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

• Published in: Journal of medicinal chemistry Vol. 32; no. 2; pp. 504 - 516
• Main Authors: Bedford, Clifford D, Harris, Ralph N, Howd, Robert A, Goff, Dane A, Koolpe, Gary A, Petesch, M, Koplovitz, Irwin, Sultan, Walter E, Musallam, H. A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-02-1989
• Subjects: Animals; Antidotes - chemical synthesis; Antidotes - pharmacology; Cholinesterase Reactivators - chemical synthesis; Cholinesterase Reactivators - pharmacology; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Imines - chemical synthesis; Imines - pharmacology; Mice; Soman - poisoning; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00122a035

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.