Identification of triazinoindol-benzimidazolones as nanomolar inhibitors of the Mycobacterium tuberculosis enzyme TDP-6-deoxy-d-xylo-4-hexopyranosid-4-ulose 3,5-epimerase (RmlC).
Bioorg Med Chem
; 18(2): 896-908, 2010 Jan 15.
Article
in En
| MEDLINE
| ID: mdl-19969466
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.
Full text:
1
Database:
MEDLINE
Main subject:
Benzimidazoles
/
Carbohydrate Epimerases
/
Enzyme Inhibitors
/
Indoles
/
Mycobacterium tuberculosis
Type of study:
Diagnostic_studies
Limits:
Humans
Language:
En
Year:
2010
Type:
Article