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.
Bibliographical noteFunding 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.
- DNA gyrase
- Natural product
- Simocyclinone D8