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

Abstract

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.

Application of triazoles in the structural modification of natural products

“…Artyushin et al. 151 synthesised six new terpene (+)-camphor and alkaloid (-)-cystine conjugates. Among them, imino-derivatives were, in general, of higher activity.…”

Modification of Sesquiterpene Lactones—Dehydrocostus Lactone and Alantolactone—by Click Chemistry Method. Cytotoxic Activity of the Obtained Conjugates

“…As the main methodology for the structural modification of the selected lactones, we chose an approach based on the use of the cycloaddition reaction of organic azides to acetylene derivatives. This technique of click chemistry has been widely used in recent years [13][14][15] due to the ease of implementation and almost quantitative yield of the target compounds. In addition, it should be noted that the triazole spacer formed as a result of click reactions is more than just a passive linker.…”

Monoterpenes and Their Derivatives—Recent Development in Biological and Medical Applications

“…al. [ 99 ] and tested for their cytotoxicity and virus-inhibiting activity. It was proven that the antiviral activity is affected by the length and nature of linkers between cytisine and (+)-camphor moieties.…”