Limits...
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 nitrogen heterocyclic ring
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4491109&req=5

Fig1: Structures of known AEDs containing nitrogen heterocyclic ring

Mentions: Epilepsy is one of the most prevalent neurological disorders, affecting approximately 0.5–1 % people worldwide. It has a chronic and progressive nature, characterized by recurring seizures of various manifestations. The basic method of the treatment of epilepsy is pharmacotherapy. It is a symptomatic treatment which allows abolishing or reducing the number of seizure episodes, however, does not inhibit the pathophysiological processes of epileptogenesis and does not eliminate organic changes in the central nervous system (CNS), which are the underlying causes of the disease. In about 25 % of patients, the desired results cannot be achieved with the use of pharmacotherapy, this form of disease is known as refractory epilepsy, the treatment of which is based on surgical vagus nerve stimulation (WHO, 2010; Bell and Sander, 2002; Chang and Lowenstein, 2003). The variety of molecular targets, not always precisely definite, makes it difficult to establish an unequivocal mechanism of action of anti-epileptic drugs (AEDs). This fact is also reflected in the limited possibilities of designing new drugs on the base of the structure of a given biological target. Therefore, currently, there are two different methods of search for new anticonvulsants: modifications of clinically effective AEDs or synthesis of entirely new structures (Khan et al., 2012). Taking into consideration the above limitations, many authors conducted attempts to identify the structural features crucial for anticonvulsant activity. On the basis of these researches, several pharmacophoric models, enabling a more rational design of new anticonvulsants, have been described. Thus, one of the important core fragments of anticonvulsants is defined by nitrogen heterocyclic system, usually imide or lactam and phenyl or alkyl groups attached to the heterocyclic system (Wong et al., 1986; Bruno-Blanch et al., 2003; Malawska, 2005). This common template is present in the structures of old, however well-established AEDs, such as ethosuximide and phenytoin as well as among the newest drugs, e.g., levetiracetam, brivaracetam or seletracetam (Rogawski and Porter, 1990; Bialer et al., 2007) (Fig. 1).Fig. 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)

Structures of known AEDs containing nitrogen heterocyclic ring
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Structures of known AEDs containing nitrogen heterocyclic ring
Mentions: Epilepsy is one of the most prevalent neurological disorders, affecting approximately 0.5–1 % people worldwide. It has a chronic and progressive nature, characterized by recurring seizures of various manifestations. The basic method of the treatment of epilepsy is pharmacotherapy. It is a symptomatic treatment which allows abolishing or reducing the number of seizure episodes, however, does not inhibit the pathophysiological processes of epileptogenesis and does not eliminate organic changes in the central nervous system (CNS), which are the underlying causes of the disease. In about 25 % of patients, the desired results cannot be achieved with the use of pharmacotherapy, this form of disease is known as refractory epilepsy, the treatment of which is based on surgical vagus nerve stimulation (WHO, 2010; Bell and Sander, 2002; Chang and Lowenstein, 2003). The variety of molecular targets, not always precisely definite, makes it difficult to establish an unequivocal mechanism of action of anti-epileptic drugs (AEDs). This fact is also reflected in the limited possibilities of designing new drugs on the base of the structure of a given biological target. Therefore, currently, there are two different methods of search for new anticonvulsants: modifications of clinically effective AEDs or synthesis of entirely new structures (Khan et al., 2012). Taking into consideration the above limitations, many authors conducted attempts to identify the structural features crucial for anticonvulsant activity. On the basis of these researches, several pharmacophoric models, enabling a more rational design of new anticonvulsants, have been described. Thus, one of the important core fragments of anticonvulsants is defined by nitrogen heterocyclic system, usually imide or lactam and phenyl or alkyl groups attached to the heterocyclic system (Wong et al., 1986; Bruno-Blanch et al., 2003; Malawska, 2005). This common template is present in the structures of old, however well-established AEDs, such as ethosuximide and phenytoin as well as among the newest drugs, e.g., levetiracetam, brivaracetam or seletracetam (Rogawski and Porter, 1990; Bialer et al., 2007) (Fig. 1).Fig. 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