Acetylcholinesterase Inhibition by Diaza- and Dioxophosphole Compounds: Synthesis and Determination of IC₅₀Values

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.

Inhibition of AChE by malathion and some structurally similar compounds

“…The replacement of sulphur with oxygen in the cases of both malaoxon and isomalathion causes an increased positive charge density on the central phosphorous atom, facilitating the nucleophilic attack of the ZOH group of serine. Recently, quantitative structure -activity relationships represented an attempt to corelate the structural properties of some carbamates and isoelectronic and isostructural diaza-and dioxophospholes with AChE inhibition [31,32]. Although the investigated organophosphates have similar structures, it is clear that the combination of substituents at the central phosphorous atom is responsible for their different inhibition powers.…”

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

“…In Table II the effect of oximes on hAChE inhibited by compounds 1 and 2 are shown. Also the K m value for the enzyme was determined and is 108.20 £ 10 25 molL 21 [17].…”

Antibacterial activities of novel nanocomposite biofilms of chitosan/phosphoramide/Ag NPs

“…Recently, the phosphoramides chemistry has become very attractive owing to the various important applications of these molecules like anticancer prodrug compounds . Moreover, these derivatives are effective inhibitors for the ureas , acetylcholinesterase and butyrylcholinesterase enzymes. The biocidal activity of phosphoramides in agriculture is well known so that they are applied as pesticides and insecticides .…”