BACKGROUND: Epilepsy is one of the most common neurological disorders, affecting approximately 1% of the world's population. The currently available anticonvulsants are effective in reducing the severity and number of seizures in less than 70% of patients. Moreover, their use is associated with undesirable side effects, ranging from cosmetic (gingival hyperplasia) to life-threatening (hepatotoxicity or megaloblastic anemia). Therefore, the continued search for safer and more effective anti-epileptic drugs is both urgent and necessary. A survey of the literature reveals that various derivatives of quinazolinone, thienopyrimidine and pyridopyrimidine have shown very promising anticonvulsant activity, along with other pharmacological activities. We therefore decided to concentrate our efforts on screening novel quinazolinone fused with thienopyrimidine/pyridopyrimidine. RESULTS: A novel series of 1,2,9,11-tetrasubstituted-7H-thieno[2´,3´:4,5]pyrimido[6,1-b]-quinazolin-7-ones and 1,3,10,12-tetrasubstituted-8H-pyrido[2´,3´:4,5]pyrimido[6,1-b]quinazolin-8-ones were synthesized by the method reported. The anticonvulsant activity of all the new compounds was evaluated against maximum electroshock-induced seizures and against subcutaneous pentylenetetrazole (scPTZ)-induced seizure models in mice. The neurotoxicity was assessed using the Rotorod procedure. All the compounds tested were administered intraperitoneally at a various dose levels ranging from 15 to 175 mg/kg body weight, and the median toxic dose (TD(50)) and the protection index values were determined. All compounds tested exhibited good activity. The structure-activity relationships based on the results obtained for these series were also studied. CONCLUSION: This study indicates that fused quinazolinones display very good anticonvulsant activity. In both series, electron-withdrawing substitutions showed more activity. Among all the compounds tested, 10,12-dibromo-1- (4-chloro-phenyl)-3- (4-tolyl)-8H-pyrido[2´,3´:4,5]pyrimido[6,1-b]quinazolin-8-one and 10,12-dibromo-3- (4-chloro-phenyl)-1-phenyl-8H-pyrido[2´,3´:4,5]pyrimido[6,1-b]quinazolin-8-one were found to be the most potent.
BACKGROUND:Epilepsy is one of the most common neurological disorders, affecting approximately 1% of the world's population. The currently available anticonvulsants are effective in reducing the severity and number of seizures in less than 70% of patients. Moreover, their use is associated with undesirable side effects, ranging from cosmetic (gingival hyperplasia) to life-threatening (hepatotoxicity or megaloblastic anemia). Therefore, the continued search for safer and more effective anti-epileptic drugs is both urgent and necessary. A survey of the literature reveals that various derivatives of quinazolinone, thienopyrimidine and pyridopyrimidine have shown very promising anticonvulsant activity, along with other pharmacological activities. We therefore decided to concentrate our efforts on screening novel quinazolinone fused with thienopyrimidine/pyridopyrimidine. RESULTS: A novel series of 1,2,9,11-tetrasubstituted-7H-thieno[2´,3´:4,5]pyrimido[6,1-b]-quinazolin-7-ones and 1,3,10,12-tetrasubstituted-8H-pyrido[2´,3´:4,5]pyrimido[6,1-b]quinazolin-8-ones were synthesized by the method reported. The anticonvulsant activity of all the new compounds was evaluated against maximum electroshock-induced seizures and against subcutaneous pentylenetetrazole (scPTZ)-induced seizure models in mice. The neurotoxicity was assessed using the Rotorod procedure. All the compounds tested were administered intraperitoneally at a various dose levels ranging from 15 to 175 mg/kg body weight, and the median toxic dose (TD(50)) and the protection index values were determined. All compounds tested exhibited good activity. The structure-activity relationships based on the results obtained for these series were also studied. CONCLUSION: This study indicates that fused quinazolinones display very good anticonvulsant activity. In both series, electron-withdrawing substitutions showed more activity. Among all the compounds tested, 10,12-dibromo-1- (4-chloro-phenyl)-3- (4-tolyl)-8H-pyrido[2´,3´:4,5]pyrimido[6,1-b]quinazolin-8-one and 10,12-dibromo-3- (4-chloro-phenyl)-1-phenyl-8H-pyrido[2´,3´:4,5]pyrimido[6,1-b]quinazolin-8-one were found to be the most potent.