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

Selectively methylated analogues of naturally occurring 2-heptyl-4(1 H )-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(1 H )-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.