title: Synthetically Tuning the 2-Position of Halogenated Quinolines: Optimizing Antibacterial and Biofilm Eradication Activities via Alkylation and Reductive Amination Pathways.
abstract: 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 μm) and biofilm eradication (MBEC 1.0-93.8 μm) 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 μm. 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.
authors.affiliation: Department of Chemistry, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Basak
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Abouelhassan
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
authors.forename: Verrill M
authors.initials: VM
authors.lastname: Norwood
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
authors.forename: Minh Thu
authors.initials: MT
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Shouguang
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Chemistry, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA. rhuigens@cop.ufl.edu.|Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA. rhuigens@cop.ufl.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Huigens
mesh_terms: D000478:Alkylation; D000586:Amination; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D018441:Biofilms / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D016984:Enterococcus faecium / Q000187:drug effects / Q000502:physiology; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054879:Halogenation; D006367:HeLa Cells; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D013210:Staphylococcus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011804:Quinolines
keywords: antibiotic tolerance; bacterial biofilms; halogenated quinolone; medicinal chemistry; structure-activity relationships