Skip to main content
SpringerLink
Log in

Structure-toxicity relationships of thiono and seleno phosphoramidate compounds: new type of acetylcholinesterase inhibitors

  • Full Length Paper
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

Novel thiono and seleno phosphoramidate compounds with the general formula (X)(Y)P(C6H5)2; (X = NMe2 & Y = S, 1a; X = NEt2 & Y = S, 2a; X = NMe(CH2Ph) & Y = S, 3a; X = NH(CH2Ph) & Y = S, 4a; X = NEt(CH2Ph) & Y = S, 5a; X = N(C(Me)3) (CH2Ph) & Y = S, 6a; X = N(CH2Ph)2 & Y = S, 7a; X = NMe2 & Y = Se, 1b; X = NEt2 & Y = Se, 2b; X = NMe(CH2Ph) & Y = Se, 3b; X = NH (CH2Ph) & Y = Se, 4b; X = NEt(CH2Ph) & Y = Se, 5b; X = N(C(Me)3)(CH2Ph) & Y = Se, 6b and X = N(CH2Ph)2 & Y = Se, 7b) were prepared and characterized by 1H, 31P and 13C NMR and IR spectroscopy and elemental analysis. 31P chemical shift of thiono and seleno derivatives didn’t show significant different because of their little difference in electronegativity sulfur and selenium. Hydrophobic parameter of compounds was determined by measurement of octanol-water partition coefficient by shake-flask technique. Determination of human erythrocyte acetylcholinesterase (hAChE) activity was carried out according to the Ellman’s modified kinetic method. IC50 values of the selected thiono and seleno compounds varied from 3.4 to 0.11 and 9.9 to 5.1 mM, respectively. The seleno compounds show lower affinities for hAChE relative to the thino compounds. These results demonstrate that hydrophobic and electronic factors of the organophosphorus compounds play a key role on the inhibitory potency.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Cohen SD, Williams RA, Killinger JM, Freudenthal RI (1985) Comparative sensitivity of bovine and rodent acetylcholinesterase to in␣vitro inhibition by organophosphate insecticides. Toxicol Appl Pharmacol 83:452–459

    Article  Google Scholar 

  2. Pardio VT, Ibarra N, Rodriguez MA (2001) Use of cholinesterase activity in monitoring organophosphate pesticide exposure of cattle produced in tropical areas. J Agric Food Chem 9:6057–6052

    Article  CAS  Google Scholar 

  3. Quistad GB, Zhang N, Sparks SE, Casida JE (2000) Phosphoacetylcholinesterase: toxicity of phosphorus oxychloride to mammals and insects that can be attributed to selective phosphorylation of acetylcholinesterase by phosphorodichloridic acid. Chem Res Toxicol 13:652–657

    Article  CAS  Google Scholar 

  4. Mallender WD, Szegletes T, Rosenberry TL (2000) Acetylthiocholine binds to Asp74 at the peripheral site of human acetylcholinesterase at the first step in the catalytic pathway. Biochem 39:7753–7763

    Article  CAS  Google Scholar 

  5. Massoulie J, Pezzementi L, Bon S, Krejci E, Vallette FM (1993) Molecular and cellular biology of cholinesterases, prog. Neurobiol 41:31–91

    CAS  Google Scholar 

  6. Casale GP, bavari S, Connolly J (1989) Inhibition of human serum complements activity by diisopropylfluorophosphates and selected anticholinestrase insecticides. Fundam Appl Toxicol 12:460–468

    Article  CAS  Google Scholar 

  7. Jokanovic M, Maksimovic M, Kilibarda V, Jovanovic D, Savic D (1996) Qxime-induced reactivation of acetylcholinesterase inhibited by phosphoramidates. Toxicol Lett 85:35–39

    Article  CAS  Google Scholar 

  8. Vilanova E, Johnson MK, Vicedo JL (1987) Interaction of some unsubstituted phosphoramidate analogs of methamidophos (O, S-dimethyl phosphorothioamidate) with acetylcholinesterase and neuropathy target esterase of hen brain. Pestic Biochem Physiol 28:224–238

    Article  CAS  Google Scholar 

  9. Maxwell DM, Brecht KM (1992) Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analogs of organophosphorus compounds. Chem Res Toxicol 5:66–71

