Synthesis of 8-alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-ones and evaluation of their anticonvulsant properties.
A series of 8-alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-one derivatives were synthesized using 7-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and the subcutaneous pentylenetetrazole test (sc-PTZ), and their neurotoxicities were measured by the rotarod neurotoxicity test (Tox). The tests demonstrated that 8-hexyloxy-4,5-dihydro-[1.2.4]triazole[4.3-a]quinoline-1-one (4e) and 8-heptyloxy-4,5-dihydro-[1,2,4] triazole[4,3-a]quinoline-1-one (4f) were the most potent anticonvulsants, with 4e having ED50 values of 17.17 mg/kg and 24.55 mg/kg and protective index (PI = TD50/ED50) values of 41.9 and 29.3 in the MES and sc-PTZ tests, respectively, and 4f having ED50 values of 19.7 mg/kg and 21.2 mg/kg and PI values of 36.5 and 33.9 in the MES and sc-PTZ tests, respectively. The PI values of 4e and 4f were many fold better than that of the marketed drugs phenytoin, carbamazepine, phenobarbital and valproate, which have PI values in the range of 1.6-8.1 in the MES test and < 0.22-5.2 in the sc-PTZ test. Structure-activity relationships were also discussed.
Sun
Xian-Yu
XY
Key Laboratory of Organism Functional Factors, Changbai Mountain (Yanbian University), Ministry of Education, Yanji, Jilin 133002, P R China.
Jin
Yun-Zhe
YZ
Li
Fu-Nan
FN
Li
Gao
G
Chai
Kyu-Yun
KY
Quan
Zhe-Shan
ZS
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D003292:Convulsants; D004597:Electroshock; D004827:Epilepsy / Q000139:chemically induced / Q000523:psychology; D005260:Female; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D010433:Pentylenetetrazole; D004856:Postural Balance / Q000187:drug effects; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D013055:Spectrophotometry, Infrared; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity
D000927:Anticonvulsants; D003292:Convulsants; D007202:Indicators and Reagents; D015363:Quinolones; D014230:Triazoles; D010433:Pentylenetetrazole