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

• Published in: Journal of medicinal chemistry Vol. 34; no. 4; pp. 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: Journal Article
• Language: English
• Published: United States American Chemical Society 01-04-1991
• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00108a019

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.