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Literature summary for 2.5.1.9 extracted from

  • Zhao, Y.; Bacher, A.; Illarionov, B.; Fischer, M.; Georg, G.; Ye, Q.Z.; Fanwick, P.E.; Franzblau, S.G.; Wan, B.; Cushman, M.
    Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis (2009), J. Org. Chem., 74, 5297-5303.
    View publication on PubMed

Application

Application Comment Organism
drug development riboflavin synthase is a target for the design of potential antibiotics Mycobacterium tuberculosis
drug development riboflavin synthase is a target for the design of potential antibiotics Escherichia coli

Inhibitors

Inhibitors Comment Organism Structure
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Escherichia coli
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Mycobacterium tuberculosis
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Escherichia coli
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Mycobacterium tuberculosis
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Escherichia coli
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Mycobacterium tuberculosis
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Escherichia coli
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Mycobacterium tuberculosis
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Escherichia coli
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Mycobacterium tuberculosis
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Escherichia coli
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone covalent hydrate of trifluoromethylated pyrazole Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
6,7-dimethyl-8-(1-D-ribityl)lumazine Mycobacterium tuberculosis
-
riboflavin + 4-(1-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine
-
?
6,7-dimethyl-8-(1-D-ribityl)lumazine Escherichia coli
-
riboflavin + 4-(1-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine
-
?
additional information Mycobacterium tuberculosis final step in the biosynthesis of riboflavin, the early steps in this pathway involve the addition of a nucleophile to the lumazine that will function as the donor of the four-carbon unit and the deprotonation of the C-7 methyl group of the lumazine that will function as the acceptor of the four-carbon unit to form the anion, although the identity of the nucleophile has not been rigorously established, likely candidates include water or one of the ribityl hydroxyl groups, nucleophilic addition of an anion to an imine affords an intermediate, which tautomerizes to yield a further intermediate, elimination of the anion results in an iminium ion which is attacked intramolecularly by the enamine to produce the pentacyclic intermediate, the pentacyclic compound has been isolated and shown to be a kinetically competent intermediate, 2 sequential elimination reactions then produce the final products ?
-
?
additional information Escherichia coli final step in the biosynthesis of riboflavin, the early steps in this pathway involve the addition of a nucleophile to the lumazine that will function as the donor of the four-carbon unit and the deprotonation of the C-7 methyl group of the lumazine that will function as the acceptor of the four-carbon unit to form the anion, although the identity of the nucleophile has not been rigorously established, likely candidates include water or one of the ribityl hydroxyl groups, nucleophilic addition of an anion to an imine affords an intermediate, which tautomerizes to yield a further intermediate, elimination of the anion results in an iminium ion which is attacked intramolecularly by the enamine to produce the pentacyclic intermediate, the pentacyclic compound has been isolated and shown to be a kinetically competent intermediate, 2 sequential elimination reactions then produce the final products ?
-
?

Organism

Organism UniProt Comment Textmining
Escherichia coli P0AFU8
-
-
Mycobacterium tuberculosis
-
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
6,7-dimethyl-8-(1-D-ribityl)lumazine
-
Mycobacterium tuberculosis riboflavin + 4-(1-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine
-
?
6,7-dimethyl-8-(1-D-ribityl)lumazine
-
Escherichia coli riboflavin + 4-(1-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine
-
?
additional information final step in the biosynthesis of riboflavin, the early steps in this pathway involve the addition of a nucleophile to the lumazine that will function as the donor of the four-carbon unit and the deprotonation of the C-7 methyl group of the lumazine that will function as the acceptor of the four-carbon unit to form the anion, although the identity of the nucleophile has not been rigorously established, likely candidates include water or one of the ribityl hydroxyl groups, nucleophilic addition of an anion to an imine affords an intermediate, which tautomerizes to yield a further intermediate, elimination of the anion results in an iminium ion which is attacked intramolecularly by the enamine to produce the pentacyclic intermediate, the pentacyclic compound has been isolated and shown to be a kinetically competent intermediate, 2 sequential elimination reactions then produce the final products Mycobacterium tuberculosis ?
-
?
additional information final step in the biosynthesis of riboflavin, the early steps in this pathway involve the addition of a nucleophile to the lumazine that will function as the donor of the four-carbon unit and the deprotonation of the C-7 methyl group of the lumazine that will function as the acceptor of the four-carbon unit to form the anion, although the identity of the nucleophile has not been rigorously established, likely candidates include water or one of the ribityl hydroxyl groups, nucleophilic addition of an anion to an imine affords an intermediate, which tautomerizes to yield a further intermediate, elimination of the anion results in an iminium ion which is attacked intramolecularly by the enamine to produce the pentacyclic intermediate, the pentacyclic compound has been isolated and shown to be a kinetically competent intermediate, 2 sequential elimination reactions then produce the final products Escherichia coli ?
-
?

