Synthesis and anticonvulsant evaluation of 2-(substituted benzylidene/ethylidene)- N -(substituted phenyl)hydrazinecarbo
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Med Chem Res (2013) 22:2746–2754 DOI 10.1007/s00044-012-0271-z
ORIGINAL RESEARCH
Synthesis and anticonvulsant evaluation of 2-(substituted benzylidene/ethylidene)-N-(substituted phenyl)hydrazine carboxamide analogues Mohamed Jawed Ahsan • Habibullah Khalilullah Sabina Yasmin • Surender Singh Jadav • James P. Stables • Jeyabalan Govindasamy
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Received: 10 March 2012 / Accepted: 3 October 2012 / Published online: 18 October 2012 Ó Springer Science+Business Media New York 2012
Abstract In the present investigation, we described herein the molecular properties prediction by Molinspiration (2008) and synthesized a series of 17 2-(substituted benzylidene/ethylidene)-N-(substituted phenyl)hydrazinecarboxamide analogues. All the title compounds (4a– q) followed the Lipinski ‘‘Rule of Five.’’ The synthesized compounds were characterised by elemental analyses and spectral data followed by anticonvulsant activity according to the Antiepileptic Drug Development Programme Protocol. 2-(4-Hydroxybenzylidene)-N-(2-chlorophenyl)hydrazinecarboxamide (4j) was found to be the most active compound of the series showing protection at 4.0 h at a dose of 100 mg/kg against maximal electroshock seizure test and 50 % (2/4, 0.25, 1–2 h) and 100 % (4/4, 0.5 h) protection in 6 Hz psychomotor seizure test without showing any neurotoxicity. N-(2-chlorophenyl)hydrazine carboxamide (3b) showed 100 % (4/4, 0.25–2 h) and
M. J. Ahsan (&) H. Khalilullah J. Govindasamy New Drug Discovery Research, Department of Pharmaceutical Chemistry, Alwar Pharmacy College, Alwar 301 030, Rajasthan, India e-mail: [email protected] M. J. Ahsan Department of Pharmaceutical Sciences, Nims University, Jaipur 303 121, Rajasthan, India S. Yasmin S. S. Jadav Department of Pharmaceutical Chemistry, Birla Institute of Technology, Mesra, Ranchi 835 215, Jharkhand, India J. P. Stables Preclinical Pharmacology Section, Epilepsy Branch, National Institute of Health, Bethesda, MD 20892-9020, USA
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66.6 % (2/3, 4 h) protection in 6 Hz psychomotor seizure test. Keywords Anticonvulsant agents 6 Hz psychomotor seizure test Maximal electroshock seizure Molecular properties prediction Neurotoxicity Semicarbazones
Introduction Epilepsy is a common neurological disorder, affecting 1–2 % of the world’s population (White, 2003). In spite of new developments in the antiepileptic drug (AED) research, roughly 28–30 % patients still remain poorly treated with the available AEDs (Meador, 2003). Also most of the AEDs have dose-related toxicity and idiosyncratic side effects (Dimmock et al., 1995a; Duncan, 2002). Thus, the search for the new and effective AEDs continues to be an active area of investigation in medicinal chemistry. CPP 115 and vigabatrin were found to be effective in 6 Hz psychomotor seizure test (Antiepileptic Drug and Device Trials XI Conference, 2011). Semicarbazones have been reported as potent anticonvulsant agents possibly act by inhibiting voltage sensitive Na? channel (Dimmock et al., 1995b). The pharmacophore model for anticonvulsant activity
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