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ChemMedChem. 2018 Jun 6;13(11):1092-1097. doi: 10.1002/cmdc.201800158. Epub 2018 Apr 23.

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

Author information

1
Department of Chemistry, Yale University, New Haven, CT, 06520-8107, USA.

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.

KEYWORDS:

MIF inhibitors; phenol bioisosteres; protein crystallography; pyrazoles; tautomerase

PMID:
29575754
PMCID:
PMC5990473
DOI:
10.1002/cmdc.201800158
[Indexed for MEDLINE]
Free PMC Article

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