Solid-phase synthesis and biological evaluation of piperazine-based novel bacterial topoisomerase inhibitors

There is an emerging global need for new and more effective antibiotics against multi-resistant bacteria. This situation has led to massive industrial investigations on novel bacterial topoisomerase inhibitors (NBTIs) that target the vital bacterial enzymes DNA gyrase and topoisomerase IV. However, several of the NBTI compound classes have been associated with inhibition of the hERG potassium channel, an undesired cause of cardiac arrhythmia, which challenges medicinal chemistry efforts through lengthy synthetic routes. We herein present a solid-phase strategy that rapidly facilitates the chemical synthesis of a promising new class of NBTIs. A proof-of-concept library was synthesized with the ability to modulate both hERG affinity and antibacterial activity through scaffold substitutions.

Automated summary

There is a growing global demand for new and more effective antibiotics to combat multi-resistant bacteria. This has resulted in extensive research on novel bacterial topoisomerase inhibitors (NBTIs) that target key bacterial enzymes DNA gyrase and topoisomerase IV. However, some NBTI compounds have been found to inhibit the hERG potassium channel, causing undesired cardiac arrhythmia and complicating medicinal chemistry efforts. In this study, a solid-phase strategy is presented for the rapid synthesis of a promising new class of NBTIs.