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.
Protein kinase C modulates the activity of a cloned gamma-aminobutyric acid transporter expressed in Xenopus oocytes via regulated subcellular redistribution of the transporter.
