ABSTRACT
Activated organophosphate (OP) insecticides and chemical agents inhibit acetylcholinesterase (AChE) to form OP-AChE adducts. Whereas the structure of the OP correlates with the rate of inhibition, the structure of the OP-AChE adduct influences the rate at which post-inhibitory reactivation or aging phenomena occurs. In this report, we prepared a panel of ß-substituted ethoxy and γ-substituted propoxy phosphonoesters of the type p-NO(2)PhO-P(X)(R)[(O(CH(2))(n)Z] (R=Me, Et; X=O, S; n=2, 3; Z=halogen, OTs) and examined the inhibition of three AChEs by select structures in the panel. The ß-fluoroethoxy methylphosphonate analog (R=Me, Z=F, n=2) was the most potent anti-AChE compound comparable (ki â¼6 × 10(6)M(-1)min(-1)) to paraoxon against EEAChE. Analogs with Z=Br, I, or OTs were weak inhibitors of the AChEs, and methyl phosphonates (R=Me) were more potent than the corresponding ethyl phosphonates (R=Et). As expected, analogs with a thionate linkage (PS) were poor inhibitors of the AChEs.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Organophosphonates/pharmacology , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Electrophorus , Humans , Molecular Structure , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Rats , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
A versatile and efficient method has been developed for the synthesis of bis(indolyl)methanes by using aluminium triflate (0.5 mol%) as a novel catalyst. Further, some of the synthesized compounds were evaluated for their efficacy as antibacterial and antifungal activities. Most of the compounds have shown moderate to good inhibitory activity.
