TY - JOUR

T1 - Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity

AU - Artyushin, Oleg I.

AU - Moiseeva, Aleksandra A.

AU - Zarubaev, Vladimir V.

AU - Slita, Aleksander V.

AU - Galochkina, Anastasiya V.

AU - Muryleva, Anna A.

AU - Borisevich, Sophia S.

AU - Yarovaya, Olga I.

AU - Salakhutdinov, Nariman F.

AU - Brel, Valery K.

N1 - © 2019 Wiley-VHCA AG, Zurich, Switzerland.

PY - 2019/10/29

Y1 - 2019/10/29

N2 - 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 (CC50), 50 % inhibition dose (IC50) 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 ((1R,5S)-3-(6-{4-[(2-{(E)-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene]amino}ethoxy)methyl]-1H-1,2,3-triazol-1-yl}hexyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one), which contains cytisine fragment separated from triazole ring by –C6H12– aliphatic linker, showed the highest activity at relatively low toxicity (CC50=168 μmol, IC50=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.

AB - 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 (CC50), 50 % inhibition dose (IC50) 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 ((1R,5S)-3-(6-{4-[(2-{(E)-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene]amino}ethoxy)methyl]-1H-1,2,3-triazol-1-yl}hexyl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one), which contains cytisine fragment separated from triazole ring by –C6H12– aliphatic linker, showed the highest activity at relatively low toxicity (CC50=168 μmol, IC50=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.

KW - (+)-camphor

KW - (−)-cytisine

KW - 1,2,3-triazoles

KW - azides

KW - camphecene

KW - cytotoxicity

KW - heterocyclization

KW - terpenoids

KW - ‘click’ chemistry

KW - DESIGN

KW - HEMAGGLUTININ

KW - BORNEOL DERIVATIVES

KW - 'click' chemistry

KW - 1

KW - 2

KW - IN-VITRO

KW - (-)-cytisine

KW - 3-triazoles

KW - (-)-CYTISINE

KW - INFLUENZA-VIRUS

KW - INHIBITORS

KW - BINDING

KW - LEAD

UR - http://www.scopus.com/inward/record.url?scp=85074762963&partnerID=8YFLogxK

U2 - 10.1002/cbdv.201900340

DO - 10.1002/cbdv.201900340

M3 - Article

C2 - 31647170

AN - SCOPUS:85074762963

VL - 16

JO - Chemistry and Biodiversity

JF - Chemistry and Biodiversity

SN - 1612-1872

IS - 11

M1 - e1900340

ER -