Drug Res (Stuttg) 2013; 63(06): 319-325
DOI: 10.1055/s-0033-1337978
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Synthesis and Anticonvulsant Activity Evaluation of 4-(2-alkoxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones in Various Experimental Seizure Models in Mice

X. Cao
1   College of Pharmacy, Yanbian University, Jilin, China
X.-Q. Deng
1   College of Pharmacy, Yanbian University, Jilin, China
2   Medical College, Jinggangshan University, Ji’an, Jiangxi, China
B. Shu
1   College of Pharmacy, Yanbian University, Jilin, China
S.-B. Wang
1   College of Pharmacy, Yanbian University, Jilin, China
Z.-S. Quan
1   College of Pharmacy, Yanbian University, Jilin, China
› Author Affiliations
Further Information

Publication History

received 21 December 2012

accepted 22 February 2013

Publication Date:
28 March 2013 (online)


A new series of 4-(2-alkoxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones was synthesized using appropriate synthetic route. Their anticonvulsant activities were evaluated experimentally against maximal electroshock test and their neurotoxicities were evaluated under the rotarod neurotoxicity test with intraperitoneally injected mice. The results showed that all target compounds exhibited anticonvulsant activity in varying degrees against maximal electroshock test. Among them, 4-(2-octyloxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5 g) was the most promising compound with the median effective dose (ED50) of 23.7 mg/kg, the median toxicity dose (TD50) of 611.0 mg/kg, and the protective index (PI) of 25.8. Compound 5 g showed the higher safety than the standard carbamazepine (PI=6.5). As well as demonstrating the anti-MES efficacy of compound 5 g, its potency against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline were also established, with the results suggesting that GABA-mediated mechanisms might be involved in its anticonvulsant activity.

  • References

  • 1 Stefan H, Feuerstein T. A randomized open-label comparison of lamotrigine and valproate in patients with juvenile myoclonic epilepsy. pharmacol Ther 2007; 113: 165-183
  • 2 Cramer JA, Smith DB, Mattson RH et al. A method of quantification for the evaluation of antiepileptic drug therapy. Neurology 1983; 33: 26-37
  • 3 Brodie MJ, Dichter MA, Multicentre N. Double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Engl J Med 1996; 334: 168-175
  • 4 Curry WJ, Kulling DL. Topiramate monotherapy for childhood absence seizures: an open label pilot study. Am Fam Physician 1998; 57: 513-520
  • 5 Deng XQ, Wei CX, Li FN et al. Design and synthesis of 10-alkoxy-5, 6-dihydro-triazolo[4,3-d]benzo[f][1,4]oxazepine derivatives with anticonvulsant activity. Eur J Med Chem 2010; 45: 3080-3086
  • 6 Karakurt A, Ozalp M, Isik S et al. Synthesis, anticonvulsant and antimicrobial activities of some new 2-acetylnaphthalene derivatives. Bioorg Med Chem 2010; 18: 2902-2911
  • 7 Alam O, Mullick P, Verma SP et al. Synthesis, anticonvulsant and toxicity screening of newer pyrimidine semicarbazone derivatives. Eur J Med Chem 2010; 45: 2467-2472
  • 8 Blanch LB, Galvez J, Domenach RG. Topological virtual screening: a way to find new anticonvulsant drugs from chemical diversity. Bioorg Med Chem Lett 2003; 13: 2749-2754
  • 9 Kitazaki T, Tasaka A, Hosono H et al. Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone and its analogs. Chem Pharm Bull (Tokyo) 1999; 47: 360-368
  • 10 Sheng C, Che X, Wang W et al. Design and synthesis of novel triazole antifungal derivatives by structure-based bioisosterism. Eur J Med Chem 2011; 46: 5276-5282
  • 11 Huang HC, Reitz DB, Chamberlain TS et al. Synthesis and structure-activity relationships of nonpeptide, potent triazolone-based angiotensin II receptor antagonists. J Med Chem 1993; 36: 2172-2181
  • 12 Mazzone G, Pignatello R, Mazzone S et al. Synthesis of carboxyalkylthio-triazoles and bicyclic derivatives with antiinflammatory and analgesic activity. Farmaco 1992; 47: 149-169
  • 13 Gitto R, Orlando V, Quartarone S et al. Synthesis and evaluation of pharmacological properties of novel annelated 2,3-benzodiazepine derivatives. J Med Chem 2003; 46: 3758-3761
  • 14 Pitucha M, Chodkowska A, Duda R et al. Journal of Biosciences 2009; 64: 615-618
  • 15 Jin HG, Sun XY, Chai KY et al. Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)- ones. Bioorg Med Chem 2006; 14: 6868-6873
  • 16 Sun XY, Jin YZ, Li FN et al. Synthesis of 8-alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-ones and evaluation of their anticonvulsant properties. Arch Pharm Res 2006; 29: 1080-1085
  • 17 Guan LP, Jin QH, Tian GR et al. J Pharm Pharm Sci 2007; 10: 254-262
  • 18 Jin YZ, Guan LP, Zao LM et al. Synthesis and anticonvulsant activity study of 7-Substituted phenoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines and quinoline-1 (2 H)-ones. Chinese J Org Chem 2007; 28: 1567-1572
  • 19 Krall RJ, Penry JK, White BG et al. Antiepileptic drug development: I. History and a program for progress. Epilepsia 1978; 19: 393-407
  • 20 Poter RJ, Cereghino JJ, Gladding GD et al. Evaluation of some thiosemicarbazones of arylidene ketones and analogues for anticonvulsant activities. Cleve Clin Q 1984; 51: 293-305
  • 21 Loscher W, Schmidt D. Gabapentin increases aminooxyacetic acid induced GABA accumulation in several regions of rat brain. Epilepsy Res 1988; 2: 145- 181
  • 22 Arnoldi A, Bonsignori A, Melloni P et al. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs in Maximal electroshock seizure models. J Med Chem 1990; 33: 2865-2872
  • 23 Okada R, Negishi N. The role of the nigrotegmental GABAergic pathway in the propagation of pentylenetetrazol-induced seizures. Brain Res 1989; 480: 383-387
  • 24 Olsen RW. GABA benzodiazepine-barbiturate receptor interactions. J Neurochem 1981; 37: 1-13
  • 25 Gale K. MRI monitoring of vigabatrin-induced intramyelinic edema in dogs. Epilepsia 1992; 33: 3-12
  • 26 Loscher W. 3-Mercaptopropionic acid: convulsant properties, effects on enzymes of the gamma-aminobutyrate system in mouse brain and antagonism by certain anticonvulsant drugs, aminooxyacetic acid and gabaculine. Biochem Pharmacol 1979; 28: 1397-1407
  • 27 Macdonald RL, Barker JL. Enhancement of GABA-mediated postsynaptic inhibition in cultured mammalian spinal cord neurons: a common mode of anticonvulsant action. Neurology 1978; 28: 325-330