Discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors

DOI: 10.1021/acs.jmedchem.5b00961
PMID: 26460684

Authors: Jing Zhang (Cubist Pharmaceuticals Inc.) , Qingyi Yang (Cubist Pharmaceuticals Inc.) , Jason B. Cross (Cubist Pharmaceuticals Inc.) , Jan Antoinette C. Romero (Cubist Pharmaceuticals Inc.) , Katherine M. Poutsiaka (Cubist Pharmaceuticals Inc.) , Felix Epie (Cubist Pharmaceuticals Inc.) , Douglas Bevan (Cubist Pharmaceuticals Inc.) , Bin Wang (Cubist Pharmaceuticals Inc.) , Yanzhi Zhang (Cubist Pharmaceuticals Inc.) , Ajit Chavan (Cubist Pharmaceuticals Inc.) , Xin Zhang (Cubist Pharmaceuticals Inc.) , Terence Moy (Cubist Pharmaceuticals Inc.) , Anu Daniel (Cubist Pharmaceuticals Inc.) , Kien Nguyen (Cubist Pharmaceuticals Inc.) , Brian Chamberlain (Cubist Pharmaceuticals Inc.) , Nicole Carter (Cubist Pharmaceuticals Inc.) , Joseph Shotwell (Cubist Pharmaceuticals Inc.) , Jared Silverman (Cubist Pharmaceuticals Inc.) , Chester A. Metcalf (Cubist Pharmaceuticals Inc.) , Dominic Ryan (Cubist Pharmaceuticals Inc.)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 58 (21) , PAGES 8503 - 8512

State: Published (Approved)
Published: October 2015

Abstract: The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.

Journal Keywords: Noncovalent interactions; Urea; Structure activity relationship; Bacteria; Inhibitors

Diamond Keywords: Bacteria

Subject Areas: Medicine, Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 27/11/2015 11:21

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)