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Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity
Author(s) -
Artyushin Oleg. I.,
Moiseeva Aleksandra A.,
Zarubaev Vladimir V.,
Slita Aleksander V.,
Galochkina Anastasiya V.,
Muryleva Anna A.,
Borisevich Sophia S.,
Yarovaya Olga I.,
Salakhutdinov Nariman F.,
Brel Valery K.
Publication year - 2019
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201900340
Subject(s) - chemistry , cytisine , conjugate , rimantadine , click chemistry , stereochemistry , cytotoxicity , selectivity , linker , alkaloid , in vitro , combinatorial chemistry , organic chemistry , influenza a virus , virus , biochemistry , mathematical analysis , receptor , mathematics , nicotinic agonist , virology , computer science , biology , operating system , catalysis
A series of camphecene and quinolizidine alkaloid (−)‐cytisine conjugates has been obtained for the first time using ‘click’ chemistry methodology. The cytotoxicity and virus‐inhibiting activity of compounds were determined against MDCK cells and influenza virus A/Puerto Rico/8/34 (H1N1), correspondingly, in in vitro tests. Based on the results obtained, values of 50 % cytotoxic dose (CC 50 ), 50 % inhibition dose (IC 50 ) and selectivity index (SI) were determined for each compound. It has been shown that the antiviral activity is affected by the length and nature of linkers between cytisine and camphor units. Conjugate 13 ((1 R ,5 S )‐3‐(6‐{4‐[(2‐{( E )‐[(1 R ,4 R )‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐ylidene]amino}ethoxy)methyl]‐1 H ‐1,2,3‐triazol‐1‐yl}hexyl)‐1,2,3,4,5,6‐hexahydro‐8 H ‐1,5‐methanopyrido[1,2‐ a ][1,5]diazocin‐8‐one), which contains cytisine fragment separated from triazole ring by –C 6 H 12 – aliphatic linker, showed the highest activity at relatively low toxicity (CC 50 =168 μmol, IC 50 =8 μmol, SI=20). Its selectivity index appeared higher than that of reference compound, rimantadine. According to theoretical calculations, the antiviral activity of the lead compound 13 can be explained by its influence on the functioning of neuraminidase.