Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 3. Synthesis and evaluation of (alkenyloxy)-, (alkynyloxy)-, and (aralykyloxy)methyl quaternarized 2-[(hydroxyimino)methyl]-1-alkylimidazolium halides as reactivators and therapy for soman intoxication

Abstract

A series of structurally related monosubstituted 1-[(alkenyloxy)methyl]-, 1-[(alkynyloxy)methyl]-, and 1-[(aralkyloxy)methyl]-2-[(hydroxyimino)methyl]-3-methyli midazolium halides were prepared and evaluated. All new compounds were characterized with respect to (hydroxyimino)methyl acid dissociation constant, nucleophilicity, and octanol-buffer partition coefficient. The alkynyloxy-substituted compounds were also evaluated in vitro with respect to reversible inhibition of human erythrocyte (RBC) acetylcholinesterase (AChE) and kinetics of reactivation of human AChE inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP). In vivo evaluation in mice revealed that coadministration of alkynyloxy-substituted imidazolium compounds with atropine sulfate provided significant protection against a 2 x LD50 challenge of GD. For the alkynyloxy-substituted imidazolium drugs there is a direct relationship between in vitro and in vivo activity: the most potent in vivo compounds against GD proved to be potent in vitro reactivators against EPMP-inhibited human AChE. These results differ from the observations made on the sterically hindered imidazolium compounds (see previous article) and suggest that several antidotal mechanisms of protective action may be applicable for the imidazolium aldoxime family of therapeutics. The ability of the alkynyloxy substituents to provide life-saving protection against GD intoxication was not transferable to the pyridinium or triazolium heteroaromatic ring systems.

Synthesis of bis(polyfluoroalkylated)imidazolium salts as key intermediates for fluorous NHC ligands

“…1- (3,3,4,4,5,5,6,6,7,7,8,8,imidazole (11) and 1,3-bis (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)imidazolium iodide (1) were prepared according to [17], 1-mesitylimidazole (23) according to [29]. 1,1,1,2,2,3,3,4,4,5,5,6,6-Tridecafluoro-8-iodooctane (5) and 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-10-iododecane (6) were kindly donated by Atochem.…”

“…88.6-90.9 8C) was obtained. 1 (2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,imidazole (10) A reaction mixture containing triflate 4 (3.00 g, 5.10 mmol, 1.0 equiv.) and imidazole (1.07 g, 15.3 mmol, 3 equiv.)…”

“…Substituted imidazolium salts are frequently employed as ionic liquids [1,2] or as a part of biologically active compounds [3][4][5]. Moreover, they are precursors for the preparation of N-heterocyclic carbenes, which are a perspective class of compounds used in medicinal chemistry [6,7] or, even more importantly, as ligands in homogeneous catalysis [8,9].…”

Oximes of five-membered heterocyclic compounds with two heteroatoms 2. Reactions and biological activity (Review)

“…Numerous publications have been devoted to the investigation of imidazole [388][389][390][391][392][393][394][395][396][397][398][399][400] and pyrazole [401] oximes as antidotes for poisoning by organophosphorus compounds.…”

N-Benzyl-4-(hydroxyiminomethyl)pyridinium bromide

“…Many classes of heterocyclic oximes have been synthesized and tested as reactivators of acethylcholinesterase (AChE) inhibited by organophosphorus (OP) compounds used as pesticides and warfare agents (Primožič et al, 2004;Sterling et al, 1993;Bedford et al, 1989). Unfortunately, only four of them are used or considered for use as antidotes against intoxication with OP compounds (toxogonin, PAM-2, HI-6 and TMB-4).…”