Design, Synthesis Potential Novel Antibacterial Agents

Substituted thiazolo ring-fused 2-pyridones, called pilicides, possess novel antibacterial properties and inhibit pilus assembly in Uropathogenic Escherichia coli. Recently, a small number of oxygen analogues of active pilicides have shown maintained ability to disrupt pilus assembly. Here an improved methodology for the synthesis of oxazolo ring-fused 2pyridones is presented, allowing dihydro oxazolo ring-fused 2-pyridones to be synthesized in good yields and with excellent enantiomeric excess. Evaluation of three novel oxazolo 2pyridones in a biofilm assay proved these analogues to be potent pilicides and able to reduce biofilm formation in UPEC at low μM-concentrations. Additionally, applying Suzuki-Miyaura cross coupling, a set of C-2 substituted unsaturated thiazolo ring-fused 2-pyridones have been synthesized using ligand-free conditions in modest to excellent yields. These C-2 substituted analogues are to be hydrolyzed and evaluated as pilicides and will result in valuable structure-activity information for the pilicide project and hopefully the discovery of new potent pilicides. List of abbreviations AcOH acetic acid Arg arginine aq. aqueous ±BINAP (±)-(1,1'-binaphthalene-2,2'-diyl)bis(diphenylphosphine) b.p. boiling point calcd calculated DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DDQ 2,3-dichloro-5,6-dicyano-1,4.benzoquinone DMF N,N’-dimethylformamide DMSO dimethylsulfoxide E. coli Escherichia coli ee enantiomeric excess EtOAc ethyl acetate EtOH ethanol eq. equivalents HMTA hexamethylenetetramine HPLC high performance liquid chromatography IC50 50% inhibitory concentration IR infrared LC-MS liquid chromatography mass spectrometry LDA lithium diisopropylamide Lys lysine MeCN acetonitrile MeOH methanol mol. molecular m.p. melting point MP-TsOH macroporus polystyrenesulfonic acid MWI microwave irradiation NMR nuclear magnetic resonance OAc acetate obsd observed Pap pyelonephritis associated pili Ph phenyl PLS partial least square projection to latent structures PPTS p-pyridinium toluenesulfonate pTsOH p-toluenesulfonic acid rt room temperature sat. saturated TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography UPEC Uropathogenic Escherichia coli UTI urinary tract infection UV ultra violet