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Phenytoin-based bivalent ligands: Design, synthesis and anticonvulsant activity

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  • Drug Design and Discovery
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Abstract

Synthesis, characterization and anticonvulsant properties of new bivalent ligands derived from phenytoin were described. Initial anticonvulsant screening was performed using maximal electroshock (MES) and pentylenetetrazole (PTZ) screens in mice. The neurotoxicity for compounds that showed significant anticonvulsant activity was determined applying the rotorod test. Most of the test compounds were found to be effective in at least one seizure model in a dose of 100 mg/kg. Compound 5e exhibited marked anticonvulsant activity in both MES and PTZ screens. The computer-aided prediction of biological activity was carried out.

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References

  • Ahsan, M. J., Samy, J. G., Khalilullah, H., Nomani, M. S., Saraswat, P., Gaur, R., and Singh, A., Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues as potential antimicrobial agents. Bioorg. Med. Chem. Lett., 21, 7246–7250 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Cramer, J. A., Mintzer, S., Wheless, J., and Mattson, R. H., Adverse effects of antiepileptic drugs: a brief overview of important issues. Expert Rev. Neurother., 10, 885–891 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Cuadrado, A. and Armijo, J. A., Beneficial interactions between vigabatrin and valproate against seizures induced by pentylenetetrazole in mice. Pharmacol. Res., 51, 489–496 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Dimmock, J. R., Pandeya, S. N., Quail, J. W., Allen, T. M., and Kao, G. Y., Evaluation of the semicarbazones, thiosemicarbazones and bis-carbohydrazones of some aryl alicycylic ketones for anticonvulsant and other biological properties. Eur. J. Med. Chem., 30, 303–314 (1995).

    Article  CAS  Google Scholar 

  • Fisher, R. S., Animal models of the epilepsies. Brain Res. Rev., 14, 245–278 (1989).

    Article  PubMed  CAS  Google Scholar 

  • George, S. R., O’Dowd, B., and Lee, S. P., G-protein-coupled receptor oligomerization and its potential for drug discovery. Nat. Rev. Drug Discov., 1, 808–820 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Greenwood, R. S., Adverse effects of antiepileptic drugs. Epilepsia, 41, 42–52 (2000).

    Article  Google Scholar 

  • Huber, D., Löber, S., Hübner, H., and Gmeiner, P., Bivalent molecular probes for dopamine D2-like receptors. Bioorg. Med. Chem., 20, 455–466 (2012).

    Article  PubMed  CAS  Google Scholar 

  • Hudkins, R. L. and DeHaven-Hudkins, D. L., Phenytoin derivatives as potent -ligands. Bioorg. Med. Chem. Lett., 4, 2185–2188 (1994).

    Article  CAS  Google Scholar 

  • Kaminski, K., Rzepka, S., and Obniska, J., Synthesis and anticonvulsant activity of new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones. Bioorg. Med. Chem. Lett., 21, 5800–5803 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Kitano, Y., Usui, C., Takasuna, K., Hirohashi, M., and Nomura, M., Increasing-current electroshock seizure test: A new method for assessment of anti- and pro-convulsant activities of drugs in mice. J. Pharmacol. Toxicol. Methods, 35, 25–29 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Krall, R. L., Penry, J. K., White, B. G., Kupferberg, H. J., and Swinyard, E. A., Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia, 19, 409–428 (1998).

    Article  Google Scholar 

  • Lenkowski, P. W., Batts, T. W., Smith, M. D., Ko, S. H., Jones, P. J., Taylor, C. H., McCusker, A. K., Davis, G. C., Hartmann, H. A., White, H. S., Brown, M. L., and Patel, M. K., A pharmacophore derived phenytoin analogue with increased affinity for slow inactivated sodium channels exhibits a desired anticonvulsant profile. Neuropharmacology, 52, 1044–1054 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Lipinski, C. A., Lombardo, F., Dominy, B. W., and Feeney, P. J., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 46, 3–26 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Löscher, W., Nau, H., Marescaux, C., and Vergnes, M., Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models of epilepsy. Eur. J. Pharmacol., 99, 211–218 (1984).

