Synthesis And Bacterial Biofilm Inhibitory Activity Of Several Naturally Furanones

Antibitotics are used to treat bacterial infections by killing the bacteria or inhibiting their growth, but resistance to antibiotics can develop readily. The discovery that bacterial quorum-sensing regulates bacterial virulence as well as the formation of bio film opens up new ways to control certain bacterial infections.Many Gram-negative bacterial involve Pseudomonas aeruginosa, capable of quorum sensing employ N-acylhomoserine lactones(AHLs) as the signaling compound. Furanone compounds capable of inhibiting quorum-sensing systems have been isolated from the Australian subtidal red alga Delisea pulchra. Both furanone compounds and AHLs contain the structure namedγ-butyrolactone. In this thesis, naturally compounds such as 4-(hydroxymethyl)-2(5H)-furanone, (Z)-5-(Bromo-methylene)furan-2(5H)-one and securinine were selected to investigate their capable of inhibiting the biofilm formation of Pseudomonas aeruginosa without killing bacterial or inhibiting their growth.Synthesis of 4-(hydroxymethyl)-2(5H)-furanone:Starting from tris(hydroxymethyl)-aminomethane hydrochloride,4-(hydroxymethyl)-2(5H)-furanone was synthesized via a procedure of protecting of two hydroxyl groups, formation of ketone by oxidation, then reacting with (ethoxycarbonylmethylene)triphenyl phosphonium ylide, deprotection and cyclization as the lactone.Synthesis of (Z)-5-(bromomethylene)furan-2(5H)-one:Starting with furanone and maleic anhydride, (E)-tert-Butyl-2-(5-oxofuran-2(5H)-ylidene) acetate was firstly obtained via Diels-Alder reaction and following Wittig reaction, then hydrolyzed to yield (E)-(5-oxofuran-2(5H)-ylidene) acetic acid. Finally the title compound was gotten by bromodecarboxylation.Biological activity tests:MHB maorodilution was used to test the natural compound's minimal inhibitory concentrations against Pseudomonas aeruginosa; then the colorimetric assay with crystal violet staining was used to test their ability to inhibit the formation of biofilm. The new synthetic route of the natural compound 4-(hydroxymethyl)-2(5H)-furanone was achieved in total yield reached 23%. And the route of synthesis (Z)-5-(Bromo-methylene)furan-2(5H)-one was improved. All synthetic compounds were characterized by 1H NMR,13C NMR and MS. The results of biological activity tests indicated that all of the natural compounds have some ability to inhibit the biofilm formation adhering to the 96 microwell plates, without affecting the strain growth.