute a major class of biologically active molecules, both from natural and synthetic sources. The quinazolinone moiety is an important pharmacophore showing many types of pharmacological activities as shown in recent exhaustive review on the chemistry of 2-heteroaryl & heteroalkyl-4-quinazolinones4-quinazolinones that are the formal condensation products of anthranilic acid and amides. They can also be prepared in this fashion through the Niementowski quinazolinone synthesis, named after it’s discoverer Stefan Niementowski. Quinazoline and condensed quinazoline exhibit potent central nervous system (CNS) activities like anti-anxiety, analgesic, anti-inflammatory and anticonvulsant. Quinazolin-4- ones with 2, 3-disubstitution is reported to possess significant analgesic, anti-inflammatory and anticonvulsant activities.

Methods: To expand these views and application profiles, efforts have been made for the synthesis of a new class of quinazolinone by incorporating different amines into synthesized benzoxazinone ring by replacing O atom in the ring. Up till now, a great number of various procedures have been proposed for the synthesis of quinazolin-4-ones in the past few years. Using microwave radiation, this reaction could be easily and rapidly performed in very good yields, providing a large number of various 3-substituted-2- propyl-quinazolin-4-one derivatives which can be employed as useful bioactive compounds. We report a facile and efficient method for the synthesis of 3-substituted-2- propyl-quinazolin-4-one by the condensation reaction of anthranilic acid or halogen substituted anthranilic acid or methyl anthranilate, butanoic anhydride with various amines. We also report a drug/ligand or receptor/protein interactions by identifying the suitable active sites in the human gamma-aminobutyric acid receptor, the gaba (a)r-beta3 homopentamer human gammaaminobutyric acid receptor, and the gaba (a)r-beta3 homopentamer protein.

Results: It was observed in the reaction, 3-alkyl/aryl-2-alkyl-quinazolin-4-one gave good yield as well as good quality of the product by using MW. All the synthesized compounds were subjected to grid-based molecular docking studies. The results show that compound 4t has good affinity to the active site residue of the human gamma-aminobutyric acid receptor, and the gaba (a)r-beta3 homopentamer.

Conclusion: The Microwave irradiation for the synthesis of the title compounds offers a reduction in reaction time, operation simplicity, cleaner reaction, easy work-up and improved yields. The procedure clearly highlights the advantages of green chemistry. The data reported in this article may be helpful for the medicinal chemists who are working in this area. The protein-ligand interaction plays a significant role in structural based drug designing. In the present work, we have docked the ligand, 2, 3-disubstituted quinazolinone with the proteins that are used as the target for GABA-A receptor.

Keywords:

Anthranilic acid, anticonvulsant activities, quinazolin-4-(3H) one, GABA-A receptor, green chemistry, NMR.

Affiliation:

Department of Pharmaceutical Chemistry, Mahatma Gandhi Vidyamandir’s, Samajshree Prashantdada Hiray College of Pharmacy, Malegaon (Nashik), Maharashtra, Department of Pharmaceutical Chemistry, B.N. College of Pharmacy, Udaipur, Rajasthan

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