Synthesis of some quinoline-2(1H)-one and 1, 2, 4 - triazolo [ 4 , 3 -a ] quinoline derivatives as potent anticonvulsants.

Purpose: A new series of substituted quinoline-2(1H)-one and 1,2,4-triazolo[4,3-a]-quinoline derivatives were designed and synthesized to meet the structural requirements essential for anticonvulsant properties.

Methods: 4-substituted-phenyl-3,4-dihydro-2(1H)-quinolines, 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3a]quinolines and 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo-[4,3-a]quinoline-1-(2H)-ones derivatives were synthesized using 3-substituted-phenyl-N-phenyl-acrylamide as a starting material. Their anticonvulsant activity were evaluated by maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxic effects were determined by the rotarod neurotoxicity test.

Results: The compounds 4-substitued-phenyl-3,4-dihydro-2(1H)-quinolines (2a-f) had increased anticonvulsant effects compared to the parental compounds. The compounds 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3-a]quinolines (3a-f) had significantly increased anticonvulsant activity compared to 2a-f. However, the compounds 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoline-1(2H)-ones(4a-f), exhibited no anticonvulsant effects even under a high dose of 300 mg/kg.

Conclusions: The triazole, but not the triazolone, modified series showed stronger anticonvulsant effects than the parent compounds. Among them, compound (3f), 5-(p-fluorophenyl)-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoline, showed the strongest anticonvulsant effect with ED50 of 27.4mg/kg and 22.0mg/kg in the anti-MES and anti-PTZ test, respectively.