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Abstract
1. Twelve oxygen and sulphur azaheterocycles were studied as potential substrates of rabbit liver aldehyde oxidase. Only benzoxazole and 1,2-benzisoxazole were found to be substrates.
2. Nine of the compounds inhibited the oxidation of quinazoline by aldehyde oxidase and in all cases mixed inhibition kinetics were observed.
3. π-Excessive heterocycles consisting of a single 5- or 6-membered ring (thiazole, oxazole) were neither substrates or inhibitors. Addition of a carbocyclic ring (benzothiazole, benzoxazole, 1,2-benzisoxazole) allowed binding to the enzyme as a substrate and/or inhibitor.
4. The mixed inhibition exhibited by the π-excessive azaheterocycles benzothiazole, 1,2-benzisoxazole, and 2-substituted benzoxazoles was characterised by a Ki/KI ratio greater than 1 0, where Ki is the inhibitor constant for binding to the free enzyme and KI is the inhibitor constant for binding to the ES complex. In contrast, five π-deficient methyl-substituted quinolines, which are known substrates for aldehyde oxidase, exhibited a Ki/KI ratio of less than 1·0.
5. The π-excessive heterocycles 2,3-benzthiophene and 2,3-benzfuran, which do not contain a nitrogen atom, exhibited weak inhibition with a very high Ki/KI ratio.
6. The results of the study indicated that whilst thiazoles and oxazoles are unlikely to be extensively metabolized by aldehyde oxidase, they may inhibit the metabolism of substrates of the enzyme.