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, Qizhuang Ye, Phillip E. Fanwick, Scott G. Franzblau, Baojie Wan, Mark Cushman

Research output: Contribution to journalArticle

38 Citations (Scopus)

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

Fingerprint

Riboflavin Synthase
Pyrazoles
Hydrates
Anti-Bacterial Agents
Screening
Throughput
Molecular modeling
Benzene
Escherichia coli
Ligands
Molecules
Enzymes

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis. / Zhao, Yujie; Bacher, Adelbert; Illarionov, Boris; Fischer, Markus; Georg, Gunda; Ye, Qizhuang; Fanwick, Phillip E.; Franzblau, Scott G.; Wan, Baojie; Cushman, Mark.

In: Journal of Organic Chemistry, Vol. 74, No. 15, 07.08.2009, p. 5297-5303.

Research output: Contribution to journalArticle

Zhao, Yujie ; Bacher, Adelbert ; Illarionov, Boris ; Fischer, Markus ; Georg, Gunda ; Ye, Qizhuang ; Fanwick, Phillip E. ; Franzblau, Scott G. ; Wan, Baojie ; Cushman, Mark. / Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis. In: Journal of Organic Chemistry. 2009 ; Vol. 74, No. 15. pp. 5297-5303.
@article{db617996ecf543b896a65674997e794f,
title = "Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis",
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.",
author = "Yujie Zhao and Adelbert Bacher and Boris Illarionov and Markus Fischer and Gunda Georg and Qizhuang Ye and Fanwick, {Phillip E.} and Franzblau, {Scott G.} and Baojie Wan and Mark Cushman",
year = "2009",
month = "8",
day = "7",
doi = "10.1021/jo900768c",
language = "English (US)",
volume = "74",
pages = "5297--5303",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
number = "15",

}

TY - JOUR

T1 - Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis

AU - Zhao, Yujie

AU - Bacher, Adelbert

AU - Illarionov, Boris

AU - Fischer, Markus

AU - Georg, Gunda

AU - Ye, Qizhuang

AU - Fanwick, Phillip E.

AU - Franzblau, Scott G.

AU - Wan, Baojie

AU - Cushman, Mark

PY - 2009/8/7

Y1 - 2009/8/7

N2 - (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.

AB - (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.

UR - http://www.scopus.com/inward/record.url?scp=68049092045&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68049092045&partnerID=8YFLogxK

U2 - 10.1021/jo900768c

DO - 10.1021/jo900768c

M3 - Article

C2 - 19545132

AN - SCOPUS:68049092045

VL - 74

SP - 5297

EP - 5303

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 15

ER -