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The Pharmaceutical Society of Korea (대한약학회)
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Synthesis of 8-Alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-ones and Evaluation of their Anticonvulsant Properties

  • Sun, Xian-Yu (College of Pharmacy, Yanbian University) ;
  • Jin, Yun-Zhe (College of Pharmacy, Yanbian University) ;
  • Li, Fu-Nan (Key Laboratory of Organism Functional Factors of the Changbai Mountain (Yanbian University), Ministry of Education) ;
  • Li, Gao (Key Laboratory of Organism Functional Factors of the Changbai Mountain (Yanbian University), Ministry of Education) ;
  • Chai, Kyu-Yun (Department of Chemistry, Wonkwang University) ;
  • Quan, Zhe-Shan (Key Laboratory of Organism Functional Factors of the Changbai Mountain (Yanbian University), Ministry of Education)
  • Published : 2006.12.31
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Abstract

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 $ED_{50}$ values of 17.17 mg/kg and 24.55 mg/kg and protective index ($PI=TD_{50}/ED_{50}$) values of 41.9 and 29.3 in the MES and sc-PTZ tests, respectively, and 4f having $ED_{50}$ 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.

Keywords

References

  1. Chimirri, A., Bevacqua, F., Gitto, R., Quartarone, S., Zappala. M., De Sarro, A., Maciocco, L., Biggo, G., and De Sarro, G., Synthesis and anticonvulsant activity of new 11H-triazole [4,5-c][2,3]benzodiazepines. Med. Chem. Res., 9, 203-212 (1999)
  2. Colin, X. and Sauleau, A., Coulon, J. 1,2,4-Triazole mercapto and aminonitriles as potent antifungal agents. Bioorg. Med. Chem. Lett., 13, 2601-2605 (2003) https://doi.org/10.1016/S0960-894X(03)00378-0
  3. Cui, L. J., Xie, Z. F., Piao, H. R., Li, G., Chai, K. Y., and Quan, Z. S. Synthesis and anticonvulsant activity of 1-substituted-7- benzyloxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline. Biol. Pharm. Bull., 28,1216-1220 (2005) https://doi.org/10.1248/bpb.28.1216
  4. Cunha, A. C., Figuerredo, J. M., and Tributino, J. L., Antiplatelet properties of novel N-substituted- phenyl-1,2,3-triazole-4- acylhydrazone derivatives. Bioorg. Med. Chem., 11, 2051- 2059 (2003) https://doi.org/10.1016/S0968-0896(03)00055-5
  5. Gitto, R., Orlando, V., Quartarone, S., De Sarro, G., De Sarro, A., Russo, E., Ferreri, G., and Chimirri, A., Synthesis and evaluation of pharmacological properties of novel annelated 2,3-benzodiazepine derivatives. J. Med. Chem., 46, 3758 (2003) https://doi.org/10.1021/jm030821p
  6. Gulerman, N. N., Dogan, H., N., Rollas, S., Johansson, C., and Celik, C., Synthesis and structure elucidation of some new thioether derivatives of 1,2,4-triazoline-3-thiones and their antimicrobial activities. Farmaco, 56, 953-958 (2001) https://doi.org/10.1016/S0014-827X(01)01167-3
  7. Kane, J. M., Baron, B. M., Dudley, M. W., Sorensen, S. M., Staeger, M. A., and Miller, F. P., 2,4-Dihydro-3H-1,2,4-triazol- 3-ones as anticonvulsant agents. J. Med. Chem., 33, 2772- 2777 (1990) https://doi.org/10.1021/jm00172a015
  8. Krall, R. J., Penry, J. K., White, B. G., and Kupferberg, H. J., Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia, 19, 409-428 (1978) https://doi.org/10.1111/j.1528-1157.1978.tb04507.x
  9. Labanauskas, L., Udrenaite, E., Gaidelis, P., and Brukstus, A., Synthesis of 5-(2-,3- and 4-PTZhoxyphenyl)-4H-1,2,4-triazole- 3-thiol derivatives exhibiting anti-inflammatory activity. Farmaco, 59, 255-259 (2004) https://doi.org/10.1016/j.farmac.2003.11.002
  10. Lazrek, H. B., Taourirte, M., Oulih, T., Barascut, J. l., Imbach, J. L., Pannecouque, C., Witrouw, M., and De Clercq, E. Synthesis and anti-HIV activity of new modified 1,2,3-triazole acyclonucleosides. Nucleosides. Nucleotides. Nucleic. Acids., 20, 1949-1960 (2001) https://doi.org/10.1081/NCN-100108325
  11. Maria, Z., Rosaria, G., Francesca, B., Silvana, Q., Alba, C., Milena, R., Giovambattista, D. S., and Angela D. S., Synthesis and Evaluation of Pharmacological and Pharmacokinetic Properties of 11H-[1,2,4] Triazole[4,5-c][2,3]benzodiazepin- 3(2H)-ones. J. Med. Chem., 43, 4834-4839 (2000) https://doi.org/10.1021/jm001012y
  12. Poter, R. J., Cereghino, J. J., Gladding, G. D., Hessie, B. J., Kupferberg, H. J., and Scoville, B., Antiepileptic drug development program. Clev. Clin. J. Med., 51, 293-305 (1984) https://doi.org/10.3949/ccjm.51.2.293
  13. Quan, Z. S., Wang, J. M., Lee, W. Y., Kwak, K. C., Kang, H. C., and Chai, K. Y., Synthesis of 6-alkyloxyl-3,4-dihydro-2(1H)- quinoliones and their Anticonvulsant Activities. Bull. Kor. Chem. Soc., 26, 1757-1760 (2005) https://doi.org/10.5012/bkcs.2005.26.11.1757
  14. Ucar, H., Van derpoorten, K., Cacciagurra, S., Spampinato, S., Stables, J. P., Depovere, P., Isa, M., Masereel, B., Delarge, J., and Poupaert, J. H., Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives. J. Med.Chem., 41, 1138-1145 (1998) https://doi.org/10.1021/jm970682+
  15. Xie, Z. F., Chai, K. Y., Piao, H. R., Kwak, K. C., and Quan, Z. S., Synthesis and anticonvulsant activity of 7-alkoxyl-4,5- dihydro-[1,2,4]triazole[4,3-a]quinolines. Bioorg. Med. Chem. Lett., 15, 4803-4805 (2005) https://doi.org/10.1016/j.bmcl.2005.07.051
  16. Zappala, M., Gitto, R., Bevacqua, F., Quartarone, S., Chimirri, A., Rizzo, M., De Sarro, G., and De Sarro, A., Synthesis and evaluation of pharmacological and pharmacokinetic properties of 11H- [1,2,4] triazole [4,5-c] [2,3] benzodiazepin-3(2H)- ones. J. Med. Chem., 43, 4834-4839 (2000) https://doi.org/10.1021/jm001012y