Carbamates of (hydroxyphenoxy)methyl heteroaromatic salts as acetylcholinesterase inhibitors and protective agents against organophosphorus compounds.

A series of N,N-dimethylcarbamates of 2-[(2'-, 3'-, and 4'-hydroxyphenoxy)methyl] heteroaromatic salts has been prepared. Pyridine, imidazole, quinoline, benzimidazole, and imidazo-[1,2-alpha]pyridine derivatives were included. Most of the compounds are inhibitors of electric eel acetylcholinesterase and also show prophylactic activity toward a 2LD50 dose of soman in mice.

Carbamate derivatives of 2-arylimidazo[1,2-a]pyridinium salts as acetylcholinesterase inhibitors and protective agents against organophosphorus compounds.

A series of 2-arylimidazo[1,2-a]pyridinium salts with (N,N-dimethylcarbamoyl)oxy or (N-methylcarbamoyl)oxy groups at the 3'- or 4'-position on the phenyl substituent and various substituents on the imidazo[1,2-a]pyridine ring have been synthesized. The compounds show in vitro inhibitory activity against electric eel acetylcholinesterase (AChE), type III, and several of the compounds show protective effects toward the organophosphorus AChE inhibitor soman in mice. The possible structural relationship of these compounds to physostigmine and pyridostigmine is considered.

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 5. Structure-activity relationships for side-chain nitro-, sulfone-, amino-, and aminosulfonyl-substituted analogues for therapy against anticholinesterase intoxication.

Several quaternary imidazolium oxime derivatives incorporating side chains bearing nitro, sulfone, amino, and aminosulfonyl substituents were prepared and evaluated as treatment therapeutics for anti-AChE intoxication. In vivo test results in the mouse revealed that many of these compounds are highly effective in providing life-saving protection against the extremely toxic cholinesterase inhibitors soman and tabun. Several structure-activity relationships were noted that were characteristic of the side-chain substituent. In vivo test results for additional selected derivatives of some of the more therapeutically active compounds indicated that the quaternary heteroaryl nucleus is essential for activity whereas a nucleophilic moiety (i.e., oxime) is not. In support of previous suspicions, these results afforded additional evidence suggesting that reactivation is not the main mode of antidotal action by the imidazolium oximes. An alternative antidotal mechanism is postulated that is consistent with all data and that involves enzyme protection by the compounds.

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 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.

Cationic antiprotozoal drugs. Trypanocidal activity of 2-(4'-formylphenyl)imidazo[1,2-a]pyridinium guanylhydrazones and related derivatives of quaternary heteroaromatic compounds.

A series of quaternary 2-phenylimidazo[1,2-a]pyridinum salts has been prepared and evaluated for antiparasitic activity. Primary attention was focused on derivatives with amido, substituted hydrazone, and heterocyclic functionality at the para position of the phenyl substituent. Guanylhydrazones and N-substituted guanylhydrazones of the 4'-formyl-substituted compounds are very active against the blood state Trypanosoma rhodesiense in mice by subcutaneous or oral administration. The most potent compounds attain 100% survival for 30 days at doses of less than 1.0 mg/kg (sc) and greater than 5.0 mg/kg (po). Weaker activity is noted for certain other 4'-substituents such as carboxamidines and carboxamide oximes. Considerable variation in structure, including replacing of the imidazo [1,2-a]pyridinium ring by other cationic heterocyclic rings and insertion of linking groups between the heterocyclic ring and phenyl group, can be done, and a high level of activity is maintained. Relationships between these structural changes and biological activity are discussed.

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.

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

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.

Endoperoxides as potential antimalarial agents.

A number of mono- and bicyclic endoperoxides were prepared and tested for antimalarial activity in search of a simplified analogue of the 5-oxygen-substituted 1,2,4-trioxane ring structure of the naturally occurring antimalarial qinghaosu. The compounds were assayed in an in vitro system for antimalarial activity against chloroquine-susceptible and chloroquine-resistant strains of P. falciparum. The most active compound in this assay was 2-[((butyloxy)-carbonyl)oxy]-1,1,10-trimethyl-6,9-epidioxy-delta 7-octalin (17a), which showed an IC50 of 100 and 57 ng/mL, respectively. For comparison, qinghaosu exhibits a mean IC50 less than 3.4 ng/mL.

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.