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Tick-borne flavivirus reproduction inhibitors based on isoxazole core linked with adamantane
Institution:1. Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1 bd. 3, Moscow 119991, Russia;2. FSBSI “Chumakov FSC R&D IBP RAS”, Moscow 108819, Russia;3. Sechenov First Moscow State Medical University, Moscow 119991, Russia;4. Institute of Physiologically Active Compounds, Severny Proezd 1, Chernogolovka, Moscow Region 142432, Russia;5. Volgograd State Technical University, Lenina Avenue 28, Volgograd 400005, Russia;1. Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation;2. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation;3. Institute of Biological Sciences, University of Rostock, D-18059 Rostock, Germany;1. Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia;2. IPhaC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region 142432, Russia;1. Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow 119991, Russian Federation;2. Institute of Physiologically Active Compounds Russian Academy of Sciences, Severnyi Proezd 1, Chernogolovka, Moscow Region 142432, Russian Federation;3. N.D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Prospect, 47, Moscow 119991, Russian Federation;4. Institute of Physical and Organic Chemistry, Southern Federal University, Stachki Av.194/2, Rostov on Don 344090, Russian Federation;1. Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation;2. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation;1. Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation;2. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russian Federation;1. Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1–3, Moscow 119991, Russia;2. IPhaC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia;3. Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208, USA
Abstract:Infections caused by flaviviruses pose a huge threat for public health all over the world. The search for therapeutically relevant compounds targeting tick-borne flaviviruses requires the exploration of novel chemotypes. In the present work a large series of novel polyfunctionalized isoxazole derivatives bearing substituents with various steric and electronic effects was obtained by our unique versatile synthetic procedure and their antiviral activity against tick-borne encephalitis, Omsk hemorrhagic fever, and Powassan viruses was studied in vitro. The majority of studied isoxazoles showed activity in low micromolar range. No appreciable cytotoxicity was observed for tested compounds. The lead compounds, 5-aminoisoxazole derivatives containing adamantyl moiety, exhibited strong antiviral activity and excellent therapeutic index.
Keywords:Aminoisoxazoles  Adamantane derivatives  Tick-borne encephalitis virus  Omsk hemorrhagic fever virus  Powassan virus  Flavivirus  β-OG"}  {"#name":"keyword"  "$":{"id":"k0040"}  "$$":[{"#name":"text"  "$$":[{"#name":"italic"  "_":"n"}  {"#name":"__text__"  "_":"-octyl-β-"}  {"#name":"small-caps"  "_":"d"}  {"#name":"__text__"  "_":"-glucoside  TBEV"}  {"#name":"keyword"  "$":{"id":"k0050"}  "$$":[{"#name":"text"  "_":"tick-borne encephalitis virus  OHFV"}  {"#name":"keyword"  "$":{"id":"k0060"}  "$$":[{"#name":"text"  "_":"Omsk hemorrhagic fever virus  POWV"}  {"#name":"keyword"  "$":{"id":"k0070"}  "$$":[{"#name":"text"  "_":"Powassan virus  PEK"}  {"#name":"keyword"  "$":{"id":"k0080"}  "$$":[{"#name":"text"  "_":"porcine embryo kidney  FBS"}  {"#name":"keyword"  "$":{"id":"k0090"}  "$$":[{"#name":"text"  "_":"fetal bovine serum
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