title: New direct inhibitors of InhA with antimycobacterial activity based on a tetrahydropyran scaffold.
abstract: Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors.forename: Stane
authors.initials: S
authors.lastname: Pajk
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors.forename: Matej
authors.initials: M
authors.lastname: Živec
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors.forename: Roman
authors.initials: R
authors.lastname: Šink
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.affiliation: Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
authors.forename: Margarete
authors.initials: M
authors.lastname: Neu
authors.affiliation: Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Martínez-Hoyos
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Herrán
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Álvarez-Gómez
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Álvarez-Ruíz
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mendoza-Losana
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Castro-Pichel
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Barros
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Ballell-Pages
authors.affiliation: Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
authors.affiliation: Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
authors.forename: Maire A
authors.initials: MA
authors.lastname: Convery
authors.affiliation: DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain. Electronic address: lourdes.p.encinas-prieto@gsk.com.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Encinas
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa-uni-lj.si.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D011714:Pyrans; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: InhA; Inhibitors; Synthesis; Tuberculosis