    Article  CAS  Google Scholar 

  10. Thompson CM, Frick JA, Natke BC, Hansen LK (1989) Preparetion, analysis and anticholinesterase properties of O, O-dimethyl phosphorothioate isomerides. Chem Res Toxicol 2:386–391

    Article  CAS  Google Scholar 

  11. Yang H-Z, Zhang Y-J, Wang L-X, Tan H-F, Cheng M-R, Xing X-D, Chen R-Y, Fujita T (1986) Quantitative structure-activity study of herbicidal O-aryl O-ethyl N-isopropylphosphoramidothioates Pesticide. Biochem Physiol 26:275–283

    CAS  Google Scholar 

  12. Segall Y, Quistad GB, Sparks SE, Casidaet JE (2003) Major intermediates in organophosphate synthesis (PCl3, POCl3, PSCl3, and their diethyl esters) are anticholinesterase agents directly or on activation. Chem Res Toxicol 16:350–356

    Article  CAS  Google Scholar 

  13. Ryu S, Lin J, Thompson CM (1991) Comparative anticholinesterase potency of chiral isoparathion methyl. Chem Res Toxicol 4:517–520

    Article  CAS  Google Scholar 

  14. Metcalf RL, Francis BM, Metcalf RA, Farage-Elawar M, Hansen LG (1988) Structure- activity relationships in the acute and delayed neurotoxicity of methyl- and etylphosphonothionates. Pestic Biochem Physiol 30:46–56

    Article  CAS  Google Scholar 

  15. Levi PE, Hollingworth RM, Hodgson E (1998) Differences in oxidative dearylation and desulfurration of fenitrothion by cytochrome p−450 isozymes and in the subsequent inhibition of monooxygenase activity. Pestic Biochem Physiol 32:224–231

    Article  Google Scholar 

  16. Lee H, Kim YA, Cho YA, Lee YT (2002) Oxidation of organophosphorus pesticides for the sensitive detection by a cholinesterase-based biosensor. Chemosphere 46:571–576

    Article  CAS  Google Scholar 

  17. Casida JE (1964) Esterase inhibitors as pesticides. Science 146:1011–1017

    Article  CAS  Google Scholar 

  18. Chevykalova MN, Manzhukova LF, Artemova NV, Luzikov YN, Nifant’ev IE, Nifant’ev EE (2003) Electron-donating ability of triarylphosphines and related compounds studied by P-31 NMR spectroscopy. Russ Chem Bull 52:78–84

    Article  CAS  Google Scholar 

  19. Pilioni G, Longato B, Bandoli G (1999) Variable coordination modes for 1,1′-bis(diphenylphosphino) ferrocene (dppf) mono- and di-chalcogenides or-oxides (dppfE and dppfE2, E = O, S or Se) in copper(1) complexes. crystal structure of [{Cu(dppf)}2 (Ix-dppfS2)](BF4)2 and [ Cu(dppfSe)2]BF4. Inorg Chim Acta 277:163–170

    Article  Google Scholar 

  20. Bhattacharyya P, Slawin AMZ, Woollins JD (2001) Bridge cleavage of [{PhP(Se)(μ-Se)}2] by 1,2-C6H4(EH)(E′H) (E, E′ = O or NH). X-ray crystal structure of PhP(Se)(NHC6H4NH-1,2). J Organomet Chem 623:116–119

    Google Scholar 

  21. Rudd MD, Creighton MA, Kautz JA (2004) Synthesis and characterization of chalcogenoic aminophosphines: X-ray structures of Bu2P(E)NHPr (E = Se, Te), Ph2P(Se)NHPr and {Et2P(Se)}2NPr, Polyhedron 23:1923–1929

    Google Scholar 

  22. Venkatakrishnan TS, Krishnamurthy SS, Nethaji M (2005) Chalcogen-capped ruthenium carbonyl clusters derived from diphosphazane mono- and dichalcogenides of the type X2P(E)N(R)PX2 and X2P(E)N (R)P(E)X2 (E = S or Se). J Organomet Chem 690:4001–4017

    Article  CAS  Google Scholar 

  23. Bayandina EV, Nuretdinov IA, Nurmukhamedova LV (1978) Synthesis of arylselenophosphinic acid derivatives and their properties. J Gen Chem USSR 48:2673–2677

