Synthesis and Antimicrobial Activity of -Related 4-Hydroxy-3-methyl-2-alkenylquinolines (HMAQs) and Their -Oxide Counterparts.

The genus offers a promising potential in medicine because of the diversity of biologically active natural products encoded in its genome. Some pathogenic spp. biosynthesize a specific class of antimicrobial 2-alkyl-4(1)-quinolones, i.e., 4-hydroxy-3-methyl-2-alkenylquinolines (HMAQs) and their -oxide derivatives (HMAQNOs). Herein, we report the synthesis of a series of six HMAQs and HMAQNOs featuring a -Δ double bond at the C2-alkyl chain. The quinolone scaffold was obtained via the Conrad-Limpach approach, while the ()-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 evaluated for their antimicrobial activity against different Gram-negative and Gram-positive bacteria as well as against molds 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 .