Design, synthesis and antimicrobial evaluation of benzodioxane-benzamides FtsZ inhibitors: modification of the linker between the two scaffolds

The bacterial cell division cycle recently gained attention as a promising target to fight antibiotic resistance. Inhibitors of FtsZ, the highly conserved bacterial protein, main player of this process, are expected to represent a new potential family of antibiotics, characterized by broad-spectrum activity, low cytotoxicity, and the ability to bypass the actual mechanisms of antibiotic-resistance. The benzodioxane-benzamide class of FtsZ inhibitors was deeply developed over the last decade, obtaining potent compounds, including a 2,6-difluorobenzamide moiety, as PC190723. We recently developed some potent derivatives, as antibacterial towards different bacterial strains. However, these are characterized by a quite high lipophilicity, which could limit their water solubility and their absorption. Thus, we aimed at the introduction of a hydroxyl group, as an anchor point to prepare appropriate prodrugs or fluorescent probes. Moreover, we aimed at also including a methyl, in place of the hydroxyl, as a control. Considering the structural modifications performed on PC190723 by Stokes and colleagues, we designed, synthesized, isolated and characterized the single treo and erythro isomers of compounds 1-3. These compounds were evaluated for their antimicrobial activity against methicillin-sensitive, methicillin-resistant, and multidrug-resistant S. aureus, as well as towards different strains of E. coli, determining their MICs. Subsequently, by using fluorescence anisotropy, we validated FtsZ as the target of these derivatives and verified their effect over the dynamics of FtsZ protofilaments.