Stereoselective synthesis of novel adamantane derivatives with high potency against rimantadine-resistant influenza A virus strains.
A series of (R)- and (S)-isomers of new adamantane-substituted heterocycles (1,3-oxazinan-2-one, piperidine-2,4-dione, piperidine-2-one and piperidine) with potent activity against rimantadine-resistant strains of influenza A virus were synthesized through the transformation of adamantyl-substituted N-Boc-homoallylamines 8 into piperidine-2,4-diones 11 through the cyclic bromourethanes 9 and key intermediate enol esters 10. Biological assays of the prepared compounds were performed on the rimantadine-resistant S31N mutated strains of influenza A - A/California/7/2009(H1N1)pdm09 and modern pandemic strain A/IIV-Orenburg/29-L/2016(H1N1)pdm09. The most potent compounds were both enantiomers of the enol ester 10 displaying IC50= 7.7 μM with the 2016 Orenburg strain.
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991, Moscow, Russian Federation. nkuznff@ineos.ac.ru.
Nikolai Yu
http://orcid.org/0000-0003-2702-5366
NY
Kuznetsov
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991, Moscow, Russian Federation. nkuznff@ineos.ac.ru.
Rabdan M
http://orcid.org/0000-0002-3830-4662
RM
Tikhov
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991, Moscow, Russian Federation. nkuznff@ineos.ac.ru.
Ivan A
IA
Godovikov
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991, Moscow, Russian Federation. nkuznff@ineos.ac.ru.
Michael G
MG
Medvedev
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991, Moscow, Russian Federation. nkuznff@ineos.ac.ru.
Konstantin A
KA
Lyssenko
N.F. Gamaleya Institute of Epidemiology and Microbiology, Russian Academy of Medicinal Sciences, Gamaleya 18, 123098, Moscow, Russian Federation.
Elena I
EI
Burtseva
N.F. Gamaleya Institute of Epidemiology and Microbiology, Russian Academy of Medicinal Sciences, Gamaleya 18, 123098, Moscow, Russian Federation.
Elena S
ES
Kirillova
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov 28, 119991, Moscow, Russian Federation. nkuznff@ineos.ac.ru and N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr. 47, 119991 Moscow, Russian Federation.
Yuri N
YN
Bubnov
D000218:Adamantane / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D024882:Drug Resistance, Viral / Q000187:drug effects*; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D012299:Rimantadine / Q000494:pharmacology*; D013237:Stereoisomerism
D000998:Antiviral Agents; D012299:Rimantadine; D000218:Adamantane