title: Nanomolar inhibitors of Mycobacterium tuberculosis glutamine synthetase 1: synthesis, biological evaluation and X-ray crystallographic studies.
abstract: A series of imidazo[1,2-a]indeno[1,2-e]pyrazin-4-ones that potently inhibit M. tuberculosis glutamine synthetase (GlnA1) has been identified by high throughput screening. Exploration of this series was performed owing to a short chemistry program. Despite possibly nanomolar inhibitions, none of these compounds was active on whole cell Mtb, suggesting that GlnA1 may not be a suitable target to find new anti-tubercular drugs.
authors.affiliation: Sanofi R&D, TSU Infectious Disease, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France. Electronic address: cedric.couturier@sanofi.com.
authors.forename: Cédric
authors.initials: C
authors.lastname: Couturier
authors.affiliation: Sanofi R&D, TSU Infectious Disease, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Silve
authors.affiliation: Sanofi R&D, Lead Generation and Candidate Realization, Structure Design and Informatics, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Morales
authors.affiliation: Sanofi R&D, Lead Generation and Candidate Realization, Structure Design and Informatics, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pessegue
authors.affiliation: Sanofi R&D, SCP Biologics, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Llopart
authors.affiliation: Sanofi R&D, Lead Generation and Candidate Realization, 2090 East Innovation Park Drive, 85755-1965 OroValley, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Nair
authors.affiliation: Sanofi Deutschland GmbH, Lead Generation and Candidate Realization, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Sanofi Deutschland GmbH, Lead Generation and Candidate Realization, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Scheiper
authors.affiliation: Sanofi Deutschland GmbH, Lead Generation and Candidate Realization, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Pöverlein
authors.affiliation: Sanofi R&D, DPU early to candidate, 16 rue d'Ankara, 67080 Strasbourg, France.
authors.forename: Axel
authors.initials: A
authors.lastname: Ganzhorn
authors.affiliation: Sanofi R&D, TSU Infectious Disease, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lagrange
authors.affiliation: Sanofi R&D, TSU Infectious Disease, 195, route d'Espagne BP 13669, 31036 Toulouse Cedex 1, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Bacqué
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011719:Pyrazines; C081173:glutamine synthetase I; D005974:Glutamate-Ammonia Ligase
keywords: GlnA1 inhibitors; Glutamine synthetase; High throughput screening; Tuberculosis; X-ray crystallography