Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor

Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic ass...

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Bibliographic Details
Published in:	Journal of the American Chemical Society Vol. 137; no. 8; pp. 2996 - 3003
Main Authors:	Dziedzic, Pawel, Cisneros, José A, Robertson, Michael J, Hare, Alissa A, Danford, Nadia E, Baxter, Richard H. G, Jorgensen, William L
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 04-03-2015 American Chemical Society (ACS)
Subjects:	BASIC BIOLOGICAL SCIENCES Chemistry Techniques, Synthetic Crystallography, X-Ray Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Hydrogen Bonding INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Intramolecular Oxidoreductases - antagonists & inhibitors Intramolecular Oxidoreductases - chemistry Macrophage Migration-Inhibitory Factors - antagonists & inhibitors Macrophage Migration-Inhibitory Factors - chemistry Models, Molecular Protein Conformation Solubility Structure-Activity Relationship Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology Water - chemistry
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Summary:	Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl–aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AC02-06CH11357 USDOE Office of Science (SC) National Science Foundation (NSF) National Institutes of Health (NIH) P.D. and J.A.C. contributed equally to this work.
ISSN:	0002-7863 1520-5126
DOI:	10.1021/ja512112j