Flavone-based analogues inspired by the natural product simocyclinone D8 as DNA gyrase inhibitors.
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.
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Biotech 1, 800 East Leigh Street, Richmond, VA 23298, USA.
Jenson
J
Verghese
Thuy
T
Nguyen
Lisa M
LM
Oppegard
Lauren M
LM
Seivert
Hiroshi
H
Hiasa
Keith C
KC
Ellis
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy; D047309:Flavones / Q000737:chemistry* / Q000494:pharmacology; D006027:Glycosides / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D003374:Coumarins; D047309:Flavones; D006027:Glycosides; D059005:Topoisomerase II Inhibitors; C416814:simocyclinone D8; D027081:DNA Gyrase
Antibiotics; DNA gyrase; Flavone; Natural product; Quercetin; Simocyclinone D8