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FtsZ is a crucial prokaryotic protein involved in bacterial cell replication. It recently arose as a promising target in the search for antimicrobial agents able to fight antimicrobial resistance. In this work, going on with our structure‐activity relationship (SAR) study, we developed variously 7‐substituted 1,4‐benzodioxane compounds, linked to the 2,6‐difluorobenzamide by a methylenoxy bridge. Compounds exhibit promising antibacterial activities not only against multidrug‐resistant Staphylococcus aureus, but also on mutated Escherichia coli strains, thus enlarging their spectrum of action toward Gram‐negative bacteria as well. Computational studies elucidated, through a validated FtsZ binding protocol, the structural features of new promising derivatives as FtsZ inhibitors.

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Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach.