Intermediate analogue inhibitors of mandelate racemase: N-Hydroxyformanilide and cupferron

Mandelate racemase (MR) catalyzes the 1,1-proton transfer that interconverts the enantiomers of mandelate. The transition state/intermediate analogues N-hydroxyformanilide (Ki = 2.79 ± 0.19 μM) and cupferron (Ki = 2.67 ± 0.09 μM) are identified as potent competitive inhibitors of MR. The pH–pKi profile indicates that MR can bind either the protonated or deprotonated forms of N-hydroxyformanilide, with a 10-fold greater affinity for the latter form.

Graphical abstractMandelate racemase (MR) catalyzes the interconversion of the enantiomers of mandelate and has been studied as a paradigm for enzyme-catalyzed proton abstraction from carbon acids. Intermediate analogues N-hydroxyformanilide (HFA; X = CH; Ki = 2.79 ± 0.19 μM) and cupferron (X = N; Ki = 2.67 ± 0.09 μM) are identified as potent competitive inhibitors of MR. The pH–pKi profile indicates that MR can bind either the protonated or deprotonated forms of HFA, with a 10-fold greater affinity for the latter form.Figure optionsDownload full-size imageDownload as PowerPoint slide