Diethylcarbamoylating/nitroxylating agents as dual action inhibitors of aldehyde dehydrogenase: a disulfiram-cyanamide merger.
Benzenesulfohydroxamic acid (Piloty's acid) was functionalized on the hydroxyl group with the N,N-diethylcarbamoyl group, and the hydroxylamine nitrogen was substituted with acetyl (1a), pivaloyl (1b), benzoyl (1c), and ethoxycarbonyl (1d) groups. Only compound 1d inhibited yeast aldehyde dehydrogenase (AlDH) in vitro (IC(50) 169 microM). When administered to rats, 1d significantly raised blood acetaldehyde levels following ethanol challenge, thus serving as a diethylcarbamoylating/nitroxylating, dual action inhibitor of AlDH in vivo. A more potent dual action agent was N-(N, N-diethylcarbamoyl)-O-methylbenzenesulfohydroxamic acid (5c), which was postulated to release diethylcarbamoylnitroxyl (9), a highly potent diethylcarbamoylating/nitroxylating agent, following metabolic O-demethylation in vivo. The dual action inhibition of AlDH exhibited by 1d, and especially 9, constitutes a merger of the mechanism of action of the alcohol deterrent agents, disulfiram and cyanamide.
Conway
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Medical Research Laboratories, VA Medical Center, One Veterans' Drive, Minneapolis, Minnesota 55417, USA.
DeMaster
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Goon
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Shirota
F N
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Nagasawa
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D000079:Acetaldehyde / Q000097:blood; D000427:Alcohol Deterrents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015003:Yeasts / Q000201:enzymology
D000427:Alcohol Deterrents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C122051:N-(N,N-diethylcarbamoyl)-O-methylbenzenesulfohydroxamic acid; C122052:N-(ethoxycarbonyl)-O-(diethylcarbamoyl)benzenesulfohydroxamic acid; D013449:Sulfonamides; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde