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

Abstract

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 k(is) of 8.7 microM 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 microM vs. M. tuberculosis replicating phenotype and 48.9 microM vs. M. tuberculosis nonreplicating phenotype. The HTS hit compound and its analogues provide the first examples of riboflavin synthase inhibitors with antibiotic activity.

• Authors: Yujie Zhao, Adelbert Bacher, Boris Illarionov, Markus Fischer, Gunda Georg, Qi-Zhuang Ye, Phillip E Fanwick, Scott G Franzblau, Baojie Wan, Mark Cushman
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 74 Issue 15 Pg. 5297-303 (Aug 07 2009) ISSN: 1520-6904 [Electronic] United States
• PMID: 19545132 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Enzyme Inhibitors
• Hydrocarbons, Fluorinated
• Pyrazoles
• Water
• Riboflavin Synthase

Topics

• Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Hydrocarbons, Fluorinated (chemical synthesis, chemistry, pharmacology)
• Hydrogen Bonding
• Microbial Sensitivity Tests
• Models, Molecular
• Molecular Structure
• Mycobacterium tuberculosis (drug effects)
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Riboflavin Synthase (antagonists & inhibitors)
• Structure-Activity Relationship
• Water (chemistry)