    CAS  Google Scholar 

  24. Cupertino D, Birdsall DJ, Slawin AMZ (1999) The preparation and coordination chemistry of iPr2P(E)NHP(E′)iPr2 (E, E′ = Se, E = Se, E′ = S, E = S, E′ = O, E,E′ = O. Inorg Chim Acta 290:1–7

    Article  CAS  Google Scholar 

  25. Schultz TW, Cronin MTD, Walker JD, Aptula AO (2003) Quantitative structure–activity relationships (QSARs) in toxicology: a historical perspective. J Mol Struct (Theochem), 622: 1–22

    Google Scholar 

  26. Karelson M, Lobanov VS, Katritzky AR (1996) Quantum-chemical descriptors in QSAR/QSPR studies. Chem Rev 96:1027–1044

    Article  CAS  Google Scholar 

  27. Lewis DF V (2004) Quantitative structure–activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes. Toxicol In Vitro 18:89–97

    Article  CAS  Google Scholar 

  28. Hansch C, Steinmetz WE, Leo AJ, Mekapati SB, Kurup A, Hoekman D (2003) On the role of polarizability in chemical-biological interactions. J Chem Inf Comput Sci 43:120–125

    Article  CAS  Google Scholar 

  29. Hansch C, Dunn W (1972) Linear relationships between lipophilic chatacter and biological activity of drugs. J Pharm Sci-Us 61:1–19

    Article  CAS  Google Scholar 

  30. Henchman RH, Tai K, Shen T, MaCammon JA (2002) Properties of water molecules in the active site gorge of acetylcholinesterase from computer simulation. Biophys J 82:2671–2682

    Article  CAS  Google Scholar 

  31. Doorn JA, Gage DA, Schall M, Talley TT, Thompson CM, Richardson RJ (2000) Inhibition of acetylcholinesterase by (1S,3S)-isomalathion proceeds with loss of thiomethyl: kinetic and mass spectral evidence for an unexpected primary leaving group. Chem Res Toxicol 13:1313–1320

    Article  CAS  Google Scholar 

  32. Barak D, Ordentlich A, Kaplan D, Barak R, Mizrahi D, Kronman C, Segall Y, Velan B, Shafferman A (2000) Evidence for P-N bond scission in phosphoroamidate nerve agent adducts of human acetylcholinesterase. Biochem 39:1156–1161

    Article  CAS  Google Scholar 

  33. Tompson CM, Suarez AI, Rodriguez OP (1996) Synthesis and 31P chemical shift identification of tripeptide active site models that represent human serum acetylcholinesterase covalently modified at serine by certain organophosphates. Chem Res Toxicol 9:1325–1332

    Article  Google Scholar 

  34. Corbridge DEC (1995) Phosphorus, an outline of its chemistry, biochemistry and technology. 5th edn. Elsevier, The Netherlands

  35. Ellman GL, Courinfy KD, Andress V, Featherstone RM (1961) A new and rapid colorimetric determination of acethylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  Google Scholar 

  36. Lee BH, Stelly TC, Colucci WJ, Garcia GJ, Gandour RD, Quinn DM (1992) Inhibition of acetylcholinesterase by hemicholiniums, conformationally constrained choline analogs. Evaluation of aryl and alkyl substituents. Comparisons with choline and (3-hydroxyphenyl)trimethylammonium. Chem Res Toxicol 5:411–418

    Article  CAS  Google Scholar 

Download references

Acknowledgements

S.D. would like to acknowledge the Alzahra University Research Council for partial support of this work. The authors are pleased to thank Professor Issa Yavari (Tarbiat Modarres University, Iran) for insightful NMR discussions.

Author information

Authors and Affiliations

  1. Department of Chemistry, Alzahra University, P.O. Box 1993891176, Tehran, Iran

    Saeed Dehghanpour & Minoo Bagheri

  2. Department of Biochemistry, Faculty of Medicine, Urmia Medical Sciences University, Urmia, Iran

    Yousef Rasmi

Authors
  1. Saeed Dehghanpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yousef Rasmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Minoo Bagheri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Saeed Dehghanpour.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dehghanpour, S., Rasmi, Y. & Bagheri, M. Structure-toxicity relationships of thiono and seleno phosphoramidate compounds: new type of acetylcholinesterase inhibitors. Mol Divers 11, 47–57 (2007). https://doi.org/10.1007/s11030-007-9056-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-007-9056-6

Keywords

Search

Navigation