Novel 4(3H)-Quinazolinone analogs: Synthesis and Anticonvulsant Activity

A new series of quinazoline analogs was designed, synthesized, and evaluated for their anticonvulsant activity. Compounds 6, 12, 21, 36, 37,and38 showed 70–100 % protection against PTZ-induced seizures acting as GABA 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 ED A values of 457 and 251 mg/kg; TD values of 562 and 447 mg/kg; PI alues of 1.22 and 1.78, LD 50 values of 1,288 and 1,380 mg/kg, and TI values of 2.82 and 5.50, respectively. Compound 38 roved to be almost twofold more active than the standard drug sodium valproate

Synthesis and investigation of novel shelf-stable, brain-specific chemical delivery system

1Department of Pharmaceutical Chemistry. 2Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh-11451, Saudi Arabia. *To whom correspondence should be addressed. E-mail: [email protected] 1,4-dihydropyridine pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs into the brain. Monoamine oxidase inhibitors (MAOIs) were used as a model example to be delivered into the brain. Chemical and biological oxidations of these compounds were investigated. The prepared 1,4-dihydropyridines were subjected to various chemical and biological oxidation to evaluate their ability to cross blood brain barrier (BBB), and to be oxidized biologically into their corresponding quaternary compounds. 1-(Ethoxy-carbonylmethyl)-3,5-bis[N-(2-fluorobenzylideneamino) carbamoyl]-1,4-dihydropyridine (31) proved to cross BBB in adequate rate and converted by the oxidizing enzymes into the corresponding quaternary salt N-(ethoxycarbonylmethyl)-3,5-bis[N-(2-fluorobenzylideneamino)carbamoyl]pyridinium bromide (20). Stability studies of the synthesized chemical delivery systems (CDSs) at various pH values and temperatures showed that the shelf life time of a solution containing compound 31 is 20.53 days at 5°C, which recommend a lower storage temperature for such solutions. The prepared CDSs proved to be fairly stable for powder form storage. The stability of the prepared compounds is attributed to the conjugation of the two carboxylic functions at C3 and C5 of the pyridine ring with their adjacent double bonds. These results are in consistency with the original rationale desig