ABSTRACT
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 0.5â µg mL(-1) (1 and 1.5â µm, respectively). This is a promising result relative to that obtained for reserpine (MIC=20â 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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Staphylococcus/drug effects , Thiophenes/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Staphylococcus/chemistry , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
The synthesis of 37 1-(1H-indol-3-yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti-staphylococcal activity. By contrast, several of the compounds restored, in a concentration-dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure-activity relationships studies revealed that the indolic aldonitrones halogenated at positionâ 5 of the indole core were the most efficient inhibitors of the S.â aureus NorA efflux pump. Among the compounds, (Z)-N-benzylidene-2-(tert-butoxycarbonylamino)-1-(5-iodo-1H-indol-3-yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA-1199B strain when used at a concentration of 0.5â mg L(-1) . To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert-butyl (2-(3-hydroxyureido)-2-(1H-indol-3-yl)ethyl)carbamate, which is not toxic for human cells, was also found.
Subject(s)
Amines/chemistry , Anti-Bacterial Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Staphylococcus aureus/metabolism , Amines/chemical synthesis , Amines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Cell Line , Cell Proliferation/drug effects , Ciprofloxacin/pharmacology , Drug Resistance, Bacterial/drug effects , Humans , Indoles/chemistry , Microbial Sensitivity Tests , Multidrug Resistance-Associated Proteins/metabolism , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
A collection of 3-substituted indole derivatives was prepared using nucleophilic addition of indoles to nitrones. The compounds were then tested for their antibacterial activity against almost thirty bacterial strains representative of common human pathogens. Two types of indolic molecules inhibit the growth of Staphylococcus aureus, including MRSA and VISA strains, with MIC values ranging from 8 to 16 mg/L.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Indoles/chemistry , Indoles/pharmacology , Anti-Bacterial Agents/chemical synthesis , Bacterial Infections/drug therapy , Humans , Indoles/chemical synthesis , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Structure-Activity RelationshipSubject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Heterocyclic Compounds/pharmacology , Methane/analogs & derivatives , Silver Compounds/pharmacology , Silver Compounds/toxicity , Anti-Bacterial Agents/chemistry , Heterocyclic Compounds/chemistry , Ligands , Methane/chemistry , Methane/pharmacology , Methane/toxicity , Molecular Structure , Silver Compounds/chemistryABSTRACT
A small library of simple 1,4-disubstituted 1,2,3-triazoles was prepared using a known one-pot procedure starting from organic halides and terminal alkynes. The compounds were then tested for their antibacterial activity against normal and resistant species of Staphylococcus aureus.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Staphylococcus aureus/drug effects , Triazoles/chemical synthesis , Triazoles/pharmacology , Anti-Bacterial Agents/chemistry , Combinatorial Chemistry Techniques , Drug Resistance, Bacterial/drug effects , Small Molecule Libraries/chemistry , Triazoles/chemistryABSTRACT
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.