Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase

Bioorg Med Chem Lett. 2018 Sep 15;28(17):2998-3003. doi: 10.1016/j.bmcl.2018.05.049. Epub 2018 May 26.

Abstract

According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.

Keywords: Anti-infectives; DNA gyrase; ESKAPE pathogens; Pyrimido[4,5-b]indol-8-amine; Topoisomerases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Cell Survival / drug effects
  • DNA Gyrase / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Gram-Positive Bacteria / drug effects*
  • Gram-Positive Bacteria / metabolism
  • Hep G2 Cells
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Topoisomerase II Inhibitors
  • DNA Gyrase