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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.


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Synthetic pathways of intermediates 1, 2 and target compounds 3–24
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Sch1: Synthetic pathways of intermediates 1, 2 and target compounds 3–24

Mentions: The synthesis of compounds 3–24 was accomplished as shown in Scheme 1. The starting materials 2-chloro-1-(3-chlorophenyl)ethanone (1) and 2-chloro-1-[3-(trifluoromethyl)phenyl]ethanone (2) were prepared by acylation of 3-chloroaniline or 3-trifluoromethylaniline with 2-chloroacetyl chloride. The reaction was carried out at 0 °C for 3 h in the mixture consisted of dichloromethane (DCM) and 2 % aqueous sodium hydroxide solution. The final compounds 3–24 were synthesized in the alkylation reaction of the corresponding amines with the previously obtained alkylating reagents 1 and 2. The reaction was carried out at a temperature of 60 °C in a biphasic liquid–solid system consisting of dry acetone, potassium carbonate and catalytic amount of potassium iodide. The progress of the reaction was monitored using HPLC chromatography. Compounds 3–24 were obtained in yields ranging from 44 to 78 %. Their purities were assessed by HPLC chromatography (the HPLC chromatogram of 22 is shown in Fig. 5). The final compounds were fully characterized by elemental analyses (C, H, N) and 1H NMR, 13C NMR, 19F NMR, LC/MS spectra. The detailed physicochemical and analytical data are listed in the experimental section.Scheme 1


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)

Synthetic pathways of intermediates 1, 2 and target compounds 3–24
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Sch1: Synthetic pathways of intermediates 1, 2 and target compounds 3–24
Mentions: The synthesis of compounds 3–24 was accomplished as shown in Scheme 1. The starting materials 2-chloro-1-(3-chlorophenyl)ethanone (1) and 2-chloro-1-[3-(trifluoromethyl)phenyl]ethanone (2) were prepared by acylation of 3-chloroaniline or 3-trifluoromethylaniline with 2-chloroacetyl chloride. The reaction was carried out at 0 °C for 3 h in the mixture consisted of dichloromethane (DCM) and 2 % aqueous sodium hydroxide solution. The final compounds 3–24 were synthesized in the alkylation reaction of the corresponding amines with the previously obtained alkylating reagents 1 and 2. The reaction was carried out at a temperature of 60 °C in a biphasic liquid–solid system consisting of dry acetone, potassium carbonate and catalytic amount of potassium iodide. The progress of the reaction was monitored using HPLC chromatography. Compounds 3–24 were obtained in yields ranging from 44 to 78 %. Their purities were assessed by HPLC chromatography (the HPLC chromatogram of 22 is shown in Fig. 5). The final compounds were fully characterized by elemental analyses (C, H, N) and 1H NMR, 13C NMR, 19F NMR, LC/MS spectra. The detailed physicochemical and analytical data are listed in the experimental section.Scheme 1

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