Design and synthesis of 2,4-difluorophenylpyruvic acid and of its azlactone precursor for macrophage migration inhibitory factor (MIF) tautomerase activity

The macrophage migration inhibitory factor (MIF) is an important cytokine implicated in several diseases and currently a target for drug development. This study aimed to synthesize phenylpyruvic acid like structures that fit the molecular requirements of MIF with respect to keto/enol tautomerism and E/Z isomerism of the enol forms. The synthesis of 2,4-difluorophenylpyruvic acid and its azlactone precursor as potential ligands to interact with the active site of MIF is reported here. Both the E and Z isomers of the azlactone of 2,4- difluorobenzaldehyde were synthesized using different synthetic methods. Hydrolysis of these isomeric azlactones yielded similar enol/keto tautomeric mixtures of 2,4-difluorophenylpyruvic acid, with the enol form predominating. NMR spectroscopy was used to confirm the structures of these compounds, while an X-ray crystallographic study also confirmed the configuration of the E isomer of the azlactone. q 2003 Elsevier B.V. All rights reserved