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Lipophilicity, electronic, steric and topological effects of some phosphoramidates on acethylcholinesterase inhibitory property

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Abstract

The differences in the inhibition potency of organophosphorus agents are manifestations of differing molecular properties of the inhibitors involved in the interaction with the active site of an enzyme. We studied the inhibition potency (IC50) of phosphoramidates with the general formula [(CH3)2N]P(O)[p-NHC6H4-X]2, where, X = F (1), Cl (2), Br (3), I (4), and [(CH3)2N]P(O)X[p-OC6H4-CH3], where, X = o-NHC6H4-CH3 (5), m-NHC6H4-CH3 (6), p-NHC6H4-CH3 (7), on human acetylcholinesterase (AchE) activity. Inhibition of hAChE was evaluated by a modified Ellman’s method, and spectrophotometric measurements. The ability of the compounds to inhibit AChE was predicted by PASS software (version 1.193). The IC50 values for inhibitors 1–7 were found to be 0.19, 0.35, 0.50, 0.63, 2.70, 2.44 and 1.50 mM, respectively. In addition, logP values, by the experimental and calculated (software) methods, were found to be 1.03, 1.64, 2.17, 2.74, 2.34, 2.28 and 2.23. Finally, parameters of IC50, logP, δ31P (phosphorus chemical shifts), σp (para-substituent constant), σ+ (electron-releasing), steric and topological effects were used for the structure-activity relationships (SAR) studies.

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Refrences

  1. W. D. Mallender, T. Szegletes, T. L. Rosenberry, Biochem. 39 (2000) 7753.

    CAS  Google Scholar 

  2. A. Baldwin, Z. Huang, Y. Jounaidi, D. J. Waxman, Arch. Biochem. Biophys. 409 (2003) 197.

    CAS  Google Scholar 

  3. K. Gholivand, A. M. Alizadehgan, F. Mojahed, G. Dehghan, A. Mohamadirad, M. Abdollahi, Z. Naturforsch. 63c (2008) 241.

    CAS  Google Scholar 

  4. K. Kamil, B. Jirl, C. Jirl, K. Jirl, Bioorg. Medic. Chem. Lett. 13 (2008) 3545.

    Google Scholar 

  5. A. K. Singh, Com. Biochem. Physico. 123 (1999) 241.

    CAS  Google Scholar 

  6. S. Basak, V. Magnuson, G. Niemi, R. Regal, G. Veith, Math. Modeling 8 (1986) 300.

    Google Scholar 

  7. C. Hansch, A. Leo, Exploring QSAR, ACS Professional References Book, Washington DC, 1995.

  8. J. H. Letcher, J. R. Van Wazer, J. Chem. Phys. 44 (1966) 815.

    CAS  Google Scholar 

  9. W. Renxiao, F. Ying, L. Luhua, J. Chem. Inf. Comput. Sci. 37 (1997) 615.

    Google Scholar 

  10. S. Ghadimi, V. Khajeh, J. Iran. Chem. Soc. 4 (2007) 325.

    CAS  Google Scholar 

  11. S. Ghadimi, S. Mousavi, Z. Javani, J. Enzy. Inhibit. Medic. Chem. 23 (2008) 213.

    CAS  Google Scholar 

  12. K. Gholivand, A. Mahmoudkhani, M. Khosravi, Phosphorus Sulfur and Silicon 106 (1995) 173.

    CAS  Google Scholar 

  13. K. Gholivand, Z. Shariatinia, A. Tadjarodi, Main. Group. Chem. 4 (2005) 111.

    CAS  Google Scholar 

  14. A. Lagunin, A. Stepanchikova, D. Filimonov, V. Poroikov, PASS. Bioinformatics Applications Note 16 (2000) 747.

    CAS  Google Scholar 

  15. A. A. Geronikaki, J. C. Dearden, D. Filimonov, I. Galaeva, L. Garibova, T. Gloriozova, V. Kranjneva, A. Lagunin, F.Z. Macaev, G. Molodavkin, V. Poroikov, S. I. Pobrebnoi, F. Shepeli, T. Voronina, M. Tsitlakido, L. Vald, J. Med. Chem. 47 (2004) 2870.

    CAS  Google Scholar 

  16. M. Medic-Saric, A. Mornar, T. Badovinac-Crnjevic, I. Jasprica, Croat. Chem. Acta 77 (2004) 367.

    CAS  Google Scholar 

  17. N. Hosa, Z. Radic, I. Tsigeling, H. Berman, D. Quinn, P. Taylor, Biochem. 35 (1996) 995.

    Google Scholar 

  18. M. Hoenicka, Anal. Biochem. 25 (1968) 192.

    Google Scholar 

  19. J. Smith, C. Simons, Enzyme and Their Inhibition Drug Development, CRC Press, 2004.

    Book  Google Scholar 

  20. C. Tolman, Chem. Rev. 77 (1977) 313.

    CAS  Google Scholar 

  21. E. Fluck, G. Heckmann, In Phosphorus-31 NMR Spectroscopy in Stereochemical Analysis, VCH, Weinheim, 1987.

    Google Scholar 

  22. E. Breitmair, W. Voelter, 13C NMR Spectroscopy, 3rd ed., VCH, Weinheim, 1990.

    Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry, Imam Hossein University, P.O. Box, 16575-347, Tehran, Iran

    S. Ghadimi & A. A. Ebrahimi-Valmoozi

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  1. S. Ghadimi
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  2. A. A. Ebrahimi-Valmoozi
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Correspondence to S. Ghadimi.

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Ghadimi, S., Ebrahimi-Valmoozi, A.A. Lipophilicity, electronic, steric and topological effects of some phosphoramidates on acethylcholinesterase inhibitory property. JICS 6, 838–848 (2009). https://doi.org/10.1007/BF03246178

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  • DOI: https://doi.org/10.1007/BF03246178

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