Benzisothiazolones as modulators of macrophage migration inhibitory factor

Substituted N-phenylbenzisothiazolones have been investigated as inhibitors of the tautomerase activity of the proinflammatory cytokine MIF (macrophage migration inhibitory factor). Numerous compounds were found to possess antagonist activity in the low micromolar range with the most potent being the 6-hydroxy analog 1w. Compound 1w and the p-cyano analog 1c were also shown to exhibit significant inhibition of the binding of MIF to its transmembrane receptor CD74. Consistently, both compounds were also found to retard the MIF-dependent phosphorylation of ERK1/2 in human synovial fibroblasts.

Substituted N-phenylbenzisothiazolones are reported as antagonists of the enzymatic activity and signaling of macrophage migration inhibitory factor (MIF). Two analogs are shown to attenuate MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts.Figure optionsDownload as PowerPoint slideHighlights
► Benzisothiazolones as inhibitors of macrophage migration inhibitory factor (MIF).
► Inhibition of MIF-CD74 binding and ERK phosphorylation.
► Mass spectral analysis of covalent modification of cysteines.
► Potential anti-inflammatory and anti-proliferative agents.