Discovery of 3-benzyl-1,3-benzoxazine-2,4-dione analogues as allosteric mitogen-activated kinase kinase (MEK) inhibitors and anti-enterovirus 71 (EV71) agents.
Enterovirus 71 (EV71) is a kind of RNA virus and one of the two causes of Hand, foot and mouth disease (HFMD). Inhibitors that target key components of Ras/Raf/MEK/ERK pathway in host cells could impair replication of EV71. A series of 3-benzyl-1,3-benzoxazine-2,4-diones were designed from a specific MEK inhibitor G8935, by replacing the double bond between C3 and C4 within the coumarin scaffold with amide bond. One compound (9f) showed submicromolar inhibitory activity among the 12 derivatives. Further optimization on 9f led to two active compounds (9k and 9m) with nanomolar bioactivities (55nM and 60nM). The results of enzymatic assays also demonstrated that this series of compounds were allosteric inhibitors of unphosphorylated MEK1. The binding mode of compound 9k was predicted by molecular dynamic simulation and the key interactions were same as published MEK1/2 allosteric inhibitors. In the cell-based assays, compounds 9k and 9m could effectively suppress the ERK1/2 pathway, expression of EV71 VP1, and EV71 induced cytopathic effect (CPE) in rhabdomyosarcoma (RD) cells.
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Jing
J
Sun
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China. Electronic address: yanniu@bjmu.edu.cn.
Yan
Y
Niu
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Chao
C
Wang
Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Hao
H
Zhang
Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Bingyu
B
Xie
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Fengrong
F
Xu
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Hongwei
H
Jin
Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Yihong
Y
Peng
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
Lei
L
Liang
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China. Electronic address: pingxu@bjmu.edu.cn.
Ping
P
Xu
D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D029821:Enterovirus A, Human / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D000998:Antiviral Agents; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases
3-Benzyl-1,3-benzoxazine-2,4-dione; Antiviral agent; EV71; MEK inhibitor