Synthesis, Anticonvulsant Activity, and SAR Study of Novel 4-Quinazolinone Derivatives.
Series of N-(4-substitutedphenyl)-4-(1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-alkanamides (5a-j) and 4-chloro-N'-((1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-alkaloyl)benzohydrazides (6a-f) were designed based on the previously reported essential structural features for anticonvulsant activity. Several amino acids were incorporated within the synthesized quinazolin-4(3H)-ones to improve their bioavailability and the anticonvulsant activity. Synthesis of the target compounds was accomplished in four steps starting from the reaction between N-methyl isatoic anhydride and the appropriate amino acid. Then, the carboxylic acid group was utilized to synthesize the required final structures. The new quinazolinone derivatives were evaluated for their anticonvulsant activity according to the Anticonvulsant Drug Development (ADD) Program protocol. All the 16 new quinazolinones exhibited good anticonvulsant activity; especially 5f, 5b, and 5c showed superior anticonvulsant activities in comparison to the reference drug, with ED50values of 28.90, 47.38, and 56.40 mg/kg, respectively.
Faculty of Pharmacy, Department of Medicinal Chemistry, Zagazig University, Zagazig, Egypt.
Nada A
NA
Noureldin
Faculty of Pharmacy, Department of Medicinal Chemistry, Zagazig University, Zagazig, Egypt.
Hend
H
Kothayer
Faculty of Pharmacy, Department of Medicinal Chemistry, Zagazig University, Zagazig, Egypt.
El-Sayed M
EM
Lashine
Faculty of Pharmacy, Department of Medicinal Chemistry, Zagazig University, Zagazig, Egypt.
Mohamed M
MM
Baraka
Department of Pharmacology, National Research Center, Dokki, Cairo, Egypt.
Wafaa
W
El-Eraky
Department of Pharmacology, National Research Center, Dokki, Cairo, Egypt.
Sally A El
SA
Awdan
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D051379:Mice; D010433:Pentylenetetrazole; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D045442:Rotarod Performance Test; D012640:Seizures / Q000517:prevention & control*; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D052999:Quinazolinones; D010433:Pentylenetetrazole
Amino acids; Anticonvulsant; Quinazolin-4(3H)-ones