Premium
Synthetically Tuning the 2‐Position of Halogenated Quinolines: Optimizing Antibacterial and Biofilm Eradication Activities via Alkylation and Reductive Amination Pathways
Author(s) -
Basak Akash,
Abouelhassan Yasmeen,
Norwood Verrill M.,
Bai Fang,
Nguyen Minh Thu,
Jin Shouguang,
Huigens Robert W.
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201600926
Subject(s) - enterococcus faecium , biofilm , staphylococcus epidermidis , microbiology and biotechnology , staphylococcus aureus , methicillin resistant staphylococcus aureus , chemistry , antimicrobial , antibacterial activity , enterococcus hirae , bacteria , antibiotics , enterococcus , biology , genetics
Agents capable of eradicating bacterial biofilms are of great importance to human health as biofilm‐associated infections are tolerant to our current antibiotic therapies. We have recently discovered that halogenated quinoline (HQ) small molecules are: 1) capable of eradicating methicillin‐resistant Staphylococcus aureus (MRSA), methicillin‐resistant Staphylococcus epidermidis (MRSE) and vancomycin‐resistant Enterococcus faecium (VRE) biofilms, and 2) synthetic tuning of the 2‐position of the HQ scaffold has a significant impact on antibacterial and antibiofilm activities. Here, we report the chemical synthesis and biological evaluation of 39 HQ analogues that have a high degree of structural diversity at the 2‐position. We identified diverse analogues that are alkylated and aminated at the 2‐position of the HQ scaffold and demonstrate potent antibacterial (MIC≤0.39 μ m ) and biofilm eradication (MBEC 1.0–93.8 μ m ) activities against drug‐resistant Staphylococcus aureus , Staphylococcus epidermidis and Enterococcus faecium strains while demonstrating <5 % haemolysis activity against human red blood cells (RBCs) at 200 μ m . In addition, these HQs demonstrated low cytotoxicity against HeLa cells. Halogenated quinolines are a promising class of antibiofilm agents against Gram‐positive pathogens that could lead to useful treatments against persistent bacterial infections.