Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor

다국어 초록 (Multilingual Abstract)

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto–enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113‐μm docking hit, we report results of structure‐based and computer‐aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60–70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl–aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.
The power of bioisosteres: A novel inhibitor series has been pursued for macrophage migration inhibitory factor (MIF). Starting from a 113‐μm docking hit, results of structure‐based and computer‐aided design are reported to yield substituted pyrazoles as alternatives to metabolically labile phenols with potencies of 60–70 nm.