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Synthesis and Antimicrobial Activity of Burkholderia-Related 4-Hydroxy-3-Methyl-2-Alkenylquinolones (HMAQs) and Their N-Oxide Counterparts

preprint
submitted on 15.02.2020 and posted on 19.02.2020 by Marianne Piochon, Pauline M. L. Coulon, Armand Caulet, Marie-Christine Groleau, Eric Déziel, Charles Gauthier
ABSTRACT: The Burkholderia genus offers a promising potential in medicine because of the diversity of biologically active natural products encoded in its genome. Some pathogenic Burkholderia spp. biosynthesize a specific class of antimicrobial 2-alkyl-4(1H)-quinolones, i.e., 4-hydroxy-3-methyl-2-alkenylquinolones (HMAQs) and their N-oxide derivatives (HMAQNOs). Herein, we report the synthesis of a series of six HMAQs and HMAQNOs featuring a trans-∆2 double bond at the C2-alkyl chain. The quinolone scaffold was obtained via the Conrad-Limpach approach while the (E)-2-alkenyl chain was inserted through Suzuki-Miyaura cross-coupling under microwave radiation without noticeable isomerization according to the optimized conditions. Subsequent oxidation of enolate-protected HMAQs cleanly led to the formation of HMAQNOs following cleavage of the ethyl carbonate group. Synthetic HMAQs and HMAQNOs were in vitro evaluated for their antimicrobial activity against different Gram-negative and Gram-positive bacteria as well as against fungi and yeasts. The biological results support and extend the potential of HMAQs and HMAQNOs as antimicrobials, especially against Gram-positive bacteria. We also confirm the involvement of HMAQs in the autoregulation of the Hmq system in Burkholderia ambifaria.

Funding

Canadian Institutes of Health Research

Natural Sciences and Engineering Research Council

Natural Sciences and Engineering Research Council

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Fonds de recherche Québec Santé

History

Email Address of Submitting Author

charles.gauthier@iaf.inrs.ca

Institution

Institut national de la recherche scientifique

Country

Canada

ORCID For Submitting Author

0000-0002-2475-2050

Declaration of Conflict of Interest

There is no conflict of interest to declare.

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