Novel inhibitors of the bacterial cell division protein FtsZ: synthesis and antibacterial activity

Nowadays, bacterial infections are one of the most prevalent health hazard and resistance towards the common antibiotics is in continuous growing. Consequently, the developing of novel antimicrobial agents, having an innovative mechanism of action is now under investigation . In this context in the latest years FtsZ (Filamentous temperature sensitive Z) emerged and was proved to be essential in bacterial cell division, because it is able to form a circumferential dynamic Z-ring. In the absence of this Z-ring, the bacterial cell division is blocked . Moreover, FtsZ is conserved in virtually all eubacteria, archea and chloroplasts, turning out to be actually a potential drug target. In the latest years, a growing number of small molecules were developed and revealed to interact with FtsZ and with bacterial cell division; their structures derived from preliminary SAR studies of 3-MBA (3- methoxy benzamide), proven to be an FtsZ inhibitor . In a recent paper , we have demonstrated that the substitution of the tiazolopyridine system of PC190723 with a benzodioxan moiety accomplished promising antibacterial agents, including compound I, having a MIC of 0,5 µg/mL. The present work focused on the synthesis of novel FtsZ inhibitors (Figure 2), where the benzodioxane scaffold is modified: - introducing different substituents at the aromatic fused ring (Fig 2A); - at the dioxane portion, in order to understand the importance of the Oxygen (Fig. 2B); - changing the linking point between the methylenic chain and the benzodioxane moiety (Fig. 2C); Inhibition of bacterial growth was tested on both Gram positive and Gram negative bacteria, in particular the minimal inhibiting concentration (MIC) and the minimal bactericidal concentration (MBC) were determined.