The Novel Chiral 2(5H)-Furanone Sulfones Possessing Terpene Moiety: Synthesis and Biological Activity.

Over the past decades, 2(5H)-furanone derivatives have been extensively studied because of their promising ability to prevent the biofilm formation by various pathogenic bacteria. Here, we report the synthesis of a series of optically active sulfur-containing 2(5H)-furanone derivatives and characterize their biological activity. Novel thioethers were obtained by an interaction of stereochemically pure 5-(l)-menthyloxy- or 5-(l)-bornyloxy-2(5H)-furanones with aromatic thiols under basic conditions. Subsequent thioethers oxidation by an excess of hydrogen peroxide in acetic acid resulted in the formation of the corresponding chiral 2(5H)-furanone sulfones. The structure of synthesized compounds was confirmed by IR and NMR spectroscopy, HRMS, and single crystal X-ray diffraction. The leading compound, 26, possessing the sulfonyl group and l-borneol moiety, exhibited the prominent activity against Staphylococcus aureus and Bacillus subtilis with MICs of 8 µg/mL. Furthermore, at concentrations of 0.4-0.5 µg/mL, the sulfone 26 increased two-fold the efficacy of aminoglycosides gentamicin and amikacin against S. aureus. The treatment of the model-infected skin wound in the rat with a combination of gentamicin and sulfone 26 speeded up the bacterial decontamination and improved the healing of the wound. The presented results provide valuable new insights into the chemistry of 2(5H)-furanone derivatives and associated biological activities.

Targeting Bacillus cereus cells: increasing efficiency of antimicrobials by the bornylpossessing 2(5Н)-furanone derivative.

Among a variety of antimicrobial compounds, the derivatives of 2(5H)-furanone exhibit different effects on Firmicutes and Proteobacteria. While inhibiting quorum-dependent biofilm formation and virulence factor expression by Gram-negative bacteria through specific interference with the AI-2 signaling pathways, these compounds demonstrate bactericidal effects against Gram-positive bacteria. Here we report that 3,4-dichloro-5(S)-[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy]-2(5H)-furanone designed as F123 inhibits growth and biofilm formation by the food-poisoning bacterium Bacillus cereus at 8 µg/ ml and kills bacteria at 16 µg/ml. While the growth of Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Bacillus subtilis were also inhibited at 8-16 µg/ml of F123, no bactericidal effect on these strains was observed at concentrations up to 128 µg/ml, suggesting pronounced specificity of F123 for B. cereus. In a checker-board assay F123 increased the efficacy of amikacin, gentamicin and benzalkonium chloride against B. cereus with medians of fractional inhibitory concentration index of 0.38, 0.56 and 0.56, respectively. Moreover, the number of viable B. cereus cells in biofilm was reduced by more than 3 orders of magnitude at 64 µg/ml of F123, suggesting its chemotype as a promising enhancer for specific treatment of B. cereus-associated topical infections, including biofilm-embedded bacteria.