Synthesis and anticonvulsant activity of some N -(benzoyl)glycinanilide derivatives
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Med Chem Res DOI 10.1007/s00044-013-0474-y
ORIGINAL RESEARCH
Synthesis and anticonvulsant activity of some N-(benzoyl)glycinanilide derivatives Zeynep Soyer • Ozlem Akgul • Ayse H. Tarikogullari Unsal Calis
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Received: 11 September 2012 / Accepted: 6 January 2013 Ó Springer Science+Business Media New York 2013
Abstract Glycine is a major inhibitory neurotransmitter and recent studies have shown that certain lipophilic glycine derivatives demonstrate anticonvulsant activity in animal epilepsy models. On the other hand, anilide is another fruitful structure for designing potential anticonvulsant agents. Ameltolide, ralitoline and some phthalimide derivatives are the examples of anilide analogs with potent anticonvulsant activity. In this study, two key structural pharmacophores were combined and a series of N-benzoylglycinanilide derivatives were designed. Their anticonvulsant activities evaluated against maximal electroshock (MES) and subcutaneous metrazole seizure tests, whereas their neurotoxicity was examined by rotarod test. The preliminary screening results indicated that majority of the compounds were effective in the MES test. None of the compounds showed neurotoxicity according to the rotarod test at studied doses. The most active compound in the series is N-(2-((4-methoxyphenyl)amino)-2-oxoethyl)benzamide (compound 8) which bearing 4-methoxy substituent on the N-phenyl ring. Keywords Anilide Glycine Glycinamide Anticonvulsant activity Amide synthesis
Z. Soyer (&) O. Akgul A. H. Tarikogullari Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, Bornova, 35100 Izmir, Turkey e-mail: [email protected] U. Calis Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye, 06100 Ankara, Turkey
Introduction Epilepsy is a chronic neurologic disorder characterized by recurrent unprovoked seizures which results from a temporary electrical disturbance of the brain due to an imbalance between excitatory and inhibitory neurotransmitters. About 50 million people world wide have epilepsy. Currently, the main treatment for epileptic disorder is the long term and consistent administration of anticonvulsant drugs. Although over 30 AEDs are available, approximately 30 % of epileptic patients are not seizure free. In many cases, the clinical use of AEDs is restricted by their side effects. Therefore, a substantial need remains to discover novel chemical entities for the development of new more effective and safer AEDs (McNamara, 2001; Lo¨scher and Schmidt, 2006; Lin and Kabada, 1997; Malawska, 2005). Many of the newer antiepileptic drugs were designed through structural modifications of available therapeutics and were developed with a specific aim to modify neurotransmitter function such as enhancement of inhibitory mediated neurotransmission or inhibition of excitatorymediated neurotransmission (Malawska, 2005; Czabinski et al., 2005). It is also known that the imbalance between inhibitory and excitatory processes leads to epileptic seizures in the
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