Study of isosteric substitution of the 1,4-benzodioxane oxygen atoms in benzamides FtsZ inhibitors

Multi-Drug Resistant bacterial infections are predicted to cause more than 10 million deaths each year by 2050. Among several factors, the development of this global health-threatening problem is primary caused by the lack of new antibiotics being developed. In this context, targeting the cell division system can be the strategy to bypass antibiotic resistance. In particular, FtsZ is an optimal target: is a crucial protein for the bacterial division system, it is highly conserved between bacteria and mycobacteria and shares only less than 20% of sequence with its human functional homologue (β-tubulin). In the last year we developed a class of potent FtsZ inhibitors with an 1,4-benzodioxane-benzamide structure characterized by high activity (MIC < 1 μg/mL vs both MSSA and MRSA). The oxygen atoms of the benzodioxane ring were successively replaced with bioisosteric atoms like Nitrogen, Sulfur and Carbon. Here we report the synthesis and the biological results of these derivatives. We demonstrated the importance of the Oxygen in 1- position in the 1,4-benzodioxane moiety in the maintaining of the antimicrobial activity. Conversely, the nature of the heteroatom at 4- position can differently modulate the antimicrobial activity of the derivative.