There is a compelling need to discover new antibacterial therapies to combat the problem of antibiotic drug resistance. One strategy to address this challenge is to develop inhibitors of previously-unexploited cellular targets. The bacterial cell division protein, FtsZ, is a novel and attractive target for small-molecule drug discovery. 3-methoxybenzamide, a low molecular weight ligand that is known to target FtsZ and inhibit cell division in Bacillus subtilis, was used as a fragment-based starting point for a medicinal chemistry programme. Initial synthetic modifications focussed on the structure-activity relationships of the benzamide moiety and extensions to the methoxy group to generate potent inhibitors of bacterial growth. Subsequent replacement of the alkyloxy chain with bicyclic substitutions led to the identification of a lead compound designated PC190723. PC190723 inhibited Staphylococcus aureus, including drug-resistant strains, with an average MIC of 1 �g/mL. Biochemical, cytological and genetic data confirmed the intracellular target of PC190723 to be FtsZ. Significantly, PC190723 was the first inhibitor of FtsZ to demonstrate efficacy in vivo. In the murine septicaemia infection model a single subcutaneous or intravenous administration of 30 mg/kg PC190723 resulted in 100 % survival of mice inoculated with a potentially-lethal dose of S. aureus. Further chemical optimisation of PC190723 led to the discovery of substituted oxazole-benzamide analogues that demonstrated enhanced antibacterial activity (MIC = 0.12 �g/mL against S. aureus), improved pharmacokinetics and efficacy in the murine thigh infection model. In summary, optimised derivatives of 3-methoxybenzamide have the potential to provide first-in-class small-molecule therapies for the treatment of drug-resistant staphylococcal infections.

Discovery and optimisation of 3-methoxybenzamide analogs as potent antibacterial inhibitors of FtsZ

248th National Meeting (2014)

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