Structure activity relationship of N-1 substituted 1,5-naphthyrid-2-one analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-9)

Bioorg Med Chem Lett. 2022 Nov 1:75:128808. doi: 10.1016/j.bmcl.2022.128808. Epub 2022 May 21.

Abstract

Novel bacterial topoisomerase inhibitors (NBTIs) are the newest members of gyrase inhibitor broad-spectrum antibacterial agents, represented by the most advanced member, gepotidacin, a 4-amino-piperidine linked NBTI, which is undergoing phase III clinical trials for treatment of urinary tract infections (UTI). We have extensively reported studies on oxabicyclooctane linked NBTIs, including AM-8722. The present study summarizes structure activity relationship (SAR) of AM-8722 leading to identification of 7-fluoro-1-cyanomethyl-1,5-naphthyridin-2-one based NBTI (16, AM-8888) with improved potency and spectrum (MIC values of 0.016-4 μg/mL), with Pseudomonas aeruginosa being the least sensitive strain (MIC 4 μg/mL).

Keywords: Antibacterial; Bacterial topoisomerase inhibitors; Broad-spectrum; Gyrase inhibitors; ParC inhibitors.

Publication types

  • Clinical Trial, Phase III

MeSH terms

  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • DNA Gyrase / metabolism
  • DNA Topoisomerase IV
  • Microbial Sensitivity Tests
  • Staphylococcus aureus / metabolism
  • Structure-Activity Relationship
  • Thioinosine / analogs & derivatives
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology
  • Topoisomerase Inhibitors* / chemistry
  • Topoisomerase Inhibitors* / pharmacology

Substances

  • 4-nitrobenzylthioinosine
  • Anti-Bacterial Agents
  • DNA Gyrase
  • DNA Topoisomerase IV
  • Thioinosine
  • Topoisomerase II Inhibitors
  • Topoisomerase Inhibitors
  • 4-aminopiperidine