Benzodioxane–benzamides as new bacterial cell division inhibitors

• The FtsZ targeting antibacterial agent 3-nonyloxy-2,6-difluorobenzamide was modified.
• Modifications at the amide function or at the end of the alkyl chain were unproductive.
• 1,4-Benzodioxane-2-methyl in place of nonyl resulted in high anti-Staphylococcus aureus activity.
• 6- and 7-Chlorination of benzodioxane enhanced the activity, primarily residing with the S form.
• FtsZ targeting mechanism is proposed analogously to the known 2,6-difluorobenzamides.

A SAR study was performed on 3-substituted 2,6-difluorobenzamides, known inhibitors of the essential bacterial cell division protein FtsZ, through a series of modifications first of 2,6-difluoro-3-nonyloxybenzamide and then of its 3-pyridothiazolylmethoxy analogue PC190723. The study led to the identification of chiral 2,6-difluorobenzamides bearing 1,4-benzodioxane-2-methyl residue at the 3-position as potent antistaphylococcal compounds.

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