Computer Aided Drug Designing, Synthesis and Pharmacological Evaluation of Quinazoline-4-one Moiety as AMPA Receptor Non-Competitive Antagonist

Abstract

Epilepsy is the third most frequent neurological disorder encountered in the elderly after cerebrovascular disease and dementia. Considering the pivotal role of AMPA receptors in physiological and pathological processes, AMPA receptor non competitive antagonist were designed using Computational chemistry tools. Pharmacophore model was generated and validated using SYBYL X1.2. Pharmacophore model revealed that, Acceptor atom, Hydrophobic moiety, Aromatic moiety are essential for good activity. As three-dimensional protein structure of Human AMPA Receptor (GLU R1) is not available in Protein Data Bank(PDB), Homology modeling was done using 3 different templates. Model developed from template 3saj was found out to be the best, and was used further for docking studies. Docking study revealed interaction of molecules with residues SER 206, GLU207, LYS287 THR 289. Some compounds showed intramolecular hydrogen bond, and π-π interaction with PHE 88 residue which was responsible for its low D score, and G score indicating low energy, and high stability of complex. Two series were synthesized containing molecules which showed significant interaction with the receptor. Series 1: 3-(5-(4-substituted)phenyl-1,3,4-thiadiazol-2-yl)-2-(2-substituted)vinyl) quinazolin- 4(3H)-one Series 2 :2-(4-oxo-2-(substituted)phenylquinazolin-3(4H)-yl)-N (substituted)phenylacetamide) Structure elucidation of synthesized compounds was done by IR spectroscopy, Mass spectroscopy, 1H-NMR spectroscopy. The anticonvulsant activity of the title compounds was evaluated using scPTZ model and carbamazepine taken as a reference standard at a dose similar to that of the test compound (100 mg/kg body weight). The synthesized compounds of both series showed anticonvulsant activity against PTZ induced convulsions and no sedation was observed as compared to reference standard (carbamazepine). Compound (N-(2-chlorophenyl)-2-(4-oxo-2- phenylquinazolin-3(4H)-yl)acetamide) showed comparable inhibition 71.27% with reference Carbamazepine (74.46%) and can be considered as strong candidates as antiepileptic agent for future investigation. Thus, Computer assisted Drug designing provides better insight for the development of potent lead molecules against specific target and decreases the number of compounds to be synthesized which might useful to predict activities of compounds quickly and accurately, reducing the cost of drug discovery to a great extent.