Diethylcarbamoylating/nitroxylating agents as dual action inhibitors of aldehyde dehydrogenase: A disulfiram-cyanamide merger

Benzenesulfohydroxamic acid (Piloty's acid) was functionalized on the hydro xyl group with the N,N-diethylcarbamoyl group, and the hydroxylamine nitrog en was substituted with acetyl (la), pivaloyl (Ib), benzoyl (Ic), and ethox ycarbonyl (Id) groups. Only compound Id inhibited yeast aldehyde dehydrogen ase (AlDH) in vitro (IC50 169 mu M). When administered to rats, Id signific antly raised blood acetaldehyde levels following ethanol challenge, thus se rving as a diethylcarbamoylating/nitroxylating, dual action inhibitor of Al DH in vivo. A more potent dual action agent was N-(N,N-diethylcarbamoyl)-O- methylbenzenesulfohydroxamic acid (5c), which was postulated to release die thylcarbamoylnitroxyl (9), a highly potent diethylcarbamoylating/nitroxylat ing agent, following metabolic O-demethylation in vivo. The dual action inh ibition of AlDH exhibited by Id, and especially 9, constitutes a merger of the mechanism of action of the alcohol deterrent agents, disulfiram and cya namide.