title: Inhibition of Enterococcus faecalis biofilm formation by highly active lactones and lactams analogues of rubrolides.
abstract: 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 ((1)H and (13)C), 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.
authors.affiliation: Department of Chemistry, Federal University of Viçosa, Av. PH Rolfs, Viçosa, MG 36570-000, Brazil.
authors.forename: Ulisses A
authors.initials: UA
authors.lastname: Pereira
authors.affiliation: Department of Chemistry, Federal University of Viçosa, Av. PH Rolfs, Viçosa, MG 36570-000, Brazil; Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil. Electronic address: lcab@ufmg.br.
authors.forename: Luiz C A
authors.initials: LC
authors.lastname: Barbosa
authors.affiliation: Department of Chemistry, Federal University of Viçosa, Av. PH Rolfs, Viçosa, MG 36570-000, Brazil.
authors.forename: Célia R A
authors.initials: CR
authors.lastname: Maltha
authors.affiliation: Department of Chemistry, Federal University of Viçosa, Av. PH Rolfs, Viçosa, MG 36570-000, Brazil.
authors.forename: Antônio J
authors.initials: AJ
authors.lastname: Demuner
authors.affiliation: Gene Solutions, LLC, One Boars Head Pointe, Suite 131, Charlottesville, VA 22903, USA.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Masood
authors.affiliation: Department of Odontology, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil; Department of Biologie, University of Cergy Pontoise, 2 Av. Adolphe Chauvin, 95302 Cergy Pontoise, France.
authors.forename: Andréa L
authors.initials: AL
authors.lastname: Pimenta
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000254:growth & development; D005663:Furans / Q000737:chemistry; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D005663:Furans; D007769:Lactams; D007783:Lactones; C014116:mucobromic acid
keywords: Anti-biofilm activity; Quorum sensing antagonist; Rubrolides; γ-Alkylidene-γ-lactams; γ-Alkylidene-γ-lactones; γ-Hydroxy-γ-lactams