As an extension of an earlier investigation (J. Med. Chem. 1984, 27, 1431), we prepared a series of 3-substituted 5-[(hydroxyimino)methyl]-1,2,4-oxadiazoles and the corresponding 5-thiocarbohydroximic acid 2-(N,N-dialkylamino)ethyl S-esters. The compounds were evaluated in vitro as reactivators of phosphonylated electric eel and human erythrocyte (RBC) acetylcholinesterases (AChE). The compounds were characterized with respect to (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol/buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivating ethyl methylphosphonylated AChE. One compound was also tested for effectiveness in preventing AChE phosphonylation. All of the tested compounds significantly reactivate ethyl methylphosphonylated AChE: the 3-n-octyl- and 3-(1-naphthyl)-substituted aldoximes are as reactive (within a factor of 5-10) toward the inhibited enzymes as the benchmark pyridinium reactivators, 2-PAM and HI-6. All of the substituted thiocarbohydroximic acid S-esters are powerful reversible inhibitors of AChE's: the 3-n-octyl- and 3-(1-naphthyl)-substituted thiocarbohydroximates inhibit eel AChE to 50% initial activity at concentrations less than 5 microM. When added to an eel AChE solution at concentrations between 5 and 50 microM, the 3-phenyl-substituted thiocarbohydroximate effectively antagonizes AChE inhibition by ethyl p-nitrophenyl methylphosphonate (EPMP), suggesting the potential utility of this compound for preventing anti-AChE-agent poisoning.

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vinyl ketone took place in this homogeneous system with no change in the optical yield. This modification, therefore, will allow the use of Michael acceptors that are not compatible with hydroxide bases.9 In summary, we have demonstrated a chiral catalytic process for the addition of MVK to indanone 1 which takes place in excellent chemical yield and up to 80% ee for the S enantiomer and 52% ee for the R enantiomer. Experimental SectionAssays for Optical Purity. Assays for optical purity were obtained by chiral liquid chromatography. A poor separation of the enantiomers 2 was obtained on a Pirkle covalent /-leucine column (Regis Chemical) with 0.75% isopropyl alcohol in hexane. However, base line resolution of the diastereomeric ketals formed from 2 and (2fi,3fi)-(-)-2,3-butanediol10 was obtained on a Pirkle ionic phenylglycine column with 88:12:0.5 hexane/chloroform/ isopropyl alcohol, flow rate of 2 mL/min, UV detector at 254 nm.Retention times S enantiomer, 5.8 min; R enantiomer, 6.2 min.Confirmation of the ee was obtained by NMR chiral shift studies on the enantiomeric mixture 2 with an equal weight (29 mol %) of tris[3-(heptafluoropropylhydroxymethylene)-d-camphoratojeuropium (III) derivative. The shift was observed in the methyl group adjacent to the carbonyl with the S enantiomer shifting to lower field relative to the R enantiomer.Catalysts. Catalysts 4 and 7 are commercially available from Chemical Dynamics Corporation, South Plainfield, NJ. Catalyst 5 was prepared from cinchonidine and 3,4-dichlorobenzyl chloride in refluxing THF. The reduced catalysts 6 and 8 were prepared by hydrogenation of 5 and 7, respectively, at 40 psi with 10% Pt/C in methanol. Catalyst 9 was prepared from 7 on an ion-exchange resin.Chiral Methyl Vinyl Ketone Additions. Preparation of 6,7-Dichloro-2,3-dihydro-5-methoxy-2-(3-oxobutyl)-2propyl-líf-inden-1-one. Three sets of conditions were employed for the Michael additions: (1) liquid/liquid phase-transfer conditions using toluene / 50% NaOH, (2) liquid/solid phase-transfer conditions using toluene/KOH pellets, and (3) homogeneous conditions using a solution of the preformed catalytic species.(13) This reaction should not be prolonged since decomposition of the catalyst does take place under these conditions.

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.

We prepared six pairs of alpha-heteroaromatic aldoximes, RC(= NOH)H, and thiohydroximates, RC(= NOH)S-(CH2)2N(C2H5)2, where R represents various oxadiazole and thiadiazole rings. Each compound was characterized with respect to the following: structure, (hydroxyimino)methyl acid dissociation constant, nucleophilicity toward trigonal carbon and tetrahedral phosphorus, octanol-buffer partition coefficient, reversible inhibition of eel acetylcholinesterase (AChE), and in vitro reactivation of AChE inhibited by ethyl p-nitrophenyl methylphosphonate. Eight of the twelve compounds significantly reactivate ethyl methylphosphonyl-AChE, but inherent reactivities are moderate to low: the most potent nonquaternary reactivator, 3-phenyl-5-[(hydroxyimino)methyl]-1,2,4-oxadiazole, is 17 times less reactive than the well-known reactivator 2-[(hydroxyimino)methyl]-1-methylpyridinium iodide (2-PAM). One of the nonquaternary compounds, 3-phenyl-1,2,4-oxadiazole-5-thiohydroximic acid 2-(diethylamino)ethyl S-ester, is a powerful reversible inhibitor of AChE (I50 = 7.5 microM). The observed relationships between nonquaternary compound structure, reactivation potency, and anti-AChE activity reveal important molecular requirements for high reactivity toward phosphonylated AChE.