Structure-guided design of antibacterials that allosterically inhibit DNA gyrase. Issue 11 (1st June 2019)

• Record Type: Journal Article
• Authors: Thalji, Reema K.; Raha, Kaushik; Andreotti, Daniele; Checchia, Anna; Cui, Haifeng; Meneghelli, Giovanni; Profeta, Roberto; Tonelli, Federica; Tommasi, Simona; Bakshi, Tania; Donovan, Brian T.; Howells, Alison; Jain, Shruti; Nixon, Christopher; Quinque, Geoffrey; McCloskey, Lynn; Bax, Benjamin D.; Neu, Margarete; Chan, Pan F.; Stavenger, Robert A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 11(2019)
• Page Start: 1407
• Page End: 1412
• Publication Date: 2019-06-01
• Subjects: Antibacterial -- Topoisomerase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.03.029
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.