TABLE 1

Known inhibitors of aldehyde dehydrogenases

Inhibitor	Active Metabolite	Type of Inhibition	IC₅₀			Other Features	References
Inhibitor	Active Metabolite	Type of Inhibition	hALDH1A1	hALDH2	hALDH3A1	Other Features	References
			μM	μM	μM
Ampal	Thioampal	Irreversible	N.A.	N.A.	N.A.	In rat hepatoma cells (JM2), thioampal derivatives inhibited ALDH1 and ALDH3 isoenzymes significantly. Also noted were growth inhibition and anti-tumor activity by these derivatives.	Quemener et al., 1989; Canuto et al., 2001; Quash et al., 2008
Benomyl	MBT	Irreversible	N.A.	N.A.	N.A.	MBT showed IC₅₀ of 0.23 μM with mouse ALDH2, with activation by microsomes. The activation is inhibited by P450 inhibitor.	Axness and Fleeker, 1979; Staub et al., 1998, 1999
Citral^{^a}	Neral and geranial	Reversible noncompetitive	N.A.	N.A.	N.A.	Geranial showed positive cooperativity with hALDH2; n ≈ 2–2.5; Citral K_i for Rat ALDH2 = 360 nM	Boyer and Petersen, 1991; Kikonyogo et al., 1999
Chloral hydrate^{^a}	Chloral hydrate	Reversible competitive	1–10	N.A.	N.A.	Also inhibits esterase activity noncompetitively (K_i = 19 μM) with NAD⁺	Blackwell et al., 1983
Chlorpropamide analogs NPI-1 API-1	NPI-1	Irreversible	N.A.	N.A.	121	All of the analogs tested were proven to be more active against human tumor isolated ALDH3A1 than against normal tissue ALDH3A1.	Lee et al., 1992; Nagasawa et al., 1995; Rekha et al., 1998
	API-1		N.A.	N.A.	223		Lee et al., 1992; Nagasawa et al., 1995; Rekha et al., 1998
Coprine	1-Amino cyclopropanol	Irreversible	50	N.A.	N.A.	Inhibits the esterase activity. Displays mutagenicity and gonadotoxicity.	Marchner and Tottmar, 1983; Michelot, 1992
Cyanamide	HNO	Irreversible	N.A.	10	N.A.	Requires activation by catalase. Also inhibits catalase activity. Liver injury reported with simultaneous consumption of alcohol.	Shirota et al., 1987; Nagasawa et al., 1990
Daidzin	Daidzin	Reversible competitive	28	0.29	N.A.	Structure analogs are being developed as antidipsotropic agents.	Lowe et al., 2008; Arolfo, 2009
CVT-10216	CVT-10216		1.3	0.029	N.A.
DEAB^{^a}	DEAB	Reversible competitive	0.55	N.A.	N.A.	No activation required. Confers sensitivity to cyclophosphamide-resistant cells.	Croker and Allan, 2011
DPAB^{^a}	DPAB		<1	N.A.	N.A.
Disulfiram	Disulfiram	Irreversible	0.15	1.45	N.A.	Inhibits dopamine β-hydroxylase; displays copper chelation activity; inhibits carboxylesterase and cholinesterase.	Lipsky et al., 2001; Lin et al., 2010; Schroeder et al., 2010; Wang et al., 2011
	DDTC-SO		0.27	2.2	N.A.
	DDTC-SO₂		0.12	62	N.A.
	DETC-SO		N.A.	1.2	N.A.
	DETC-SO₂		N.A.	0.4	N.A.
Gossypol	Gossypol	Reversible noncompetitive	75	45	7.5 (competitive)	Inhibits several other dehydrogenase enzymes. Interacts with alcohol in system to form a toxic metabolite, sufficient for aversion from drinking. Known for antitumor, antiviral, and antiparasitic activities.	Burgos et al., 1986; Rekha and Sladek, 1997; Pang et al., 2011
Kynurenine Tryptophan metabolites	KA	N.A.	N.A.	N.A.	N.A.	Tryptophane metabolites in the kynurenine pathway seem to have the potential for ALDH2 specific inhibition.	Badawy and Morgan, 2007; Badawy et al., 2011
	3-HK	N.A.	N.A.	N.A.	N.A.
	3-HAA	N.A.	N.A.	N.A.	N.A.
Molinate	Molinate	Irreversible	N.A.	>50	N.A.	Molinate sulfoxide was found to inhibit ALDH activity in mouse striatal synaptosomes only, suggesting other isozymes as possible targets.	Allen et al., 2010
	Molinate sulfoxide			High
	Molinate sulfone			<50
Nitroglycerin^{^a}	NO₃⁻	Irreversible	N.A.	N.A.	N.A.	DTT but not GSH partially protected GTN-induced inhibition of dehydrogenase activity. ALDH2 inactivation has a role in impaired GTN reduction and nitrate tolerance	Chen, 2002; Beretta et al., 2008; Daiber et al., 2010; Wenzl et al., 2011
Pargyline^{^a}	Propiolaldehyde	Reversible competitive	1.6	1.8	N.A.	Activated by CYP2E1 in liver microsomes; irreversible inhibitor of monoaminoxidase	DeMaster et al., 1980, 1986; Moridani et al., 2001

N.A., inhibition data not available for hALDHs, although data exists for inhibition of mouse and other mammalian isozymes; API-1, 4-chloro-N-ethyl-N-[(propylamino)carbonyl]benzenesulfonamide; NPI-1, (benzoyloxy)[(4-chlorophenyl)sulfonyl]carbamic acid 1,1-dimethylethyl ester; KA, kynurenic acid; 3-HK, 3-hydroxykynurenine; 3-HAA, 3-hydroxyanthranilic acid.
↵a These compounds are not strict inhibitors but competitive substrates capable of inactivation through Michael-adduct formation in the active site.