Isolation of 2-Alkyl-4-quinolones with Unusual Side Chains from a Chinese Pseudomonas aeruginosa Isolate

Abstract

Chemical investigation of a Pseudomonas aeruginosa strain isolated from Hebei, China, led to the isolation of a suite of quinolones, quinolone-N-oxides, and phenazines, the structures of which were elucidated by detailed spectroscopic analysis. Most notable among the secondary metabolites isolated was an unprecedented 4-quinolone containing an S-methyl group in the side chain and a new derivative including a phenyl ring in the side chain, which expand significantly the variety of structural motifs found in the quinolones and raise interesting questions about their biosynthesis.

Synthesis of Natural and Unnatural Quinolones Inhibiting the Growth and Motility of Bacteria

“…Finally, the target quinolone 1 was achieved by NaOH-promoted cyclization of 26 at 110 °C in dioxane for 1 h (Scheme ), along with the Z -isomer 2 , in a 5:1 ratio. Spectroscopic data for the target quinolone were identical to those for the natural product …”

Bacterial Alkyl-4-quinolones: Discovery, Structural Diversity and Biological Properties

“…While the majority of alkylquinolones reported have simple saturated or unsaturated hydrocarbon side chains, a handful of quinolones have been reported with more complex substituents. These include one example containing a cyclopropyl ring in the side chain (H12a), first reported from a P. aeruginosa strain [25], and sulfide-and benzylsubstituted quinolones (H3a, H7b), from a Chinese P. aeruginosa isolate [24]. The first of these are the classical alkyl-4-quinolones, also known as the hydroxy-alkylquinolones (HAQs) characterized by HHQ and its derivatives, which are substituted solely at the 2-position.…”

“…Alkylquinolones with odd-numbered numbers of carbons are more commonly found than those with even numbers of carbon atoms, with seven-carbon and nine-carbon examples being particularly prominent; this may reflect their biosynthesis [23]. More recently, several branched chain examples have been described from Pseudomonas (H7a, H8b) [24] and Pseudoalteromonas (H5a, H6a) strains, respectively [22]. Numerous alkylquinolones with unsaturated alkyl chains have also been described (Figure 2), the best known and most widely distributed of which is 2-(∆1 -nonenyl-)-4-quinolone (H9∆1), one of the originally reported Pyo series of compounds [6].…”

“…The last class, the tetrahydroquinolines, are included here as they commonly co-occur with the alkylquinolones and share a biosynthetic origin (Table A2). To date, they have only been reported from Pseudomonas species [4,8,9,24,25]. The first isolation of 3-n-heptyl-3-hydroxy-1,2,3,4-tetra-hydro quinoline-2,4-dione (T7) and 3-n-nonyl-3-hydroxy-1,2,3,4-tetra-hydroquinoline-2,4-dione (T9) from P. aeruginosa was reported by Hays in 1945 as part of the original Pyo series of quinolones [4].…”

“…This compound was previously isolated as a plant metabolite from Isatis tinctoria (Brassicaceae) and displayed anti-tuberculosis activity with an IC 90 of 6.8 µM [66][67][68]. An extensive isolation report in 2020 described the isolation of six new HAQs, including the highly unusual sulfide and benzyl derivatives H3a and H7b, in addition to fifteen known AQs, three AQNOs, and the tetrhydroquinoline T7 [24]. While no significant biological studies were reported in the initial isolation report, a subsequent synthetic investigation revealed that the natural products H3a, H7b and H7∆2 inhibited the growth of S. aureus, with the latter reducing growth by over 80% at 1.1 µM.…”