Acetylcholinesterase inhibition by diaza- and dioxophosphole compounds: synthesis and determination of IC50 values.

Abstract

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 (CH3C6H3 O2P(O)Cl) and B (CH3C6H3(NH)2P(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 IC50 values of 0.48 and 1.54mM, respectively and inactivation constants (k(i)) of 0.0363 and 0.0207min(-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.

• Authors: Khodayar Gholivand, Zahra Shariatinia, Said Ghadimi, Fresia Mojahed, Ahlam Madani Alizadegan, Khosro Khajeh, Hossein Naderi-Manesh
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 19 Issue 5 Pg. 403-7 (Oct 2004) ISSN: 1475-6366 [Print] England
• PMID: 15648654 (Publication Type: Journal Article)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Cholinesterase Inhibitors
• N,N'-(3-methyl)phenylenediaminophosphorylchloridate
• O,O'-(3-methyl)phenylenediphorylchloride
• Organophosphorus Compounds
• Acetylcholinesterase

Topics

• Acetylcholinesterase (chemistry, drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (chemical synthesis, chemistry, pharmacology)
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Inhibitory Concentration 50
• Kinetics
• Organophosphorus Compounds (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Time Factors