Lead optimization of 8-(methylamino)-2-oxo-1,2-dihydroquinolines as bacterial type II topoisomerase inhibitors

Bioorg Med Chem. 2020 Nov 15;28(22):115776. doi: 10.1016/j.bmc.2020.115776. Epub 2020 Sep 22.

Abstract

The global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets. TP0480066 (compound 32) has been identified by using structure-based optimization originated from lead compound 1, which was obtained as a result of our previous lead identification studies. The MIC90 values of TP0480066 against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and genotype penicillin-resistant Streptococcus pneumoniae (gPRSP) were 0.25, 0.015, and 0.06 μg/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class.

Keywords: Antibacterial agent; Antimicrobial resistance; Bacterial type II topoisomerase; DNA gyrase; Topoisomerase IV.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Cell Survival / drug effects
  • DNA Topoisomerases, Type II / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Bacterial / drug effects
  • Hep G2 Cells
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Methicillin-Resistant Staphylococcus aureus / enzymology
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Streptococcus pneumoniae / drug effects
  • Streptococcus pneumoniae / enzymology
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*
  • Transcriptional Regulator ERG / antagonists & inhibitors
  • Transcriptional Regulator ERG / metabolism
  • Vancomycin-Resistant Enterococci / drug effects
  • Vancomycin-Resistant Enterococci / enzymology

Substances

  • Anti-Bacterial Agents
  • ERG protein, human
  • Quinolines
  • Topoisomerase II Inhibitors
  • Transcriptional Regulator ERG
  • DNA Topoisomerases, Type II