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

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., 4hydroxy-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. The Burkholderia genus includes a vast group of Gram-negative bacteria found in diverse ecological niches. 1,2 Some Burkholderia spp. are of serious pathogenic concerns, such as the Centers for Disease Control and Prevention (CDC) Tier 1 select agents 3 Burkholderia pseudomallei and B. malleithe infectious agents of melioidosis 4,5 and glanders, 6 respectively,and the devastating plant crop pathogens B. glumae and B. gladioli, which cause major yield losses in rice productions. 7,8 Others, like those forming the B. cepacia complex, include species that can both live in beneficial associations with their eukaryotic hots (mammals, plants, and fungi) 2 and cause several hard-to-treat opportunistic infections, such as the cepacian syndrome in individuals suffering from cystic fibrosis. 9Burkholderia spp. offer a tantalizing potential in medicine because of their capacity to produce highly potent and structurally diverse metabolites. 10,11 A plethora of natural products exhibiting various biological functions have been identified or isolated so far from Burkholderia spp. 10 To name few examples, only for B. pseudomallei, cytotoxic siderophores (e.g., malleilactone), 12 proteasome inhibitors (e.g., deoxyglidobactin C), 13 tensioactive lipopeptides (e.g., malleipeptin A), 13 and rhamnolipids, 14 as well as quorum sensing modulators such as N-acyl homoserine lactones (AHLs) 15 and 2-alkyl-4(1H)-quinolones (AQs) 16,17 have been reported.Burkholderia spp. biosynthesize a specific class of AQs, namely 4-hydroxy-3-methyl-2alkenylquinolones (HMAQ, 1-3), which feature a methyl group at C3 and a trans- 2 insaturation at the C2-alkyl chain (Figure 1). [17][18][19][20][21][22][23][24][25][26][27] HMAQs 1 and 3, respectively the heptenyl and nonenyl congeners, exhi...