Novel 4(3 H )-quinazolinone analogs: synthesis and anticonvulsant activity
- PDF / 447,182 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 55 Downloads / 258 Views
Med Chem Res (2013) 22:2815–2827 DOI 10.1007/s00044-012-0280-y
ORIGINAL RESEARCH
Novel 4(3H)-quinazolinone analogs: synthesis and anticonvulsant activity Adel S. El-Azab • Sami G. Abdel-Hamide • Mohamed M. Sayed-Ahmed Ghada S. Hassan • Tariq M. El-Hadiyah • Othman A. Al-Shabanah • Omar A. Al-Deeb • Hussein I. El-Subbagh
•
Received: 25 June 2012 / Accepted: 15 October 2012 / Published online: 26 October 2012 Ó Springer Science+Business Media New York 2012
Abstract A new series of quinazoline analogs was designed, synthesized, and evaluated for their anticonvulsant activity. Compounds 6, 12, 21, 36, 37, and 38 showed 70–100 % protection against PTZ-induced seizures acting as GABAA receptor agonists. Compound N-(3,4,5,6-tetrachlorophthalimido)-2-[(3-phenyl-4-oxo-6-methyl-3H-quinazolin2-yl)-thio]acetamide (12) representing the moderate active compounds and 2-[6-iodo-4-oxo-2-(thiophen-2-yl)-quinazolin-3(4H)-yl]-isoindoline-1,3-dione (38) representing the remarkably active compounds in this stud, showed ED50 values of 457 and 251 mg/kg; TD50 values of 562 and 447 mg/kg; PI values of 1.22 and 1.78, LD50 values of 1,288 and 1,380 mg/kg, and TI values of 2.82 and 5.50,
A. S. El-Azab G. S. Hassan O. A. Al-Deeb Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia A. S. El-Azab Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt S. G. Abdel-Hamide Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz University, Alkharj, Saudi Arabia M. M. Sayed-Ahmed T. M. El-Hadiyah O. A. Al-Shabanah Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia G. S. Hassan Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt H. I. El-Subbagh (&) Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, Cairo 12311, Egypt e-mail: [email protected]
respectively. Compound 38 proved to be almost twofold more active than the standard drug sodium valproate. Keywords Synthesis 4(3H)-Quinazolinones Anticonvulsant activity
Introduction Methaqualone (1) as a quinazoline analog is an important landmark in the field of synthetic anticonvulsants; its 6-chloro analog (2) found to possess marked anticonvulsant potency, which is 1.5 times more potent than phenytoin sodium against electroshock-induced convulsions and 10 times more active than troxidone against pentylenetetrazol (PTZ)-induced seizures (Armarego, 1963; Bhaduri et al., 1964; Salimath et al., 1956), Chart 1. In spite of the fact that literally hundreds of quinazolinones related to compound 1 have been synthesized and tested for their anticonvulsant activity, none of those drugs are currently in use. A persistent problem with those compounds arises from the fact that nearly every derivative tested exhibited neurotoxicity values (TD50’s) which are less or slightly higher than the effective doses (ED50’s), (B
Data Loading...
