Synthesis, characterization and inhibitory potency of two oxono and thiono analogues of phosphoramidate compounds on acetylcholinesterase.
Two novel structurally related phosphoramidate compounds, 1 and 2, with likely beta-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 k(i) values of 1 and 2 were 1.39 to 2.65 min(-1) respectively. A comparison of the bimolecular rate constant (k(i)) 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.
Gholivand
Khodayar
K
Department of Biochemistry and Biophysics, Faculty of Science, Tarbiat Modares University, Tehran, Iran. gholi_kh@modares.ac.ir
Mojahed
Fresia
F
Salehi
Marjan
M
Naderi-Manesh
Hossein
H
Khajeh
Khosro
K
D000110:Acetylcholinesterase / Q000378:metabolism*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D000577:Amides; D002800:Cholinesterase Inhibitors; D010756:Phosphoric Acids; D013438:Sulfhydryl Compounds; C011067:phosphoramidic acid; D000110:Acetylcholinesterase; D010100:Oxygen