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

Thomas Flagstad, Mette T. Pedersen, Tim H. Jakobsen, Jakob Felding, Tim Tolker-Nielsen, Michael Givskov, Katrine Qvortrup*, Thomas E. Nielsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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.
Original languageEnglish
Article number128499
JournalBioorganic & Medicinal Chemistry Letters
Number of pages4
Publication statusPublished - 2022


  • Antibiotics
  • Bacterial Topoisomerase Inhibitors (NBTIs)
  • hERG potassium channel
  • Solid-Phase Synthesis
  • SAR study


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