Inhibition of Enterococcus faecalis biofilm formation by highly active lactones and lactams analogues of rubrolides

• Rubrolides analogues are effective in inhibiting biofilm formation by Enterococcus faecalis.
• γ-Hydroxy- and γ-alkylidene-γ-lactams were synthesized from rubrolides analogues.
• The activity of compounds against E. faecalis biofilm formation was evaluated.
• γ-Alkylidene-γ-lactams as inhibitors of biofilm formation by E. faecalis.
• γ-Hydroxy-γ-lactams are potent inhibitors of biofilm formation by E. faecalis.

Seven β-aryl substituted γ-alkylidene-γ-lactones analogues of rubrolides were synthesized from mucobromic acid and converted through a lactamization with isobutylamine into their corresponding γ-hydroxy-γ-lactams (76–85%). These lactams were converted into (Z)- and (E)-γ-alkylidene-γ-lactams (23–45%). All compounds were fully characterized by IR, NMR (1H and 13C), COSY and HETCOR bidimensional experiments, and NOE difference spectroscopy experiments when necessary. Evaluation of these three different classes of compounds against Enterococcus faecalis biofilm formation showed that all classes are active and the highest biofilm inhibition activity was caused by lactam 13f (IC50 = 0.76 μg/mL). Moreover, in almost all cases at least one of the lactams is more active than its correspondent γ-alkylidene-γ-lactone. The use of rubrolides as a lead structure has proven successful for the identification of new compounds displaying novel antibacterial activities, namely biofilm inhibition, which have the potential for the development of antimicrobial drugs targeted to inhibition of the initial stages of bacterial infections, rather than bacterial viability. Such drugs are less prompt to induce bacterial resistance, being therefore a more cost-effective investment for pharmaceutical research.

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