Synthesis, characterization and inhibitory potency of two oxono and thiono analogues of phosphoramidate compounds on acetylcholinesterase

Abstract

Two novel structurally related phosphoramidate compounds, 1 and 2, with likely β-diketone system were synthesized and characterized by 1H, 13C, 31P NMR, IR spectroscopy and elemental analysis. Compound 2 exhibited a 31P NMR signal which was significantly shielded (8 ppm) relative to compound 1. Determination of human erythrocyte acetylcholinesterase (hAChE) inhibitory activity was carried out according to Ellman's modified kinetic method and the IC50 values of compounds 1 and 2 were 1.567 and 2.986 mM, respectively. The ki values of 1 and 2 were 1.39 to 2.65 min -1 respectively. A comparison of the bimolecular rate constant (ki) and IC50 values for the irreversible inhibitors 1 and 2 revealed that the oxono analogue has greater affinity for hAChE than the thiono compound. Furthermore effects of two conventional oximes paralidoxime (A) and obidoxime (B) on reactivation of the inhibited hAChE were studied but low reactivity was shown by both the oximes.