title: Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor.
abstract: 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.
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, United States.
authors.forename: Pawel
authors.initials: P
authors.lastname: Dziedzic
authors.forename: José A
authors.initials: JA
authors.lastname: Cisneros
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Robertson
authors.forename: Alissa A
authors.initials: AA
authors.lastname: Hare
authors.forename: Nadia E
authors.initials: NE
authors.lastname: Danford
authors.forename: Richard H G
authors.initials: RH
authors.lastname: Baxter
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008263:Macrophage Migration-Inhibitory Factors; D014230:Triazoles; D014867:Water; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human