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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. [ABSTRACT FROM AUTHOR]

Carbacylamidophosphates with the general formula RC(O)NHP(O)R1R2 constitute organophosphorus compounds that are used as insecticides, pesticides and ureas inhibitors. In this work, we studied the inhibition potency of CCl3 C(O)NHP(O)Cl21, CHCl2C(O)NHP(O)Cl22, CH2ClC(O)NHP(O)Cl23 and CF3C(O)NHP(O)Cl24, which are the major intermediates for carbacylamidophosphates synthesis towards human erythrocyte acetylcholinesterase (hAChe) activity using Ellman's modified kinetic method. Unexpectedly, it was observed that they were not only hydrolytically unstable but also inhibited hAChE in a similar manner to that produced by organophosphorus insecticides. Enzymatic data, bimolecular inhibition rate constants (ki) and IC50 values for inhibition of hAChE demonstrated that they are irreversible inhibitors and the inhibition potency of compound 2 (IC50 = 88 µM) was the greatest in comparison with compounds 1, 3 and 4. Also the electropositivity of the phosphorus atom and the hydrophobicity of the compounds demonstrated that these two factors play an additional effect and different role in the inhibitory activity of these compounds. Hydrolytic stability of the compounds was determined by Zip NMR monitoring of the loss of the parent molecules with D20 as a function of time. This study considers antiacetylcholinesterase activity according to the structural and the electronic aspects of compounds 1 4, according to IR, ¹H, 13C and 31P NMR spectral data. [ABSTRACT FROM AUTHOR]

Cholinesterases are targets for organophosphorus compounds which are used as pesticides, insecticides, chemical warfare agents and drugs for the treatment of disease such as glaucoma or parasitic infections. Most organophosphorus compounds impart their toxic action via inhibition of cholinesterases by reacting at an essential serine hydroxyl group. The inhibition process depends on the leaving group, stereochemistry and reactivity of the organophosphorus compound. In this study, the inhibitory potency of two isoelectronic and isostructural diaza- and dioxophospholes A (CH 3 C 6 H 3 O 2 P(O)Cl) and B (CH 3 C 6 H 3 (NH) 2 P(O)Cl) against human acetylcholinesterase (hAChE) was examined by spectrophotometric measurements based on Ellman's method. Results indicated that compounds A and B were irreversible inhibitors with IC 50 values of 0.48 and 1.54 mM, respectively and inactivation constants (k i ) of 0.0363 and 0.0207 min -1 , respectively. The differences in the inhibitory potency of two phosphole compounds is discussed with respect to their structures. In addition, the synthesis and characterization of compound A is discussed. [ABSTRACT FROM AUTHOR]