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 |
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| Institution: | 1. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China;2. Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China;3. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China;1. Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 Stachka Ave., 344090 Rostov-on-Don, Russian Federation;2. Institute of Problems of Chemical Physics, Russian Academy of Sciences, 1 Akad. Semenova Ave., 142432 Chernogolovka, Moscow Region, Russian Federation;1. Department of Physics, Tsinghua University, Beijing 100084, PR China;2. Center for High Energy Physics, Tsinghua University, Beijing 100084, PR China;3. Collaborative Innovation Center of Quantum Matter, Beijing 100084, PR China;4. Key Laboratory of Particle and Radiation Imaging (Ministry of Education) and Department of Engineering Physics, Tsinghua University, Beijing 100084, PR China;5. College of Physical Science and Technology, Sichuan University, Chengdu 610064, PR China;1. Catholic Kwandong University International St. Mary’s Hospital, Seo-go, Incheon Metropolitan City 22711, Republic of Korea;2. Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do 25601, Republic of Korea;3. Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea;4. Institute for Integrative Medicine, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do 25601, Republic of Korea;5. Department of Integrated OMICS for Biomedical Sciences (WCU Program), Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea;6. Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea;7. Department of Cardiovascular Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Gangnam-gu, Seoul 06273, Republic of Korea;1. Korea Research Institute of Chemical Technology, Daejon, 34144, South Korea;2. Major of Green Chemistry and Environmental Biotechnology, University of Science & Technology, Daejon, 34113, South Korea;3. Department of Life Science, Ewha Womans University, Seoul, 03760, South Korea;1. Metabolic Biophysics and Applied Pharmacology Laboratory, Department of Biophysics, Faculty of Medicine of Sousse, 4002 Sousse, Tunisia;2. Department of Clinical Pharmacology, Faculty of Medicine of Sousse, 4002 Sousse, Tunisia |
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| Abstract: | 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 (55 nM and 60 nM). 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. |
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| Keywords: | 3-Benzyl-1 3-benzoxazine-2 4-dione MEK inhibitor EV71 Antiviral agent |
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