Abstract
High-throughput screening of 201,368 compounds revealed that 1-(3-(5-ethyl-5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)propyl)-1H-benzo[d]imidazol-2(3H)-one (SID 7975595) inhibited RmlC a TB cell wall biosynthetic enzyme. SID 7975595 acts as a competitive inhibitor of the enzyme's substrate and inhibits RmlC as a fast-on rate, fully reversible inhibitor. An analog of SID 7975595 had a K(i) of 62nM. Computer modeling showed that the binding of the tethered two-ringed system into the active site occurred at the thymidine binding region for one ring system and the sugar region for the other ring system.
Copyright 2009 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aorta / cytology
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Aorta / drug effects
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology*
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Carbohydrate Epimerases / antagonists & inhibitors*
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Catalytic Domain
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Cell Survival / drug effects
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Computer Simulation
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Dose-Response Relationship, Drug
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Endothelial Cells / drug effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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High-Throughput Screening Assays
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Humans
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Indoles / chemical synthesis
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Indoles / chemistry
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Indoles / pharmacology*
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Models, Chemical
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Mycobacterium tuberculosis / enzymology*
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Structure-Activity Relationship
Substances
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1-(3-(5-ethyl-5H-(1,2,4)triazino(5,6-b)indol-3-ylthio)propyl)-1H-benzo(d)imidazol-2(3H)-one
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Benzimidazoles
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Enzyme Inhibitors
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Indoles
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Carbohydrate Epimerases
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dTDP-4-ketorhamnose 3,5-epimerase