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C-2 phenyl replacements to obtain potent quinoline-based Staphylococcus aureus NorA inhibitors
- 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.
- Subjects :
- Staphylococcus aureus
Stereochemistry
Short Communication
RM1-950
Microbial Sensitivity Tests
medicine.disease_cause
NorA
chemistry.chemical_compound
Structure-Activity Relationship
Antibiotic resistance
Bacterial Proteins
Drug Discovery
medicine
Structure–activity relationship
antimicrobial resistance
Antimicrobial resistance breakers
efflux pump inhibitors
Anti-Bacterial Agents
Molecular Structure
Multidrug Resistance-Associated Proteins
Quinolines
Pharmacology
Aryl
Quinoline
General Medicine
Ciprofloxacin
chemistry
Efflux
Therapeutics. Pharmacology
medicine.drug
Subjects
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