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.
Background & Objective: A series of novel 3-Substituted-1,3,4,5-Tetrahydro-2H-benzo [b]
azepine-2-one Derivatives (4, 5, 7, 10, 12, 5a-j, 8a-e) were synthesized from 1,2,3,4-Tetrahydro-1-
naphthalenone. The structures of these compounds were confirmed by IR, 1H NMR, 13C NMR, MASS
spectra and elemental analysis. Their anticonvulsant activity was evaluated by the maximal electroshock
(MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated
by the rotarod neurotoxicity test. Compound 4 showed the maximum anticonvulsant activity against
the maximal electroshock test (ED50=26.4, PI =3.2) and against the subcutaneous pentylenetetrazol
test (ED50=40.2, PI =2.1).
Conclusion:
Possible structure-activity relationship was discussed.
Neuroinflammation is an integral part of epilepsy pathogenesis and other convulsive conditions, and non-steroidal anti-inflammatory drugs (NSAIDs) present a potent tool for the contemporary search and design of novel anticonvulsants. In the present paper, evaluation of the anticonvulsant activity of the potential NSAID dual COX-2/5-LOX inhibitor darbufelone methanesulfonate using an scPTZ model in mice in dose 100 mg/kg is reported. Darbufelone possesses anticonvulsant properties in the scPTZ model and presents interest for in-depth studies as a possible anticonvulsant multi-target agent with anti-inflammatory activity. The series of 4-thiazolidinone derivatives have been synthesized following the analogue-based drug design and hybrid-pharmacophore approach using a darbufelone matrix. The synthesized derivatives showed a significant protection level for animals in the scPTZ model and are promising compounds for the design of potential anticonvulsants with satisfactory drug-like parameters.
Evaluation of Anticonvulsant Activity of Dual COX-2/5-LOX Inhibitor Darbufelon and Its Novel Analogues