Synthesis and evaluation of new arylbenzo[ b]thiophene and diarylthiophene derivatives as inhibitors of the NorA multidrug transporter of Staphylococcus aureus

• Published in: Bioorganic & medicinal chemistry 2007-07, Vol.15 (13), p.4482-4497
• Main Authors: Fournier dit Chabert, Jérémie, Marquez, Béatrice, Neville, Luc, Joucla, Lionel, Broussous, Sylvie, Bouhours, Pascale, David, Emilie, Pellet-Rostaing, Stéphane, Marquet, Bernard, Moreau, Nicole, Lemaire, Marc
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Benzo[ b]thiophene; Biological and medical sciences; Cell Line, Tumor; Chemical Sciences; Ciprofloxacin - metabolism; Drug Resistance, Multiple, Bacterial - genetics; Drug Screening Assays, Antitumor; Ethidium; Heck-type coupling; Humans; Indicators and Reagents; Macrolides - pharmacology; Medical sciences; Microbial Sensitivity Tests; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; NorA multidrug transporter; Organic chemistry; Pharmacology. Drug treatments; Quinolones - pharmacology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - metabolism; Structure-Activity Relationship; Thiophene; Thiophenes - chemical synthesis; Thiophenes - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.04.023

New arylbenzo[ b]thiophene and arylthiophene derivatives were synthesised and evaluated as inhibitors of the NorA multidrug transporter of Staphylococcus aureus. The synthesis based on palladium catalytic coupling of 38 new-arylated benzo[ b]thiophenes or thiophenes is described in a few steps. We also report the direct arylation of the position 3 of the benzo[ b]thiophenic structure, a ‘one pot’ 2,5-heterodiarylation of thiophenes as well as the synthesis of precursors of amino-acids with a 2-arylated benzo[ b]thiophene core. These compounds were evaluated on bacteria strains: most of them did not exhibit any antibiotic activity but were found to selectively inhibit the NorA multidrug transporter of Staphylococcus aureus. As such, they restored the activity of the NorA substrates ciprofloxacin against a resistant S. aureus strain in which this efflux pump is over-expressed.