Discovery of chromenes as inhibitors of macrophage migration inhibitory factor

Tjie Kok, Hannah Wapenaar, Kan Wang, Constantinos G Neochoritis, Tryfon Zarganes-Tzitzikas, Giordano Proietti, Nikolaos Eleftheriadis, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Robbert H Cool, Gerrit J Poelarends, Alexander Dömling, Frank J Dekker

Research output: Contribution to journalArticlepeer-review


Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aimed to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC50's in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved.

Original languageEnglish
Pages (from-to)999-1005
Number of pages7
JournalBioorganic and Medicinal Chemistry
Issue number5
Publication statusPublished - 1 Mar 2018


  • benzopyrans
  • binding sites
  • crystallography
  • humans
  • inhibitory concentration 50
  • intramolecular oxidoreductases
  • kinetics
  • macrophage migration-inhibitory factors
  • molecular conformation
  • molecular dynamics simulation
  • protein binding
  • structure-activity relationship
  • X-Ray


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