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Synthesis, characterisation, and biological activity of three new amide prodrugs of lamotrigine with reduced hepatotoxicity

Saurabh K. Sinha, Prabhat K. Shrivastava, and Sushant K. Shrivastava

Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi, 221005 India

 

E-mail: skshrivastava.phe@itbhu.ac.in

Abstract: Lamotrigine (LTG) is an antiepileptic drug used for the prevention of convulsions. Except several known side effects, hepatic dysfunction is also reported. Hepatotoxic side effects occur due to the dichlorophenyl moiety which develops an abnormally low level of glutathione. Depletion of glutathione causes oxidative stress and hepatic cell damage. The goal of the present study was to test the action and side effects of the three compounds synthesised and compared to LTG. Three amide prodrugs of LTG were synthesised by its reaction with N-acetylamino acids, viz, glycine, glutamic acid, and methionine. Purified synthesised prodrugs were subjected to thin layer chromatography, melting point, solubility and partition coefficients determination and characterised by UV, FTIR, 1H and 13C NMR spectroscopy. The synthesised prodrugs were subjected to in vitro hydrolysis and to anticonvulsant and hepatotoxic activity studies. Significant reduction in hepatotoxicity and comparable anticonvulsant activities were obtained in all synthesised prodrugs as compared to LTG.

Keywords: prodrug – glutathione – LTG – hepatotoxicity – in vitro hydrolysis – anticonvulsant activity

Full paper is available at www.springerlink.com.

DOI: 10.2478/s11696-010-0094-7

 

Chemical Papers 65 (1) 70–76 (2011)

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