Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 2. Preparation and in vitro and in vivo evaluation of 1-(alkoxymethyl)-2-[(hydroxyimino)methyl]-3-methylimida zolium halides for reactivation of organophosphorus-inhibited acetylcholinesterases.

A series of structurally related mono- and bis-1,3-disubstituted 2-[(hydroxyimino)methyl]imidazolium halides were evaluated in vitro for their ability to reactivate electric eel, bovine, and human erythrocyte (RBC) acetylcholinesterases (AChE) inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methyl-phosphonofluoridate (soman, GD). All new compounds were characterized for (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol-buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivation of EPMP-inhibited AChEs. For GD-inhibited AChEs, maximal reactivation was used to compare compounds since rapid phosphonyl enzyme dealkylation "aging" complicated interpretation of kinetic constants. For comparison, we also evaluated three known pyridinium therapeutics, 2-PAM, HI-6, and toxogonin. In vivo evaluation in mice revealed that when selected imidazolium compounds were coadministered with atropine sulfate, they were effective in providing lifesaving protection against both GD and EPMP challenges. This was a major accomplishment in the search for effective anticholinesterase therapeutics--the synthesis and preliminary evaluation of the first new monoquaternary soman antidotes with potencies superior to 2-PAM. Significantly, there was an apparent inverse relationship between in vitro and in vivo results; the most potent in vivo compounds proved to be the poorest in vitro reactivators. These results suggested that an alternative and possibly novel antidotal mechanism of protective action may be applicable for the imidazolium aldoximes. Selected compounds were also evaluated for their inhibition of AChE phosphorylation by GD and antimuscarinic and antinicotinic receptor blocking effects.

Experience with a sulfonamide diuretic in a large urine drug testing program.

Gas chromatography/mass spectrometry (GC/MS) with selected ion monitoring is a common confirmation method for tetrahydrocannabinol (THC) metabolites in urine. Department of Defense laboratories use this method for analysis of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THCA) following ion exchange column purification and methylation. Furosemide, a common diuretic which is excreted into urine, will be isolated with THCA in the extraction procedure, will appear in the chromatographic window [retention time relative to 11-nor-delta-9-tetrahydrocannabinolmethyl ether-9-carboxylic acid methyl ester (THCA-Me) of 1.13], and will exhibit the six ions monitored for THCA-Me and its trideuterated analog. The results indicate that methylated furosemide and other common diuretics can easily be distinguished from THCA-Me. They also allow one to explain in court the extraneous peaks in a chromatogram and to correct for the overutilization of derivatizing reagent.

Potential antiradiation drugs containing no nitrogen, and related compounds.

Capabilities are reported of di- and higher sulfides (RSnR') terminated by sulfinate functions [-S(O)O-] for protecting mice against otherwise lethal effects of ionizing radiation. With the use of congeners, structure-activity correlations are developed for the effects of esterification of the sulfinate function, of changing the length of the chain of sulfur atoms, of reduction to a mercapto sulfinate, and of changing the substituents R and R' to chiral and other types of groups. Neither a trisulfide nor a sulfinate by itself was significantly radioprotective. The key requirement for radio-protection in the series appears to be the presence of a sulfur function (-Sn-) from which a thiol can be engendered by a neighboring-group effect of an electron-donating group; sulfoxide functions may afford alternatives to sulfinate functions as such neighboring groups. The relevance of structure-activity relations to the chemical and biological mechanisms involved in the radioprotective activities is discussed.

Antimalarial agents. 1. alpha-Santonin-derived cyclic peroxide as potential antimalarial agent.

An alpha-santonin-derived cyclic peroxide (7) related to qinghaosu (1) has been synthesized and tested for antimalarial activity in vitro against the chloroquine-resistant (Smith) isolates of Plasmodium falciparum as well as in vivo against Plasmodium berghei in mice and was found to be devoid of activity.