Discovery of Metal Ions Chelator Quercetin Derivatives with Potent Anti-HCV Activities.
Analogues or isosteres of α,γ-diketoacid (DKA) 1a show potent inhibition of hepatitis C virus (HCV) NS5B polymerase through chelation of the two magnesium ions at the active site. The anti-HCV activity of the flavonoid quercetin (2) could partly be attributed to it being a structural mimic of DKAs. In order to delineate the structural features required for the inhibitory effect and improve the anti-HCV potency, two novel types of quercetin analogues, 7-O-arylmethylquercetins and quercetin-3-O-benzoic acid esters, were designed, synthesized and evaluated for their anti-HCV properties in cell-based assays. Among the 38 newly synthesized compounds, 7-O-substituted derivative 3i and 3-O-substituted derivative 4f were found to be the most active in the corresponding series (EC50 = 3.8 μM and 9.0 μΜ, respectively). Docking studies suggested that the quercetin analogues are capable of establishing key coordination with the two magnesium ions as well as interactions with residues at the active site of HCV NS5B.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. 12211030012@fudan.edu.cn.
Dongwei
D
Zhong
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. 09111030009@fudan.edu.cn.
Mingming
M
Liu
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. 14111030010@fudan.edu.cn.
Yang
Y
Cao
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. 09301030045@fudan.edu.cn.
Yelin
Y
Zhu
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. 08301030057@fudan.edu.cn.
Shihui
S
Bian
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. 09301030009@fudan.edu.cn.
Jiayi
J
Zhou
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. 11307120169@fudan.edu.cn.
Fengjie
F
Wu
Institute of Pharmacy, HamHung Pharmaceutical University, HamHung 999093, Democratic People's Republic of Korea. yegroup@126.com.
Kum-Chol
KC
Ryu
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. zhoulu@fudan.edu.cn.
Lu
L
Zhou
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhang-Heng Rd, Shanghai 201203, China. dyye@shmu.edu.cn.
Deyong
D
Ye
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D008274:Magnesium / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011794:Quercetin / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D002614:Chelating Agents; D008274:Magnesium; D011794:Quercetin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase