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

Kamiński K, Wiklik B, Obniska J - Med Chem Res (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

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.

No MeSH data available.


Related in: MedlinePlus

Structures of known AEDs containing chain amide bound
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Fig3: Structures of known AEDs containing chain amide bound

Mentions: Another important structural fragment of many anticonvulsants as well as compounds being currently in clinical trials is an amide moiety presented in a chain form (Bruno-Blanch et al., 2003; Hadjipavlou-Litina, 1998; Luszczki, 2009; Hen et al., 2010; Morieux et al., 2008; Ghidini et al., 2006; Beguin et al., 2003; Masereel et al., 2002). It should be stressed that this chemical structure possessed several the newest AEDs such as lacosamide (chemically the functionalized amino acid) or valrocemide and valnoctamide which are the unteratogenic derivatives of valproic acid (Fig. 3).Fig. 3


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

Kamiński K, Wiklik B, Obniska J - Med Chem Res (2015)

Structures of known AEDs containing chain amide bound
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4491109&req=5

Fig3: Structures of known AEDs containing chain amide bound
Mentions: Another important structural fragment of many anticonvulsants as well as compounds being currently in clinical trials is an amide moiety presented in a chain form (Bruno-Blanch et al., 2003; Hadjipavlou-Litina, 1998; Luszczki, 2009; Hen et al., 2010; Morieux et al., 2008; Ghidini et al., 2006; Beguin et al., 2003; Masereel et al., 2002). It should be stressed that this chemical structure possessed several the newest AEDs such as lacosamide (chemically the functionalized amino acid) or valrocemide and valnoctamide which are the unteratogenic derivatives of valproic acid (Fig. 3).Fig. 3

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

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.

No MeSH data available.


Related in: MedlinePlus