C2 Arylated Benzo[b]thiophene Derivatives as Staphylococcus aureus NorA Efflux Pump Inhibitors

• Published in: ChemMedChem 2016-02, Vol.11 (3), p.320-330
• Main Authors: Liger, François, Bouhours, Pascale, Ganem-Elbaz, Carine, Jolivalt, Claude, Pellet-Rostaing, Stéphane, Popowycz, Florence, Paris, Jean-Marc, Lemaire, Marc
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibiotics; arylation; Bacterial Proteins - antagonists & inhibitors; Dose-Response Relationship, Drug; efflux pump inhibitors; inhibitors; Microbial Sensitivity Tests; Molecular Structure; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Staphylococcus - chemistry; Staphylococcus - drug effects; Staphylococcus aureus; Structure-Activity Relationship; sulfur heterocycles; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500463

An innovative and straightforward synthesis of second‐generation 2‐arylbenzo[b]thiophenes as structural analogues of INF55 and the first generation of our laboratory‐made molecules was developed. The synthesis of C2‐arylated benzo[b]thiophene derivatives was achieved through a method involving direct arylation, followed by simple structural modifications. Among the 34 compounds tested, two of them were potent NorA pump inhibitors, which led to a 16‐fold decrease in the ciprofloxacin minimum inhibitory concentration (MIC) against the SA‐1199B strain at concentrations of 0.25 and 0.5 μg mL−1 (1 and 1.5 μm, respectively). This is a promising result relative to that obtained for reserpine (MIC=20 μg mL−1), a reference compound amongst NorA pump inhibitors. These molecules thus represent promising candidates to be used in combination with ciprofloxacin against fluoroquinolone‐resistant strains. Pump stoppers: Synthetic methods based on the regioselective functionalization of a benzo[b]thiophene derivative afford a series of original INF55 analogues as potential NorA pump inhibitors. Two derivatives display minimal inhibitory concentrations (MICs) of 0.25 and 0.5 µg mL−1, which is a promising result relative to that shown by reserpine (MIC=20 µg mL−1) a reference compound.