Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

Abstract

Selectively methylated analogues of naturally occurring 2-heptyl-4(1H)-quinolones, which are alkaloids common within the Rutaceae family and moreover are associated with quorum sensing and virulence of the human pathogen Pseudomonas aeruginosa, have been prepared. While the synthesis by direct methylation was successful for 3-unsubstituted 2-heptyl-4(1H)-quinolones, methylated derivatives of the Pseudomonas quinolone signal (PQS) were synthesized from 3-iodinated quinolones by methylation and iodine–metal exchange/oxidation. The two N- and O-methylated derivatives of the PQS showed strong quorum sensing activity comparable to that of PQS itself. Staphylococcus aureus, another pathogenic bacterium often co-occurring with P. aeruginosa especially in the lung of cystic fibrosis patients, was inhibited in planktonic growth and cellular respiration by the 4-O-methylated derivatives of HQNO and HHQ, respectively.

Isolation and Characterization of Plant Growth-Promoting Endophytic Bacteria Paenibacillus polymyxa SK1 from Lilium lancifolium

“…In Pseudomonas, this compound provided the core for the quinolone-based QS system called Pseudomonas quinolone signal (PQS). In addition to its role as a QS signaling molecule, the PQS was reported to mediate iron acquisition, cytotoxicity, and resistance to environmental stresses including infectious disease-causing agents [44,45]. Oxocativic acid is a diterpene that was previously reported from Cistus ladanifer L. with a potential role in the allelopathic activity of this Mediterranean species [46].…”

Bromination of alkyl quinolones by Microbulbifer sp. HZ11, a marine Gammaproteobacterium, modulates their antibacterial activity

“…Preparation of alkyl quinolones HHQ and HQNO were prepared according to literature procedures (Thierbach et al, 2019). BrHHQ (Reen et al, 2012) and NHQ (Lu et al, 2012) were synthesized using slightly modified literature procedures.…”

Modification of the Pseudomonas aeruginosa toxin 2‐heptyl‐1‐hydroxyquinolin‐4(1H)‐one and other secondary metabolites by methyltransferases from mycobacteria

“…Methylation of PQS may affect its antibacterial properties, however, the MTase product 2‐heptyl‐3‐hydroxy‐4‐methoxyquinoline ( 16 ) still exhibits quorum sensing activity in P. aeruginosa . The HHQ ( 4 ) methylation product 2‐heptyl‐4‐methoxyquinoline ( 15 ), albeit somewhat less inhibitory on growth of S. aureus than 4 , significantly inhibited cellular O 2 consumption in S. aureus [58]. Thus, modification of plant or bacterial secondary metabolites by methylation can modulate their biological properties in diverse ways and may also result in potentiation rather than attenuation of their biological activities.…”

“…The following compounds were synthesized according to literature: 1‐hydroxyquinolin‐4(1 H )‐one ( 2 ) [60], 3‐bromo‐2‐heptylquinolin‐4(1 H )‐one ( 5 ) [61], HMOQ ( 11 ) [25], 3‐bromo‐2‐heptyl‐1‐hydroxyquinolin‐4(1 H )‐one ( 10 ) [62], HHQ ( 4 ), 2‐heptyl‐1‐methylquinolin‐4(1 H )‐one ( 7 ), 2‐heptyl‐3‐hydroxy‐1‐methylquinolin‐4(1 H )‐one ( 8 ), HQNO ( 9 ), 2‐heptyl‐4‐methoxyquinoline‐1‐oxide ( 14 ), 2‐heptyl‐4‐methoxyquinoline ( 15 ) and 2‐heptyl‐3‐hydroxy‐4‐methoxyquinoline ( 16 ) [58]. 4‐Methoxyisoquinolin‐1(2 H )‐one ( 22 ) was bought from AnalytiCon Discovery (Potsdam, Germany).…”

“…In case of the antibacterial P. aeruginosa secondary metabolite HQNO, however, methylation of the N-hydroxy moiety by the mycobacterial MTases clearly led to detoxification, protecting the mycobacteria from inactivation of menaquinol oxidase activity and from the ROS-inducing effect of HQNO [25]. The product HMOQ (11) also was observed to be less inhibitory on cellular O 2 consumption of S. aureus than HQNO (9) [58]. Methylation of PQS may affect its antibacterial properties, however, the MTase product 2-heptyl-3-hydroxy-4methoxyquinoline (16) still exhibits quorum sensing activity in P. aeruginosa.…”