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

doi:10.1016/j.bmcl.2021.128499

Abstract

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.

Highlights

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
Several of the NBTI compound classes have been associated with inhibition of the human ether-a-go-go related gene (hERG) potassium channel, an undesired cause of cardiac arrhythmia, which challenges medicinal chemistry efforts through lengthy synthetic routes
The mortality rate for humans infected with methicillinresistant S. aureus (MRSA) is 15–60%, and in Europe 25,000 people die every year from infections caused by multidrug-resistant bacteria.[1]

Summary

Introduction

There is an emerging global need for new and more effective antibiotics against multi-resistant bacteria. We present a solid-phase strategy that rapidly facilitates the chemical synthesis of a promising new class of NBTIs. A proof-ofconcept library was synthesized with the ability to modulate both hERG affinity and antibacterial activity through scaffold substitutions. The extensive use of β-lactam antibiotics has resulted in development of resistance among bacteria, such as the Gram-positive methicillinresistant S. aureus (MRSA).

Results

Conclusion