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

Novel thiono and seleno phosphoramidate compounds with the general formula (X)(Y)P(C(6)H(5))(2); (X = NMe(2) & Y = S, 1a; X = NEt(2) & Y = S, 2a; X = NMe(CH(2)Ph) & Y = S, 3a; X = NH(CH(2)Ph) & Y = S, 4a; X = NEt(CH(2)Ph) & Y = S, 5a; X = N(C(Me)(3)) (CH(2)Ph) & Y = S, 6a; X = N(CH(2)Ph)(2) & Y = S, 7a; X = NMe(2) & Y = Se, 1b; X = NEt(2) & Y = Se, 2b; X = NMe(CH(2)Ph) & Y = Se, 3b; X = NH (CH(2)Ph) & Y = Se, 4b; X = NEt(CH(2)Ph) & Y = Se, 5b; X = N(C(Me)(3))(CH(2)Ph) & Y = Se, 6b and X = N(CH(2)Ph)(2) & Y = Se, 7b) were prepared and characterized by (1)H, (31)P and( 13)C NMR and IR spectroscopy and elemental analysis. (31)P 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. IC(50 )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.