Abstract
<p><strong>Objective: </strong>The present work is designed to synthesise some isomeric new series of Quinazoline-4-one/4-thione derivatives, based on the pharmacophoric model of central nervous system (CNS) activity by structural modifications retaining the essential structural features for the activity and evaluated for their anticonvulsant and CNS depressant properties.</p><p><strong>Methods: </strong>A series of 7-chloro-3-[substituted (amino/phenylamino)]-2-phenyl quinazolin-4 (3H)-one/thione derivatives and 1-(7-chloro-4-oxo/-2-phenylquinazoline-3 (4H-yl)) substituted urea derivatives were prepared. The reaction scheme proceeds through the intermediate 7-chloro-2-phenyl-4H-benzo[d] [1, 3] oxazin-4-one. The structures of the newly synthesised compounds were characterized from infrared (IR), <sup>1</sup>H nuclear magnetic resonance (NMR) and mass spectra (m/z) and elemental analysis. The anti-convulsant and CNS depressant activity were investigated by maximum electroshock (MES) seizure test and porsolt’s behavioural despair test (forced swimming) respectively. The rota-rod test was performed to assess any probable changes in motor coordination induced by the test compounds.</p><p><strong>Results: </strong>The physicochemical and spectroscopic data clearly confirmed the synthesis of quinazoline derivatives with a common skeleton. The synthesised compounds were evaluated for their anticonvulsant and CNS depressant properties. Among them, six compounds <strong>(IIc, </strong>IIg, IIj, IIIc, IIIg, IIIj) exhibited a good activity profile in CNS depressant activity. Five compounds (IIc, IIg, IIj, IIIg, IIIh) showed protection against MES-induced seizures.</p><p><strong>Conclusion: </strong>The Quinazoline derivatives obtained from this research work indicates that the methyl/methoxy group in phenyl ring, amine and thiourea substitution at 3<sup>rd</sup> position of quinazoline derivatives are essential for CNS depressant activity as well as anticonvulsant activity. Compounds IIc, IIg, IIj, IIIc, IIIg, IIIj, and IIIh were found to be a potent compound which may be effective as a potential source for the development of CNS depressant and anti-convulsant drugs with lesser side effects</p>
Highlights
Epilepsy is a chronic neurological disorder characterised by unprovoked seizures and affects at least 1 percent (50 million) people worldwide [1, 2]
The anti-epileptic drugs mainly act through different mechanisms such as (a) enhancement of gamma amino butyric acid (GABA) mediated inhibition or another effect on the GABA system, (b) modulation of voltage-dependent Na+/Ca2+ channels, (c) modulation of synaptic release, (d) inhibition of synaptic excitation mediated by ionotropic glutamate receptors [7]
Quinazoline derivatives have been focused recently in the design of novel anti-convulsant and central nervous system (CNS) depressant agents [11, 12] suggested that the presence of aryl hydrophobic binding site, hydrogen bonding domain and electron donor group regulate the pharmacokinetic properties of the anticonvulsant drug
Summary
Epilepsy is a chronic neurological disorder characterised by unprovoked seizures and affects at least 1 percent (50 million) people worldwide [1, 2]. Quinazoline derivatives have been focused recently in the design of novel anti-convulsant and CNS depressant agents [11, 12] suggested that the presence of aryl hydrophobic binding site, hydrogen bonding domain and electron donor group regulate the pharmacokinetic properties of the anticonvulsant drug. The introduction of electron withdrawing group at ortho/para position in aromatic ring may increase the CNS activity [13]. Based on these mentioned hypotheses, the present research work focuses on the following objectives: (a) design and synthesis of some hybrid compounds having above mentioned molecular features, (b) anticonvulsant screening of the synthesised compounds by MES method, (c) CNS depressant screening by forced swimming test method.
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