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Novel Fused quinazolinones: Further studies on the anticonvulsant activity of 1,2,9,11 tetrasubstituted-7H-thieno[2',3':4,5]pyrimido[6,1-b]-quinazolin-7-one and 1,3,10,12- tetrasubstituted-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one
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1  Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India

Abstract: Background: Epilepsy is one of the most common neurological disorders, affecting about 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 usage is associated with undesirable side effects ranging from cosmetic (gingival hyperplasia) to life threatening (hepatotoxicity, megaloblastic anemia). Therefore, the continued search for the safer and more effective antiepileptic drugs is urgently necessary. Literature survey reveals that various derivatives of quinazolinone, thienopyrimidine and pyridopyrimidine shown very promising anticonvulsant activity along with other pharmacological activities. So we concentrate our aim to screen novel quinazolinone fused with thienopyrimidine/pyridopyrimidine. Result: A novel series of 1,2,9,11-tetrasubstituted-7H-thieno[2',3':4,5]pyrimido[6,1-b]-quinazolin-7-ones (1–15) and 1,3,10,12- tetrasubstituted-8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-ones (16-36) were synthesized by reported method. The anticonvulsant activity of all the new compounds (1-15 and 16-36) was evaluated against Maximum Electroshock (MES) induced seizures and against subcutaneous pentylenetetrazole (scPTZ) induced seizures model in mice. The neurotoxicity was assessed using the Rotorod procedure. All the compounds tested were administered intraperitoneally at a various dose levels ranging from 15-175 mg/Kg body weight and the median toxic dose (TD50) and the protection index (PI) values were determined. All test compounds exhibited good activity. The structure–activity relationships based on the results obtained for these series were also studied. Conclusion: The present study indicates that fused quinazolinones shown very good anticonvulsant agents. In both series, electronwithdrawing substitutions showed more activity. Among all the tested compounds, 10,12-dibromo-1-(4-chloro-phenyl)-3-(4-tolyl)- 8H-pyrido[2',3':4,5]pyrimido[6,1-b]quinazolin-8-one 29 and 10,12-dibromo-3-(4-chloro-phenyl)-1-phenyl-8H-pyrido[2',3':4,5] pyrimido[6,1-b]quinazolin-8-one 25 were found to be most potent.
Keywords: Anticonvulsant activity, Fused quinazolinones, Maximum Electroshock, Neurotoxicity, Pentylenetetrazole