    Article  PubMed  Google Scholar 

  • Löscher, W., Honack, D., Fassbender, C. P., and Nolting, B., The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs, III: Pentylenetetrazole seizure models. Epilepsy Res., 8, 171–189 (1991).

    Article  PubMed  Google Scholar 

  • Löscher, W., New visions in the pharmacology of anticonvulsion. Eur. J. Pharmacol., 342, 1–13 (1998).

    Article  PubMed  Google Scholar 

  • Löscher, W. and Schmidt, D., New horizons in the development of antiepileptic drugs: Innovative strategies. Epilepsy Res., 69, 183–272 (2006).

    Article  PubMed  Google Scholar 

  • Obniska, J., Kaminski, K., Dorota, S., and Pichor, J., Synthesis and anticonvulsant activity of new N-[(4-arylpiperazin-1-yl)-alkyl] derivatives of 3-phenyl-pyrrolidine-2,5-dione. Eur. J. Med. Chem., 44, 2224–2233 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Ouchi, M., Inoue, Y., Liu, Y., Nagamune, S., Nakamura, S., Wada, K., and Hakushi, T., Convenient and efficient tosylation of oligoethylene glycosl and the related alcohols in tetrahydrofuran-water in the presence of sodium hydroxide. Bull. Chem. Soc. Jpn., 63, 1260–1262 (1990).

    Article  CAS  Google Scholar 

  • Pandeya, S. N., Yogeeswari, P., and Stables, J. P., Synthesis and anticonvulsant activity of 4-bromophenyl substituted aryl semicarbazones. Eur. J. Med. Chem., 35, 879–886 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Paxton, J. W., Rowell, F. J., and Ratcliffe, J. G., Production and characterisation of antisera to diphenylhydantoin suitable for radioimmunoassay. J. Immunol. Methods, 10, 317–327 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Poupaert, J. H., Mergen, F., and Lerot, T., Synthesis of bivalent ligands derived from phenytoin. Bull. Soc. Chim. Belg., 97, 469–470 (1988).

    Article  CAS  Google Scholar 

  • Refsgaard, H. H., Jensen, B. F., Brockhoff, P. B., Padkjaer, S. B., Guldbrandt, M., and Christensen, M. S., In silico prediction of membrane permeability from calculated molecular parameters. J. Med. Chem., 48, 805–811 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Rogawski, M. A., Molecular targets versus models for new antiepileptic drug discovery. Epilepsy Res., 68, 22–28 (2006).

    Article  PubMed  Google Scholar 

  • Scheurer, M. L. and Pedley, T. A., The evaluation and treatment of seizures. N. Engl. J. Med., 323, 1468–1474 (1990).

    Article  Google Scholar 

  • Schlögl, K., Wessely, F., and Korger, G., Zur kenntnis der hydantoinpeptide. Monatsh. Chem., 83, 493–512 (1952).

    Article  Google Scholar 

  • Upton, N., Mechanisms of action of new antiepileptic drugs: rational design and serendipitous findings. Trends Pharmacol. Sci., 15, 456–463 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Veber, D. F., Johnson, S. R., Cheng, H. Y., Smith, B. R., Ward, K. W., and Kapple, K. D., Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 45, 2615–2623 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Wright, D. and Usher, L., Multivalent binding in the design of bioactive compounds. Curr. Org. Chem., 5, 1107–1131 (2001).

    Article  CAS  Google Scholar 

  • Zha, C., Brown, G. B., and Brouillette, W. J., Synthesis and structure-activity relationship studies for hydantoins and analogues as voltage-gated sodium channel ligands. J. Med. Chem., 47, 6519–6528 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Zhao, Y. H., Abraham, M. H., Le, J., Hersey, A., Luscombe, C. N., Beck, G., Sherborne, B., and Cooper, I., Rate-limited steps of human oral absorption and QSAR studies. Pharm. Res., 19, 1446–1457 (2002).

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Samir Botros.

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Botros, S., Khalil, N.A., Naguib, B.H. et al. Phenytoin-based bivalent ligands: Design, synthesis and anticonvulsant activity. Arch. Pharm. Res. 35, 2105–2116 (2012). https://doi.org/10.1007/s12272-012-1207-3

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  • DOI: https://doi.org/10.1007/s12272-012-1207-3

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