Abstract
A series of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles were synthesized. The anticonvulsant effect and neurotoxicity of the compounds (intraperitoneally) were evaluated with the maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests in mice. 2-Phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3g) was the most active and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED50) of 29.5 mg/kg, a median toxicity dose (TD50) of 285 mg/kg, and a protective index (PI) of 9.7, which is greater than the reference drug, carbamazepine, which has a PI of 6.4.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdel-Megeed, A. M., Abdel-Rahman, H. M., Alkaramany, G. E., and El-Gendy, M. A., Design, synthesis and molecular modeling study of acylated 1,2,4-triazole-3-acetates with potential anti-inflammatory activity. Eur. J. Med. Chem., 1 (2008).
Al-Soud, Y. A., Al-Masoudi, N. A., and Ferwanah, Ael-R., Synthesis and properties of new substituted 1,2,4-triazoles: potential antitumor agents. Bioorg. Med. Chem., 11, 1701–1708 (2003).
Chen, J., Sun, X. Y., Chai, K. Y., Lee, J. S., Song, M. S., and Quan, Z. S., Synthesis and anticonvulsant evaluation of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazoles as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a] quinolines. Bioorg. Med. Chem., 15, 6775–6781 (2007).
Dawood, K. M., Abdel-Gawad, H., Rageb, E. A., Ellithey, M., and Mohamed, H. A., Synthesis, anticonvulsant, and anti-inflammatory evaluation of some new benzotriazole and benzofuran-based heterocycles. Bioorg. Med. Chem., 14, 3672–3680 (2006).
Díaz-Molina, M., Sánchez-Rodríguez, M. N., Bu, M., and Pérez-Saad, H., The anticonvulsive effect of 4,4-bis (hydroxymethyl)-2-phenyl-2-oxazoline. Rev. Neurol., 40, 652–655 (2005).
Gasior, M., Carter, R. B., Goldberg, S. R., and Witkin, J. M., Anticonvulsant and behavioral effects of neuroactive steroids alone and in conjunction with diazepam. J. Pharmacol. Exp. Ther., 282, 543–553 (1997).
Gülerman, 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).
Krall, R. J., Penry, J. K., White, B. G., Kupferberg, H. J., and Swinyard, E. A., Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia, 19, 409 (1978).
Küçükgüzel, I., Güniz Küçükgüzel, S., Rollas, S., Otük-Sanio, G., Ozdemir, O., Bayrak, I., Altug, T., and Stables, J. P., Synthesis of some 3-(arylalkylthio)-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazole derivatives and their anticonvulsant activity. Farmaco, 59, 893–901 (2004).
Leppik, I. E., Antiepileptic drugs in development: prospects for the near future. Epilepsia, 35, 29–40 (1994).
Pandeya, S. N., Sriram, D., Nath, G., and DeClercq, E., Synthesis, antibacterial, antifungal and anti-HIV activities of Schiff and Mannich bases derived from isatin derivatives and N-[4-(4′-chlorophenyl)thiazol-2-yl] thiosemicarbazide. Eur. J. Pharm. Sci., 9, 25–31 (1999).
Piao, Z. T., Guan, L. P., Zhao, L. M., Piao, H. R., and Quan, Z. S., Synthesis of novel 7-benzylamino-2H-1,4-benzoxazin-3(4H)-ones as anticonvulsant agents. Eur. J. Med. Chem., 43, 1216–1221 (2008).
Pinar, A., Yurdakul, P., Yildiz, I., Temiz, A. O., Acan, N. L., Aki-Sener, E., and Yalcin, I., Some fused heterocyclic compounds as eukaryotic topoisomerase II inhibitors. Biochem. Biophys. Res. Commun, 317, 670–674 (2004).
Poter, R. J., Cereghino, J. J., Gladding, G. D., Hessie, B. J., Kupferberg, H. J., Scoville, B., and White, B. G., Antiepileptic Drug Development Program. Cleve. Clin. Q., 51, 293 (1984).
Reynolds, M. B., DeLuca, M. R., and Kerwin, S. M., PRELIMINARY COMMUNICATION The Novel Bis(benzoxazole) Cytotoxic Natural Product UK-1 Is a Magnesium Ion-Dependent DNA Binding Agent and Inhibitor of Human Topoisomerase II. Bioorganic. Chemistry, 27, 326–337 (1999).
Sener, E. A., Arpaci, O. T., Yalçin, I., and Altanlar, N., Synthesis and microbiological activity of some novel 5-benzamido- and 5-phenylacetamido-substituted-2-phenylbenzoxazole ∖derivatives. Farmaco, 55, 397–405 (2000).
Shi, D. F., Bradshaw, T. D., Wrigley, S., McCall, C. J., Lelieveld, P., Fichtner, I., and Stevens, M. F., Antitumor benzothiazoles 3. Synthesis of 2-(4-aminophenyl)benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo. J. Med. Chem., 39, 3375–3384 (1996).
Silva, F. D., Souza, M. C., Frugulhetti, II., Castro, H. C., Souza, S. L., Souza, T. M., Rodrigues, D. Q., Souza, A. M., Abreu, P. A., Passamani, F., Rodrigues, C. R., and Ferreira, V. F., Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates. Eur. J. Med. Chem., Mar 16 (2008).
Stocks, M. J., Cheshire, D. R., and Reynolds, R., Efficient and regiospecific one-pot synthesis of substituted 1,2,4-triazoles. Org. Lett., 6, 2969–2971 (2004).
Sun, X. Y., Jin, Y. Z., Li, F. N., Li, G., Chai, K. Y., and Quan, Z. S., 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., 29, 1080–1085 (2006).
Temiz, O., Oren, I., Sener, E., Yalçin, I., and Uçartürk, N., Synthesis and microbiological activity of some novel 5- or 6-methyl-2-(2,4-disubstituted phenyl) benzoxazole derivatives. Farmaco, 53, 337–341 (1998).
Temiz, A. O., Ozdemir, A., Yalçin, I., Yildiz, I., Aki-Sener, E., and Altanlar, N., Synthesis and antimicrobial activity of some 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted piperazin-1-yl)acetamido]-2-(p-substituted-phenyl) benzoxazoles. Arch Pharm (Wein heim), 338, 105–111 (2005).
Unlü, S., Baytas, S. N., Kupeli, E., and Yesilada, E., Studies on novel 7-acyl-5-chloro-2-oxo-3H-benzoxazole derivatives as potential analgesic and anti-inflammatory agents. Arch. Pharm. (Weinheim), 336, 310–321 (2003).
Yildiz, O. I., Tekiner, G. B., Yalcin, I., Temiz, A. O., Aki, S. E., and Altanlar, N., Synthesis and antimicrobial activity of new 2-[p-substituted-benzyl]-5-[substituted-carbonylamino] benzoxazoles. Arch. Pharm. (Weinheim), 337, 402–410 (2004).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wei, CX., Guan, LP., Jia, JH. et al. Synthesis of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles as potential anticonvulsant agents. Arch. Pharm. Res. 32, 23–31 (2009). https://doi.org/10.1007/s12272-009-1114-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-009-1114-4