A series of analogues ofPseudonocardiasp. natural products were synthesized, which have been reported to possess potent antibacterial activity againstHelicobacter pyloriand induce growth defects inEscherichia coliandStaphylococcus aureus. Taking inspiration from a methodology used in our total synthesis of natural products, we applied this methodology to access analogues possessing bulky N-substituents, traditionally considered to be challenging scaffolds. Screening of the library provided valuable insights into the structure–activity relationship of the bacterial growth defects, and suggested that selectivity between bacterial species should be attainable. Furthermore, a structurally related series of analogues was observed to inhibit production of the virulence factor pyocyanin in the human pathogenPseudomonas aeruginosa, which may be a result of their similarity to thePseudomonasquinolone signal (PQS) quorum sensing autoinducer. This provided new insights regarding the effect of N-substitution in PQS analogues, which has been hitherto underexplored.
Total Synthesis and Biological Evaluation of Phaeosphaerides
