title: Trisubstituted imidazoles as Mycobacterium tuberculosis glutamine synthetase inhibitors.
abstract: Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC(50) values and promising antituberculosis MIC values.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Gising
authors.forename: Mikael T
authors.initials: MT
authors.lastname: Nilsson
authors.forename: Luke R
authors.initials: LR
authors.lastname: Odell
authors.forename: Samir
authors.initials: S
authors.lastname: Yahiaoui
authors.forename: Martin
authors.initials: M
authors.lastname: Lindh
authors.forename: Harini
authors.initials: H
authors.lastname: Iyer
authors.forename: Achyut M
authors.initials: AM
authors.lastname: Sinha
authors.forename: Bachally R
authors.initials: BR
authors.lastname: Srinivasa
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Mowbray
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D007093:Imidazoles; D000255:Adenosine Triphosphate; D005974:Glutamate-Ammonia Ligase