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

Jenson Verghese, Thuy Nguyen, Lisa M. Oppegard, Lauren M. Seivert, Hiroshi Hiasa, Keith C. Ellis

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5874-5877
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2013

Bibliographical note

Funding Information:
Funding for this work was provided by the VCU/MCV A.D. Williams Trust Fund, the Thomas F. and Kate Miller Jeffress Memorial Trust Fund, and the VCU School of Pharmacy (to K.C.E.). The author thanks Professor Richard A. Glennon and Professor John C. Hackett for helpful discussions and Professor Glen Kellogg for assistance in preparing this manuscript.

Keywords

  • Antibiotics
  • DNA gyrase
  • Flavone
  • Natural product
  • Quercetin
  • Simocyclinone D8

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