Design, synthesis and evaluation of triazole functionalized ring-fused 2-pyridones as antibacterial agents

Antibacterial resistance is today a worldwide problem and the demand for new classes of antibacterial agents with new mode of action is enormous. In the strive for new antibacterial agents that inhibit pilus assembly, an important virulence factor, routes to introduce triazoles in position 8 and 2 of ring-fused bicyclic 2-pyridones have been developed. This was made via Sonogashira couplings followed by Huisgen 1,3-dipolar cycloadditions. The method development made it possible to introduce a diverse series of substituted triazoles and their antibacterial properties were tested in a whole cell pili-dependent biofilm assay. Most of the twenty four candidates tested showed low to no activity but interestingly three compounds, one 8-substituted and two 2-substituted, showed promising activities with EC50's between 9 and 50 μM. [Display omitted] ► Antibacterial agents. ► Chaperone/usher pathway inhibition. ► Huisgen 1,3-dipolar cycloaddition. ► Ring-fused bicyclic 2-pyridone.