title: Substituted 3-benzylcoumarins as allosteric MEK1 inhibitors: design, synthesis and biological evaluation as antiviral agents.
abstract: In order to find novel antiviral agents, a series of allosteric MEK1 inhibitors were designed and synthesized. Based on docking results, multiple optimizations were made on the coumarin scaffold. Some of the derivatives showed excellent MEK1 binding affinity in the appropriate enzymatic assays and displayed obvious inhibitory effects on the ERK pathway in a cellular assay. These compounds also significantly inhibited virus (EV71) replication in HEK293 and RD cells. Several compounds showed potential as agents for the treatment of viral infective diseases, with the most potent compound 18 showing an IC₅₀ value of 54.57 nM in the MEK1 binding assay.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Science, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Fengrong
authors.initials: F
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Niu
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Yihong
authors.initials: Y
authors.lastname: Peng
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Lei
authors.initials: L
authors.lastname: Liang
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003374:Coumarins; D029821:Enterovirus A, Human / Q000502:physiology*; D004769:Enterovirus Infections / Q000188:drug therapy* / Q000201:enzymology; D057809:HEK293 Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D003374:Coumarins; D047428:Protein Kinase Inhibitors; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human