Synthesis of novel antimicrobial agents

This thesis presents the development offuranones and peptidomimetics as novel antimicrobial agents that inhibit quorum sensing in Gram-negative and Gram-positive bacteria respectively.A versatile synthetic route to generate novel furanone compounds was developed. Ketones bearing bulky C3-substituents such as iso-propyl or tert-butyl underwent C1-selective condensation with glyoxylic acid to afford 4-oxohept-2-enoic acids which were brominated, dehydratedin the presence of phosphorus pentoxide and dehydrobrominated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give 3-bromo-5-propylidenefuran-2-ones. Conversely, treatment with sulfuric acid gave 4-bromo-5-propylidenefuran-2-ones in one step.The related dihydropyrrolone compounds were also obtained through a lactone-lactamization reaction. Ketones bearing less bulky alkyl groups underwent C3-selective condensation with glyoxylic acid to give 3-acetylpent-2-enoic acids which were brominated and cyclised to give 4-alkyl-3-bromo-5-methylenefuranones. Further bromination and dehydrobromination gave the corresponding 5-bromomethylene analogues. 4-Aryl-5-bromomethylene furanones were similarly prepared. Cyclization of aryl-substituted alkenoic acids in the presence of phosphorus pentoxide gave poor yields, however, good yields were obtained upon treatment with thionyl chloride to give the related 4-aryl-5-chlorofuranones.The Suzuki-Miyaura coupling reaction was employed as an alternate strategy towards aryl-substituted furanones, with a series of 3-aryl, 4-aryl and 5-arylidene furanones being prepared in good yields. 4-Bromo-5-(bromomethylene) furan-2(5H)-one was found to preferentially react at the exocyclic vinylic bromo substituent in the presence of one equivalent of the boronic acid and generate the related diaryl analogue when an excess was used. This reactivity was exploited to develop unsymmetrically substituted diaryl furanones.5-Fluoromethylene furanones were prepared via condensation of fluoroketones with glyoxylic acid. Alternatively, 5-hydroxylfuranones were converted to 5-fluorofuranones using diethylaminosulfur trifluoride(DAST). Direct conversion of a bromide atom to a fluoride was unsuccessful.Novel peptidomimetics were prepared using the facilenucleophilic ring-opening reaction of N-acetylisatin.Different bis-N-acetylisatins were prepared via the Sandmeyer isonitrosoacetanilide isatin synthesis and their ring-opening reactions with amines, alcohols and amino acid methyl esters wereinvestigated