title: Optimization of physicochemical properties and safety profile of novel bacterial topoisomerase type II inhibitors (NBTIs) with activity against Pseudomonas aeruginosa.
abstract: Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: Folkert.Reck@Novartis.com.
authors.forename: Folkert
authors.initials: F
authors.lastname: Reck
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Ehmann
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Dougherty
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Newman
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Sussie
authors.initials: S
authors.lastname: Hopkins
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Stone
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Nikunj
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Drug Safety and Metabolism Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ciaccio
authors.affiliation: Drug Safety and Metabolism Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: John
authors.initials: J
authors.lastname: McNulty
authors.affiliation: Drug Safety and Metabolism Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Barthlow
authors.affiliation: Drug Safety and Metabolism Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Donnell
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Kosalaram
authors.initials: K
authors.lastname: Goteti
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: John
authors.initials: J
authors.lastname: Breen
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Janelle
authors.initials: J
authors.lastname: Comita-Prevoir
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cornebise
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cronin
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Eyermann
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Bolin
authors.initials: B
authors.lastname: Geng
authors.affiliation: AstraZeneca, Pharmaceutical Development, Chemical Sciences, Silk Road Business Park, Macclesfield, Cheshire, England SK10 4TG, United Kingdom.
authors.forename: Greg R
authors.initials: GR
authors.lastname: Carr
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Lakshmipathi
authors.initials: L
authors.lastname: Pandarinathan
authors.affiliation: Adesis Inc., 27 McCullough Drive, New Castle, DE 19720, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Adesis Inc., 27 McCullough Drive, New Castle, DE 19720, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cottone
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Natascha
authors.initials: N
authors.lastname: Bezdenejnih-Snyder
mesh_terms: D000818:Animals; D002627:Chemistry, Physical; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: Bacterial toposisomerases; Gyrase; Pseudomonas aeruginosa; hERG