Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors

• Azetidine ene-amide based Staphylococcus aureus FabI inhibitors were designed and synthesized.
• Compounds were screened for FabI inhibition and in vitro antibacterial activity.
• Leads displayed IC50 ≥ 0.058 μM and MIC ≥ 0.06 μg/mL against MSSA, MRSA and MRSE.
• Leads showed good metabolic stability and in vivo pharmacokinetic profile.
• In vivo efficacy for the lead AEA16 was demonstrated in a systemic infection model.

A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.

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