Discovery of chromenes as inhibitors of macrophage migration inhibitory factor

Kok, Tjie and Wapenaar, Hannah and Wang, Kan and Neochoritis, Constantinos G. and Zarganes-Tzitzikas, Tryfon and Proietti, Giordano and Eleftheriadis, Nikolaos and Kurpiewska, Katarzyna and Kalinowska-Tłus ́cik, Justyna and Cool, Robbert H. and Poelarends, Gerrit J. and Dömling, Alexander and Dekker, Frank J. (2018) Discovery of chromenes as inhibitors of macrophage migration inhibitory factor. Bioorganic & Medicinal Chemistry, 26 (5). pp. 999-1005. ISSN 0968-0896; Online ISSN: 1464-3391

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Abstract

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 aim to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tau- tomerase 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.

Item Type:	Article
Uncontrolled Keywords:	Macrophage migration inhibitory factor, Chromenes, Inhibitor, Enzyme kinetics
Subjects:	R Medicine > RS Pharmacy and materia medica
Divisions:	Faculty of Pharmacy > Department of Pharmacy
Depositing User:	Ester Sri W. 196039
Date Deposited:	30 Aug 2019 09:38
Last Modified:	10 Jul 2023 08:34
URI:	http://repository.ubaya.ac.id/id/eprint/36075

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