Synthesis and anticonvulsant activity of new N-phenyl-2-(4-phenylpiperazin-1-yl)acetamide derivatives

Abstract

Twenty-two new N-phenyl-2-(4-phenylpiperazin-1-yl)acetamide derivatives have been synthesized and evaluated for their anticonvulsant activity in animal models of epilepsy. These molecules have been designed as analogs of previously obtained anticonvulsant active pyrrolidine-2,5-diones in which heterocyclic imide ring has been changed into chain amide bound. The final compounds were synthesized in the alkylation reaction of the corresponding amines with the previously obtained alkylating reagents 2-chloro-1-(3-chlorophenyl)ethanone (1) or 2-chloro-1-[3-(trifluoromethyl)phenyl]ethanone (2). Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole screens in mice and/or rats. Several compounds were tested additionally in the psychomotor seizures (6-Hz model). The acute neurological toxicity was determined applying the rotarod test. The results of pharmacological studies showed activity exclusively in the MES seizures especially for 3-(trifluoromethyl)anilide derivatives, whereas majority of 3-chloroanilide analogs were inactive. It should be emphasize that several molecules showed also activity in the 6-Hz screen which is an animal model of human partial and therapy-resistant epilepsy. In the in vitro studies, the most potent derivative 20 was observed as moderate binder to the neuronal voltage-sensitive sodium channels (site 2). The SAR studies for anticonvulsant activity confirmed the crucial role of pyrrolidine-2,5-dione core fragment for anticonvulsant activity.

Development and pharmacologic characterization of the rat 6 Hz model of partial seizures

“…Efficacy in the mouse 6 Hz model has been observed for compounds comprising several distinct mechanisms of action, including sodium channel blockers, benzodiazepines and barbiturates, the SV2A ligands, δ2δ ligands, potassium channel modifiers, and others, with varying degrees of efficacy . This model has also been used to identify and screen novel compounds and distinguish lead analogs . Moreover, in some cases where compounds may effectively block seizures at lower stimulus intensities, it has been observed that this efficacy is lost at the 44 mA stimulus intensity.…”

“…3,5,6,13 This model has also been used to identify and screen novel compounds and distinguish lead analogs. 4,8,14 Moreover, in some cases where compounds may effectively block seizures at lower stimulus intensities, it has been observed that this efficacy is lost at the 44 mA stimulus intensity. For example, levetiracetam has a median effective dose (ED 50 ) value that is at least 50 times higher at the 44 mA stimulus intensity versus the 32 mA stimulus intensity, which has led to the designation of 44 mA as a more discriminatory pharmacoresistant screening model when compared to 32 mA.…”

Synthesis of Novel Triazolyl/Oxadiazolyl/Thiadiazolyl-Piperazine as Potential Anticonvulsant Agents

“…The newly synthesized compounds i. e. compounds (3-8), (9)(10)(11)(12)(13)(14), (15)(16)(17)(18)(19)(20) and (21)(22)(23)(24)(25)(26) were studied for anticonvulsant activity at a dose of 30 mg/kg i.p. These compounds were also evaluated for approximate lethal dose (ALD 50 ).…”

“…Further, the series was characterized by its trifurcation which leads to the synthesis of triazoles (9)(10)(11)(12)(13)(14), oxadiazole (15)(16)(17)(18)(19)(20) and thiadiazoles (21)(22)(23)(24)(25)(26). Studying the anticonvulsant activity of triazoles (9)(10)(11)(12)(13)(14) it was noticed that compound 9 having substitution with bromo group at 2 nd position of phenyl ring showed good protection of 80 % against seizures which is equipotent to standard drug phenytoin sodiyum (80 %). Compounds 4 and 5 having chloro and methoxy group at 4 th and 2 nd position of phenyl ring respectively also showed good protection of 70 %.…”

“…Heterocyclic compounds forms the backbone for the discovery of many bioactive compounds. Chemical literature survey reveals that piperazine derivatives are biologically versatile compounds which possess potent antifungal [1,2], antimicrobial [3,4], antihistamine [5], antipsychotic [6,7], anticonvulsant [8][9][10] properties.…”