Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 4. Effect of various side-chain substituents on therapeutic activity against anticholinesterase intoxication

A series of quaternary salt derivatives of 2-[(hydroxyimino)methyl]-1-methylimidazole incorporating various side chains bearing ether, silyl, nitrile, ester, halogen, nitro, sulfone, amino, or aminosulfonyl substituents was prepared and evaluated in vivo for the treatment of anticholinesterase intox...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1991-04, Vol.34 (4), p.1363-1368
Main Authors: Goff, Dane A, Koolpe, Gary A, Kelson, Andrew B, Vu, Huynh M, Taylor, Dorris L, Bedford, Clifford D, Harris, Ralph N, Mussalam, H. A, Koplovitz, Irwin
Format: Article
Language:English
Subjects:
Acetylcholinesterase - metabolism
Animals
Atropine - pharmacology
Cholinesterase Inhibitors - pharmacology
Cholinesterase Inhibitors - toxicity
Cholinesterase Reactivators - chemical synthesis
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Imines - chemistry
Imines - pharmacology
Indicators and Reagents
Kinetics
Mice
Mice, Inbred ICR
Molecular Structure
Oximes - chemical synthesis
Oximes - chemistry
Oximes - pharmacology
Salts
Structure-Activity Relationship
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Summary:A series of quaternary salt derivatives of 2-[(hydroxyimino)methyl]-1-methylimidazole incorporating various side chains bearing ether, silyl, nitrile, ester, halogen, nitro, sulfone, amino, or aminosulfonyl substituents was prepared and evaluated in vivo for the treatment of anticholinesterase intoxication. Test results in the mouse revealed that the type and location of the side-chain substituent both have a significant influence on the toxicity and antidotal effectiveness of the compounds. Some of the more active examples represent the most potent therapeutics to date against intoxication by the powerful cholinesterase inhibitors soman and tabun. Significantly, the antidotal effectiveness of the compounds was not dependent on the inhibiting agent nor was there any correlation between in vivo efficacy and in vitro reactivation of ethyl (4-nitrophenyl)methylphosphonate inhibited human acetylcholinesterase. These observation suggested that the main mode of antidotal protection by the compounds is something other than enzyme reactivation.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00108a019