ABSTRACT
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 multidrug resistant Gram-negative bacteria. By 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 cocrystal 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 physicochemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series, such as 18d, are discussed.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Escherichia coli Infections/drug therapy , Gram-Negative Bacteria/drug effects , Hydroxamic Acids/therapeutic use , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Escherichia coli/drug effects , Female , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Klebsiella pneumoniae/drug effects , Mice, Inbred ICR , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Pyrroles/therapeutic useABSTRACT
Oxazolidinone-quinolone hybrids that combine the pharmacophores of a quinolone and an oxazolidinone were synthesised and shown to be active against a variety of resistant and susceptible Gram-positive and fastidious Gram-negative organisms. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens. The nature of the spacer greatly influences the antibacterial activity. The dual mode of action could be demonstrated for compounds having a piperazinyl spacer. Antibacterial activity was higher at acidic pH.