Stereoisomers of oseltamivir - synthesis, in silico prediction and biological evaluation.
Oseltamivir is an important antiviral drug, which possess three chirality centers in its structure. From eight possible stereoisomers, only two have been synthesized and evaluated so far. We describe herein the stereoselective synthesis, computational activity prediction and biological testing of another three diastereoisomers of oseltamivir. These isomers have been synthesized using stereoselective organocatalytic Michael addition, cyclization and reduction. Their binding to viral neuraminidase N1 of influenza A virus was evaluated by quantum-chemical calculations and their anti-influenza activities were tested by an in vitro virus-inhibition assay. All three isomers displayed antiviral activity lower than that of oseltamivir, however, one of the stereoisomers, (3S,4R,5S)-isomer, of oseltamivir showed in vitro potency towards the Tamiflu-sensitive influenza viral strain A/Perth/265/2009(H5N1) comparable to Tamiflu.
SYNKOLA, Ltd, Mlynská dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia. fisera@synkola.sk.
Viktória
V
Hajzer
SYNKOLA, Ltd, Mlynská dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia. fisera@synkola.sk.
Roman
R
Fišera
SYNKOLA, Ltd, Mlynská dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia. fisera@synkola.sk.
Attila
A
Latika
SYNKOLA, Ltd, Mlynská dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia. fisera@synkola.sk.
Július
J
Durmis
Comenius University in Bratislava, Faculty of Pharmacy, Department of Pharmaceutical Analysis and Nuclear Pharmacy, Odbojárov 10, SK-83232 Bratislava, Slovakia and Comenius University in Bratislava, Faculty of Mathematics, Physics and Informatics, Department of Nuclear Physics and Biophysics, Mlynská dolina, SK-84248 Bratislava, Slovakia.
Jakub
J
Kollár
Comenius University in Bratislava, Faculty of Pharmacy, Department of Physical Chemistry of Drugs, Odbojárov 10, SK-83232 Bratislava, Slovakia and ICARST n.o., Jamnického 19, SK-84104 Bratislava, Slovakia.
Vladimír
V
Frecer
University of SS. Cyril and Methodius, Faculty of Natural Sciences, Department of Biotechnologies, Námestie J. Herdu 2, SK-91701 Trnava, Slovakia.
Zuzana
Z
Tučeková
ICARST n.o., Jamnického 19, SK-84104 Bratislava, Slovakia and University of SS. Cyril and Methodius, Faculty of Natural Sciences, Department of Biotechnologies, Námestie J. Herdu 2, SK-91701 Trnava, Slovakia.
Stanislav
S
Miertuš
Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Department of Orthomyxovirus Research, Dúbravská cesta 9, SK-84505 Bratislava, Slovakia.
František
F
Kostolanský
Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Department of Orthomyxovirus Research, Dúbravská cesta 9, SK-84505 Bratislava, Slovakia.
Eva
E
Varečková
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynská dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia. radovan.sebesta@fns.uniba.sk.
Radovan
http://orcid.org/0000-0002-7975-3608
R
Šebesta
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D009980:Influenza A virus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D053139:Oseltamivir / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D013237:Stereoisomerism
D000998:Antiviral Agents; D053139:Oseltamivir