title: 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.affiliation: Department of Chemistry, Faculty of Sciences, Tarbiat Modarres University, Tehran, Iran. gholi_kh@modares.ac.ir
authors.forename: Khodayar
authors.initials: K
authors.lastname: Gholivand
authors.forename: Zahra
authors.initials: Z
authors.lastname: Shariatinia
authors.forename: Said
authors.initials: S
authors.lastname: Ghadimi
authors.forename: Fresia
authors.initials: F
authors.lastname: Mojahed
authors.forename: Ahlam Madani
authors.initials: AM
authors.lastname: Alizadegan
authors.forename: Khosro
authors.initials: K
authors.lastname: Khajeh
authors.forename: Hossein
authors.initials: H
authors.lastname: Naderi-Manesh
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002800:Cholinesterase Inhibitors; C503164:N,N'-(3-methyl)phenylenediaminophosphorylchloridate; C503163:O,O'-(3-methyl)phenylenediphorylchloride; D009943:Organophosphorus Compounds; D000110:Acetylcholinesterase