Synthesis of C(7) modified chrysin derivatives designing to inhibit beta-ketoacyl-acyl carrier protein synthase III (FabH) as antibiotics.
As a naturally wide distributed flavone, chrysin exhibits numerous biological activities including anticancer, anti-inflammatory, and antimicrobials activities. Beta-ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of antibacterial agents. We first used a structure-based approach to develop 18 novel chrysin analogues that target FabH for the development of new antibiotics. Structure-based design methods were used for the expansion of the chrysin derivatives including molecular docking and SAR research. Based on the results, 5-hydroxy-2-phenyl-7-(2-(piperazin-1-yl)ethoxy)-4H-chromen-4-one (3g) showed the most potent antibacterial activity with MIC of 1.56-6.25 microg/mL against the test bacterial stains, and docking simulation was performed to position compound 3g into the Escherichia coli FabH active site to determine the probable binding conformation. The biological assays indicated that compound 3g is a potent inhibitor of E.coli FabH as antibiotics.
Li
Huan-Qiu
HQ
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Shi
Lei
L
Li
Qing-Shan
QS
Liu
Peng-Gang
PG
Luo
Yin
Y
Zhao
Jing
J
Zhu
Hai-Liang
HL
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; C043561:chrysin; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase