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Bioorg Med Chem. 2014 Oct 1;22(19):5392-409. doi: 10.1016/j.bmc.2014.07.040. Epub 2014 Aug 4.

Optimization of physicochemical properties and safety profile of novel bacterial topoisomerase type II inhibitors (NBTIs) with activity against Pseudomonas aeruginosa.

Author information

1
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: Folkert.Reck@Novartis.com.
2
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
3
Drug Safety and Metabolism Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
4
AstraZeneca, Pharmaceutical Development, Chemical Sciences, Silk Road Business Park, Macclesfield, Cheshire, England SK10 4TG, United Kingdom.
5
Adesis Inc., 27 McCullough Drive, New Castle, DE 19720, USA.

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.

KEYWORDS:

Bacterial toposisomerases; Gyrase; Pseudomonas aeruginosa; hERG

PMID:
25155913
DOI:
10.1016/j.bmc.2014.07.040
[Indexed for MEDLINE]

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