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Int. J. Mol. Sci. 2014, 15(9), 16911-16935; doi:10.3390/ijms150916911

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

1
Medicinal and Pharmaceutical Chemistry Department (Medicinal Chemistry Group), Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza 12622, Egypt
2
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia
3
Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group) Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza 12622, Egypt
4
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
5
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr University for Science & Technology, 6th of October City 12566, Egypt
*
Author to whom correspondence should be addressed.
Received: 19 August 2014 / Revised: 10 September 2014 / Accepted: 12 September 2014 / Published: 23 September 2014
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Synthesis and anticonvulsant potential of certain new 6-aryl-9-substituted-6,9-diazaspiro[4.5]decane-8,10-diones (6al) and 1-aryl-4-substituted-1,4-diazaspiro[5.5] undecane-3,5-diones (6mx) are reported. The intermediates 1-[(aryl)(cyanomethyl)amino] cycloalkanecarboxamides (3af) were prepared via adopting Strecker synthesis on the proper cycloalkanone followed by partial hydrolysis of the obtained nitrile functionality and subsequent N-cyanomethylation. Compounds 3af were subjected to complete nitrile hydrolysis to give the respective carboxylic acid derivatives 4af which were cyclized under mild conditions to give the spiro compounds 5af. Ultimately, compounds 5af were alkylated or aralkylated to give the target compounds 6ai and 6mu. On the other hand, compounds 6jl and 6vx were synthesized from the intermediates 5af through alkylation, dehydration and finally tetrazole ring formation. Anticonvulsant screening of the target compounds 6ax 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 6ax did not show any minimal motor impairment at the maximum administered dose in the neurotoxicity screen. View Full-Text
Keywords: cycloalkanones; Strecker synthesis; alkylation; spiro compounds; tetrazole; anticonvulsant cycloalkanones; Strecker synthesis; alkylation; spiro compounds; tetrazole; anticonvulsant
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Aboul-Enein, M.N.; El-Azzouny, A.A.; Attia, M.I.; Maklad, Y.A.; Aboutabl, M.E.; Ragab, F.; El-Hamid, W.H.A.A. 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. Int. J. Mol. Sci. 2014, 15, 16911-16935.

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