title: 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).
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.
authors.affiliation: Penn Center for Molecular Discovery, Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, 1024 Vagelos Research Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Sivendran
authors.forename: Victoria
authors.initials: V
authors.lastname: Jones
authors.forename: Dianqing
authors.initials: D
authors.lastname: Sun
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Anna E
authors.initials: AE
authors.lastname: Grzegorzewicz
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scherman
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Napper
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
authors.forename: Michael
authors.initials: M
authors.lastname: McNeil
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D013329:Structure-Activity Relationship; D001426:Bacterial Proteins; D002237:Carbohydrate Dehydrogenases
chemical_list: D001562:Benzimidazoles; D002238:Carbohydrate Epimerases; D004791:Enzyme Inhibitors; D007211:Indoles; C548633:1-(3-(5-ethyl-5H-(1,2,4)triazino(5,6-b)indol-3-ylthio)propyl)-1H-benzo(d)imidazol-2(3H)-one; C020092:dTDP-4-ketorhamnose 3,5-epimerase; D001426:Bacterial Proteins; D002237:Carbohydrate Dehydrogenases