Discovery of Novel Inhibitors of LpxC Displaying Potent In Vitro Activity against Gram-Negative Bacteria

UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multi-drug resistant Gram-negative bacteria. Using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using co-crystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on i) isoindolin-1-ones, ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones and iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physico-chemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong ...