Discovery of Furan-2-Carboxylic Acid Derivatives as Novel D-Dopachrome Tautomerase (D-DT) and Macrophage Migration Inhibitory Factor-1 (MIF-1) Dual Inhibitors

D-dopachrome tautomerase (D-DT), also known as macrophage migration inhibitory factor-2, is a member of the MIF cytokine family and plays a key role in cancer and inflammation. Molecules that bind to the D-DT or MIF-1 tautomerase site could block their biological activity. However, relatively few D-DT inhibitors have been reported. In this study, we designed, synthesized, and screened a focused compound library. This led to the identification of <b>4h</b>, a furan-2-carboxylic acid derivative with IC₅₀ values of 2.4 μM for D-DT and 9.8 μM for MIF-1. Subsequent SAR optimization yielded the more potent inhibitor <b>10b</b>, exhibiting IC₅₀ values of 1.5 μM for D-DT and 1.0 μM for MIF-1. The specific interactions of <b>4h</b> with D-DT and MIF-1 were explored using ¹H-¹⁵N NMR endpoint titrations. <b>4h</b> also inhibited D-DT-induced ERK phosphorylation in A549 cells. Thus, <b>4h</b> and <b>10b</b> represent a new class of inhibitors that can be utilized as tools to investigate the biological functions of D-DT and MIF-1.