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C-2 phenyl replacements to obtain potent quinoline-based Staphylococcus aureus NorA inhibitors

Authors :
Maria Letizia Barreca
Stefano Sabatini
Gianmarco Mangiaterra
Andrea Astolfi
Francesca Biavasco
Violetta Cecchetti
Tommaso Felicetti
Oriana Tabarrini
Giuseppe Manfroni
Rolando Cannalire
Serena Massari
Donatella Pietrella
Nicholas Cedraro
Felicetti, Tommaso
Mangiaterra, Gianmarco
Cannalire, Rolando
Cedraro, Nichola
Pietrella, Donatella
Astolfi, Andrea
Massari, Serena
Tabarrini, Oriana
Manfroni, Giuseppe
Letizia Barreca, Maria
Cecchetti, Violetta
Biavasco, Francesca
Sabatini, Stefano
Source :
Journal of Enzyme Inhibition and Medicinal Chemistry, Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 584-597 (2020)
Publication Year :
2020
Publisher :
Taylor & Francis, 2020.

Abstract

NorA is the most studied efflux pump of Staphylococcus aureus and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative 37a showed an improved EPI activity (16-fold) with respect to the starting hit 1. Moreover, compound 37a exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (norA+). Also, 37a exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of “selectivity index” in comparison to 1.

Details

Language :
English
ISSN :
14756374 and 14756366
Volume :
35
Issue :
1
Database :
OpenAIRE
Journal :
Journal of Enzyme Inhibition and Medicinal Chemistry
Accession number :
edsair.doi.dedup.....6e49eec3bcb3aeef3c30cb29ee4f9e77