Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with In Vivo Efficacy against MRSA

J Med Chem. 2021 Oct 28;64(20):15214-15249. doi: 10.1021/acs.jmedchem.1c01250. Epub 2021 Oct 6.

Abstract

Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound 79. This molecule demonstrates potent antibacterial activity against diverse Gram-positive pathogens, inhibition of both DNA gyrase and topoisomerase IV, a low frequency of resistance, a favorable in vitro cardiovascular safety profile, and in vivo efficacy in a murine model of methicillin-resistant Staphylococcus aureus infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • DNA Gyrase / metabolism
  • DNA Topoisomerase IV / antagonists & inhibitors
  • DNA Topoisomerase IV / metabolism
  • Dioxanes / chemical synthesis
  • Dioxanes / chemistry
  • Dioxanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Dioxanes
  • Enzyme Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • DNA Topoisomerase IV
  • DNA Gyrase