Synthesis, in Vivo and in Silico Studies of N-Aryl-4-(1,3-Dioxoisoindolin-2-Yl)Benzamides as an Anticonvulsant Agent

Abstract

Background: These days epilepsy is a common neurological disorder, which can affect on quality of life by unpredictable seizure. Thalidomide is one of the drugs to control the epilepsy but side effects such as teratogenicity, made it difficult to use. Methods: Six new analogues of N-aryl-4-(1,3-dioxoisoindolin-2-yl)benzamides were synthesized and tested for anti-seizure activity. To evaluate the anti-seizure activity of these new derivatives, 40 mice in 8 groups were received 10 mg/Kg of each new derivatives 30 min before the injection of pentylenetetrazole (PTZ, 70 mg/kg) to induced seizures. Latency time to first symptom of seizure was measured and compared to vehicle and standard groups. Docking methodology was applied to study on mode of interaction between GABA A receptor and synthetized compounds. Results: Structures of the all synthesized compounds were confirmed by NMR and mass spectroscopy. The latency time and mortality rate were individually measured for an hour after injection of pentylenetetrazole. Docking study revealed that synthesized compounds and thalidomide interact in similar conformation with GABA A receptor. Conclusion: The experimental and docking results were found in good correlation and demonstrated that the most active compound (5a), with 3,4-dimethylphenyl residue increased the duration of seizure inhibition threshold in comparison with thalidomide.

Anticonvulsive evaluation and histopathological survey of thalidomide synthetic analogs on lithium-pilocarpine-induced status epilepticus in rats

“…Due to its potent activity of thalidomide in these tests, many attempts were made to design analogs of thalidomide to treat seizures and epilepsy. Different analogs are designed and tested in animal models of epilepsy to evaluate their ability to confront seizures ( 14 15 16 34 ). Among them, N-arylphthalimide analogs are wieldy studied.…”

“…Lithium chloride (Sigma, St Louis, MO, USA), pilocarpine HCl (Sina Daru Pharmaceutical Company, Tehran, Iran), diazepam, and scopolamine butylbromide (Hyoscine N-butylbromide, ChemiDarou Company, Tehran, Iran) were used as received. Thalidomide and three previously synthesized thalidomide derivatives (compound 5B, N-(4-chlorophenyl)-2-((1, 3-dioxoisoindolin-2-yl) methyl)-4, 5-dihydrothiazole-4-carboxamide; compound 5C, 2-(1,3-dioxoisoindolin-2-yl)-N,3-diphenylpropanamide; and compound 5D, N-(3,4-dimethylphenyl)-4-(1, 3-dioxoisoindolin-2-yl)benzamide) were received as gifts from the Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences ( 14 15 16 ).…”

“…Data for docking binding energies, lipophilicity index (ClogP), and PTZ-induced seizures latency times were extracted from recently published studies ( 12 13 14 ).…”

“…Considering the beneficial effects of thalidomide on refractory epilepsy as well as, the beneficial impact of this drug and related compounds in recent reports, the latest researches were designed with the intention to increase its anti-epileptic activity and reduce its main side effects ( 11 12 14 15 16 ).…”

“…In the present study, the anti-epileptic effects and histopathological evaluation of the three most potent phthalimide analogs of thalidomide (compounds 5B, 5C, and 5D) in which the glutarimide ring was replaced by non-aliphatic side chains were investigated employing the lithium-pilocarpine-induced status epilepticus model in rats and the results compared to previously reported anticonvulsive activity in the pentylenetetrazole (PTZ)-induced seizures model in mice ( 14 15 16 ).…”