Synonyms

Synonyms Comment Organism
riboflavin synthase
-
Mycobacterium tuberculosis
riboflavin synthase
-
Escherichia coli

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.0067
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone Ki value, mechanism is partial Mycobacterium tuberculosis
0.0087
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone noncompetitive mechanism, compound has a kis value of 0.0087 mM and moderate antibiotic activity against both Mycobacterium tuberculosis replicating phenotype and non-replicating persistent phenotype Mycobacterium tuberculosis
0.01
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone Kis value, mechanism is partial Mycobacterium tuberculosis
0.01
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone Kis value, mechanism is partial Mycobacterium tuberculosis
0.014
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone Ki value, mechanism is partial Mycobacterium tuberculosis
0.016
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone Ki value, mechanism is partial Mycobacterium tuberculosis
0.016
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone Kis value, mechanism is partial Mycobacterium tuberculosis
0.02
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone partial mechanism, Kis value Escherichia coli
0.023
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone Ki value, mechanism is partial Mycobacterium tuberculosis
0.031
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone partial mechanism, Ki value Escherichia coli
0.036
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone partial mechanism, Kis value Escherichia coli
0.0366
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone noncompetitive mechanism, the most potent antibiotic compound displays a minimum inhibitory concentration of 0.0366 mM versus Mycobacterium tuberculosis replicating phenotype, the compound and its analogues provide the first examples of riboflavin synthase inhibitors with antibiotic activity Mycobacterium tuberculosis
0.038
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone Kis value, mechanism is partial Mycobacterium tuberculosis
0.0489
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone noncompetitive mechanism, the most potent antibiotic compound displays a minimum inhibitory concentration of 0.0489 mM versus Mycobacterium tuberculosis nonreplicating phenotype Mycobacterium tuberculosis
0.05
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone partial mechanism, Ki value Escherichia coli
0.057
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone Kis value, mechanism is partial Escherichia coli
0.061
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone Ki value, mechanism is partial Escherichia coli
0.091
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone Kis value, mechanism is partial Escherichia coli
0.104
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone Kis value, mechanism is partial Escherichia coli
0.106
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](m-tolyl)methanone Ki value, mechanism is partial Escherichia coli
0.135
-
[3-(4-chlorophenyl)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](p-tolyl)methanone Ki value, mechanism is competitive Escherichia coli
0.312
-
[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl](o-tolyl)methanone Ki value, mechanism is partial Escherichia coli

General Information

General Information Comment Organism
physiological function the product of the enzyme, riboflavin (also known as vitamin B2) is the central component of the cofactors FAD and FMN, enzyme plays a key role in energy production, and is required for the metabolism of fats, carbohydrates, and proteins Mycobacterium tuberculosis
physiological function the product of the enzyme, riboflavin (also known as vitamin B2) is the central component of the cofactors FAD and FMN, enzyme plays a key role in energy production, and is required for the metabolism of fats, carbohydrates, and proteins Escherichia coli