Design, synthesis, and biological evaluation studies of novel quinazolinone derivatives as anticonvulsant agents
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Med Chem Res DOI 10.1007/s00044-013-0569-5
ORIGINAL RESEARCH
Design, synthesis, and biological evaluation studies of novel quinazolinone derivatives as anticonvulsant agents Mohamed F. Zayed • Hany E. A. Ahmed • Abdel-Sattar M. Omar • Adel S. Abdelrahim Khaled El-Adl
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Received: 8 December 2012 / Accepted: 2 March 2013 Ó Springer Science+Business Media New York 2013
Abstract In view of their expected anticonvulsant activity, some novel derivatives of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones (4–14) were synthesized, evaluated for their anticonvulsant activity by the maximal electroshock-induced seizure and subcutaneous pentylenetetrazole tests. The neurotoxicity was assessed using rotorod test. All the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 5, 6, and 8 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test when compared with the reference drugs. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogs.
M. F. Zayed (&) H. E. A. Ahmed Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-madinah Al-munawarah, Kingdom of Saudi Arabia e-mail: [email protected]; [email protected] A.-S. M. Omar Pharmaceutical Chemistry Department, Faculty of Pharmacy, King AbdulAziz University, Jeddah, Kingdom of Saudi Arabia A. S. Abdelrahim Pharmaceutical Chemistry Department, Faculty of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia M. F. Zayed A.-S. M. Omar A. S. Abdelrahim K. El-Adl Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt H. E. A. Ahmed Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
Keywords Quinazolin-4(3H)-one Epilepsy Neurotoxicity Synthesis Anticonvulsant
Introduction Epilepsy is ubiquitous disease characterized by recurrent seizures and inflicts [60 million people worldwide according to epidemiological studies (Leppik, 1994). Every year *250,000 new cases are added to this figure. About 28–30 % of epilepsy patients have a multidrug resistance and develop refractory epilepsy (RE). This particular refractoriness is now attributed to overexpression and upregulation of p-glycoprotein in brain, leading to impaired access of antiepileptic drugs to CNS targets. These findings were documented in both human as well as in experimental models of RE after the biological examination of brain capillary endothelial cells from cerebral cortex biopsies from normal and drug-resistant epileptic patients (Chen et al., 2007). Despite the development of several new anticonvulsants, the treatment of epilepsy remains still inadequate and the patients suffer from many side effects like neurotoxicity, depression, and other CNS disorders. Therefore, it is necessary to search for safer and more effective anticonvuls
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