Optimisation of a Novel Class of DNA Gyrase Inhibitors to Improve Antibacterial Activity

As antibiotic resistance continues to rise, the need for new antibacterials is clear. In this context, Gram‐negative bacteria pose a specific challenge due to their multiple possible resistance mechanisms and unique outer membrane. Poor outer membrane permeability limits the activity of many antibiotics. This has led to a growing interest in identifying structural features capable of enhancing small molecule antibiotics’ ability to cross the Gram‐negative outer membrane. Examples of such approaches include the incorporation of ionisable amines to promote uptake and the attachment of siderophore moieties to exploit bacterial iron‐transport systems. Here, we apply these strategies to a newly discovered class of potent DNA gyrase inhibitors known as the isoquinoline sulphonamides, typified by the compound LEI‐800, with the aim of enhancing its Gram‐negative activity. In doing so, the distal aromatic ring of the LEI‐800 scaffold was functionalised with primary amine, guanidine and siderophore moieties. These studies reveal that the introduction of an ionisable amine group is tolerated at selected positions of the LEI‐800 scaffold, resulting in an increased antibacterial activity and mitigating membrane permeability barriers.