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 4h, 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 10b, exhibiting IC50 values of 1.5 μM for D-DT and 1.0 μM for MIF-1. The
specific interactions of 4h with D-DT and MIF-1 were
explored using 1H–15N NMR endpoint titrations. 4h also inhibited D-DT-induced ERK phosphorylation in A549
cells. Thus, 4h and 10b represent a new
class of inhibitors that can be utilized as tools to investigate the
biological functions of D-DT and MIF-1.