title: Anticonvulsant profiles of certain new 6-aryl-9-substituted-6,9-diazaspiro-[4.5]decane-8,10-diones and 1-aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones.
abstract: Synthesis and anticonvulsant potential of certain new 6-aryl-9-substituted-6,9-diazaspiro[4.5]decane-8,10-diones (6a-l) and 1-aryl-4-substituted-1,4-diazaspiro[5.5] undecane-3,5-diones (6m-x) are reported. The intermediates 1-[(aryl)(cyanomethyl)amino] cycloalkanecarboxamides (3a-f) were prepared via adopting Strecker synthesis on the proper cycloalkanone followed by partial hydrolysis of the obtained nitrile functionality and subsequent N-cyanomethylation. Compounds 3a-f were subjected to complete nitrile hydrolysis to give the respective carboxylic acid derivatives 4a-f which were cyclized under mild conditions to give the spiro compounds 5a-f. Ultimately, compounds 5a-f were alkylated or aralkylated to give the target compounds 6a-i and 6m-u. On the other hand, compounds 6j-l and 6v-x were synthesized from the intermediates 5a-f through alkylation, dehydration and finally tetrazole ring formation. Anticonvulsant screening of the target compounds 6a-x revealed that compound 6g showed an ED50 of 0.0043 mmol/kg in the scPTZ screen, being about 14 and 214 fold more potent than the reference drugs, Phenobarbital (ED50 = 0.06 mmol/kg) and Ethosuximide (ED50 = 0.92 mmol/kg), respectively. Compound 6e exhibited an ED50 of 0.019 mmol/kg, being about 1.8 fold more potent than that of the reference drug, Diphenylhydantoin (ED50 = 0.034 mmol/kg) in the MES screen. Interestingly, all the test compounds 6a-x did not show any minimal motor impairment at the maximum administered dose in the neurotoxicity screen.
authors.affiliation: Medicinal and Pharmaceutical Chemistry Department (Medicinal Chemistry Group), Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza 12622, Egypt. mnaboulenein@yahoo.com.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Aboul-Enein
authors.affiliation: Medicinal and Pharmaceutical Chemistry Department (Medicinal Chemistry Group), Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza 12622, Egypt. elazzounyaida@yahoo.com.
authors.forename: Aida A
authors.initials: AA
authors.lastname: El-Azzouny
authors.affiliation: Medicinal and Pharmaceutical Chemistry Department (Medicinal Chemistry Group), Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza 12622, Egypt. mattia@ksu.edu.sa.
authors.forename: Mohamed I
authors.initials: MI
authors.lastname: Attia
authors.affiliation: Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group) Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza 12622, Egypt. yousreya_maklad@yahoo.com.
authors.forename: Yousreya A
authors.initials: YA
authors.lastname: Maklad
authors.affiliation: Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group) Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza 12622, Egypt. monaaboutabl@gmail.com.
authors.forename: Mona E
authors.initials: ME
authors.lastname: Aboutabl
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. fatmarag@hotmail.com.
authors.forename: Fatma
authors.initials: F
authors.lastname: Ragab
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr University for Science & Technology, 6th of October City 12566, Egypt. dr_walaa_hamada@yahoo.com.
authors.forename: Walaa H A
authors.initials: WH
authors.lastname: Abd El-Hamid
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D003292:Convulsants / Q000633:toxicity; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000633:toxicity; D011897:Random Allocation; D045442:Rotarod Performance Test; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D054659:Diketopiperazines; D013141:Spiro Compounds; D010433:Pentylenetetrazole