Background:
N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2-
isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational
study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good
docking with iGluRs (Kainate) glutamate receptor.
Methods:
QSAR and ADMET screening results suggested that QS11 would possess good potency
for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and
neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and
scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values
as compared to the standard drugs in both MES and scPTZ screen. A high safety profile
(HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher
doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized
QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of
the sample was investigated. The result revealed that the pharmacokinetic performance of QS11
achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area
under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h
and elimination rate constant was found 0.110 ± 0.013 h-1.
Results and Conclusion:
Above evidences indicate that QS11 could serve as a lead for development
of new antiepileptic drugs.
Synthesis, Anticonvulsant Evaluation and Molecular Docking Studies of Novel
Benzo[1,3]dioxol-5-yloxy-N′-(4-substituted benzylidene)acetohydrazide Derivatives