title: New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases.
abstract: We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular pH values. Our structure-activity analysis of 134 novel compounds considers primarily imidazole aldoximes and N-substituted 2-hydroxyiminoacetamides. Reactivation capacities of novel oximes are rank ordered by their relative reactivation rate constants at 0.67 mm compared with 2-pyridinealdoxime methiodide for reactivation of four organophosphate (sarin, cyclosarin, VX, and paraoxon) conjugates of human acetylcholinesterase (hAChE). Rank order of the rates differs for reactivation of human butyrylcholinesterase (hBChE) conjugates. The 10 best reactivating oximes, predominantly hydroxyimino acetamide derivatives (for hAChE) and imidazole-containing aldoximes (for hBChE) also exhibited reasonable activity in the reactivation of tabun conjugates. Reactivation kinetics of the lead hydroxyimino acetamide reactivator of hAChE, when analyzed in terms of apparent affinity (1/K(ox)) and maximum reactivation rate (k(2)), is superior to the reference uncharged reactivators monoisonitrosoacetone and 2,3-butanedione monoxime and shows potential for further refinement. The disparate pH dependences for reactivation of ChE and the general base-catalyzed oximolysis of acetylthiocholine reveal that distinct reactivator ionization states are involved in the reactivation of ChE conjugates and in conferring nucleophilic reactivity of the oxime group.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Sit
authors.forename: Zoran
authors.initials: Z
authors.lastname: Radić
authors.forename: Valeria
authors.initials: V
authors.lastname: Gerardi
authors.forename: Limin
authors.initials: L
authors.lastname: Zhang
authors.forename: Edzna
authors.initials: E
authors.lastname: Garcia
authors.forename: Maja
authors.initials: M
authors.lastname: Katalinić
authors.forename: Gabriel
authors.initials: G
authors.lastname: Amitai
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.forename: K Barry
authors.initials: KB
authors.lastname: Sharpless
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D002801:Cholinesterase Reactivators / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010755:Organophosphates / Q000737:chemistry; D010091:Oximes / Q000737:chemistry*; D010766:Phosphorylation
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase