Flavone-based analogues inspired by the natural product simocyclinone D8 as DNA gyrase inhibitors

Bioorg Med Chem Lett. 2013 Nov 1;23(21):5874-7. doi: 10.1016/j.bmcl.2013.08.094. Epub 2013 Sep 5.

Abstract

The increasing occurrence of drug-resistant bacterial infections in the clinic has created a need for new antibacterial agents. Natural products have historically been a rich source of both antibiotics and lead compounds for new antibacterial agents. The natural product simocyclinone D8 (SD8) has been reported to inhibit DNA gyrase, a validated antibacterial drug target, by a unique catalytic inhibition mechanism of action. In this work, we have prepared simplified flavone-based analogues inspired by the complex natural product and evaluated their inhibitory activity and mechanism of action. While two of these compounds do inhibit DNA gyrase, they do so by a different mechanism of action than SD8, namely DNA intercalation.

Keywords: Antibiotics; DNA gyrase; Flavone; Natural product; Quercetin; Simocyclinone D8.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Coumarins / chemistry
  • Coumarins / pharmacology
  • DNA Gyrase / chemistry
  • DNA Gyrase / metabolism*
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology*
  • Escherichia coli Infections / drug therapy
  • Flavones / chemistry*
  • Flavones / pharmacology
  • Glycosides / chemistry
  • Glycosides / pharmacology
  • Humans
  • Models, Molecular
  • Topoisomerase II Inhibitors / chemistry*
  • Topoisomerase II Inhibitors / pharmacology

Substances

  • Anti-Bacterial Agents
  • Coumarins
  • Flavones
  • Glycosides
  • Topoisomerase II Inhibitors
  • simocyclinone D8
  • DNA Gyrase