Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis

Yujie Zhao, Adelbert Bacher, Boris Illarionov, Markus Fischer, Gunda Georg, Qi Zhuang Ye, Phillip E. Fanwick, Scott G. Franzblau, Baojie Wan, Mark Cushman

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

(Chemical Equation Presented) A high-throughput screening (HTS) hit compound displayed moderate inhibition of Mycobacterium tuberculosis and Escherichia coli riboflavin synthases. The structure of the hit compound provided by the commercial vendor was reassigned as [3-(4-chlorophenyl)-5- hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone (18). The hit compound had a kis of 8.7 μM vs. M. tuberculosis riboflavin synthase and moderate antibiotic activity against both M. tuberculosis replicating phenotype and nonreplicating persistent phenotype. Molecular modeling studies suggest that two inhibitor molecules bind in the active site of the enzyme, and that the binding is stabilized by stacking between the benzene rings of two adjacent ligands. The most potent antibiotic in the series proved to be [5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5- dihydro-1H-pyrazol-1-yl](m-tolyl)methanone (16), which displayed a minimum inhibitory concentration (MIC) of 36.6 μM vs. M. tuberculosis replicating phenotype and 48.9 μM vs. M. tuberculosis nonreplicating phenotype. The HTS hit compound and its analogues provide the first examples of riboflavin synthase inhibitors with antibiotic activity.

Original languageEnglish (US)
Pages (from-to)5297-5303
Number of pages7
JournalJournal of Organic Chemistry
Volume74
Issue number15
DOIs
StatePublished - Aug 7 2009
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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