Synthesis and study of complexes of the novel Russian antiviral drug Camphecene with Plant’s Flavonoids


Chimica Techno Acta ARTICLE
published by Ural Federal University 2021, vol. 8(2), № 20218202 

eISSN 2411-1414; chimicatechnoacta.ru DOI: 10.15826/chimtech.2021.8.2.02 

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Synthesis and study of complexes of the novel Russian 
antiviral drug Camphecene with Plant’s Flavonoids 

S.S. Khizrieva
*

, E.V. Vetrova, S.N. Borisenko, 
E.V. Maksimenko, N.I. Borisenko 

Research Institute of Physical and Organic Chemistry, Southern Federal University, 

Stachki Ave., 194/2, Rostov-on-Don, 344090, Russia 
* Corresponding author: hizrieva@sfedu.ru

This article belongs to the regular issue. 

© 2021, The Authors. This article is published in open access form under the terms and conditions of the Creative 

Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 

Abstract 

Traditionally, glycyrrhizic acid has been used to form polydentate 

complexes. For the first time in the presented paper, the complexa-

tion of the Plant’s Flavonoids (Quercetin (Qu) and its glycoside - Ru-

tin (Rut)) with the novel Russian antiviral drug Camphecene 

(Camph) was investigated. The complexes obtained at different mo-

lar ratios were studied using UV/Vis spectroscopy. Formation of the 

host: guest complexes were registered: Qu and Rut molecular com-

plexes (Camph+2Qu; Camph+2Rut) with a stability constant 
K = 3.3·10

8
 M

-2
. Comparison of the binding constants of the obtained 

complexes shows that the efficiency of Camphecene complexation 

with the participation of flavonoids is more efficient than with the 

participation of triterpenoids. Besides, it was found that the com-

plexes of Camphecene with the quercetin and rutin are soluble in wa-

ter, in contrast to the complexes with triterpenoids, which makes it 

possible to increase the bioavailability of both Camphecene and fla-

vonoids. The obtained results demonstrate the high potential of fla-

vonoids Qu and Rut to the development of novel pharmaceutical 

forms using the example of Camphecene in the form of molecular 

complexes, as the novel forms of delivery. 

Keywords 
Camphecene 

Quercetin 

Rutin 

antiviral activity 

supramolecular complexes

Received: 01.03.2021 

Revised: 22.04.2021 

Accepted: 27.04.2021 

Available online: 28.04.2021 

1. Introduction

It is known that a decrease in therapeutic doses of medici-

nal substances and prolongation of action is possible when 

they are clathrate with plant glycosides. This property was 

used in the approach of Academician G. A. Tolstikov to 

reduce therapeutic doses of drugs and prolong the action 

[1-3]. In this regard, the presented work considers the 

possibilities of synthesizing new supramolecular complex-

es of Qu and Rut using the new antiviral drug Camphecene 

for the development of low-dose pharmaceutical substanc-

es on their basis. The authors consider that these pharma-

ceutical substances can be used to suppress the multiplica-

tion of viruses in the early stages. It is known that Cam-

phecene 1 (Fig. 1), has a broad spectrum of antiviral activi-

ty. It is proved to be active against the influenza virus 

strains type A and type B [4]. 

The purpose of this work is to synthesize and study su-

pramolecular complexes based on the scaffold monoterpe-

noid Camphecene and plant flavonoids to develop, in the 

future, previously unknown low-dose pharmaceutical sub-

stances with antiviral activity. Influenza is known to be 

the most common and dangerous respiratory viral infec-

tion. It causes annual epidemics and pandemics, leading to 

significant increases in morbidity and mortality in all re-

gions of the world. In connection with the growing num-

ber of cases of viral infections and especially resistant 

viral strains, it is necessary to improve the available ther-

apeutic methods, complementing them with the discovery 

of new antiviral agents. On the other fist, it is widely rec-

ognized that the medical heritage of plants is a valuable 

resource for the treatment of infectious disorders. This 

indicates a growing interest in antiviral products based on 

secondary plant metabolites [5, 6]. 

One of the unique plant components used in traditional 

medicine is bioflavonoids quercetin and rutin (Fig. 1). 

Plant flavonoids 2 and 3 are attracting more and more 

attention of chemists and pharmacologists due to the wide 

spectrum of their biological activity. Flavonoids have long 

attracted scientific interest as antiviral agents - in a few  

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Chimica Techno Acta 2021, vol. 8(2), № 20218202 ARTICLE 

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C12H21NO 

a) Camph(1)

C15H10O7 

b) Qu (2)

C27H30O16 

c) Rut (3)

Fig. 1 Structures of a) Camphecene (1), C12H21NO; b) Quercetin 
(2), C15H10O7; c) Rutin (3), C27H30O16 

studies, they have shown an inhibitory effect on proteases 

of various types of coronaviruses [7]. 

Quercetin (Qu) is one of the most important plant mol-

ecules, showing pharmacological activity such as antiviral 

and anti-inflammatory effects. It has also been demon-

strated to have a wide range of anti-cancer properties, and 

several reports indicate its efficacy as a cancer‐preventing 

agent [8]. Quercetin 2 (Fig. 1), chemical name 

2‐(3,4‐dihydroxy phenyl)‐3,5,7‐trihydroxychromen‐4‐one 

or 3,3′,4′,5,7‐pentahydroxyflavone, is classified as a flavo-

nol, one of the six subcategories of flavonoid compounds, 

and is the major polyphenolic flavonoid found in various 

vegetables and fruits, such as berries, dill, apples, and 

onions [9]. 

According to research results [10], Qu and other sever-

al substances exhibited better potential inhibition than 

Hydroxy-Chloroquine against COVID-19 main protease 

active site and ACE2. Based on the results obtained by 

computational methods on molecular docking, it is antici-

pated that Qu could affect SARS‐CoV‐2 by interacting with 

3CLpro, PLpro, and/or S protein [8, 11]. 

Thus, Qu is currently promising as a biologically active 

substance of natural origin, capable of exerting a nonspe-

cific complex effect on inflammatory and destructive pro-

cesses in the body, and Qu be considered promising in the 

treatment of allergic pathology, inflammatory and non-

inflammatory diseases (Alzheimer's). One of the special 

effects of quercetin is its protective effect on the vascular 

endothelium, which is important in COVID-19 since endo-

thelial dysfunction inevitably develops in this pathology 

[7]. 

2. Experimental

The following reagents were used in this study: Quercetin 

(purity 98.2%) from DIA-M (Russia) and Rutin (99.4% 

purity) from Sichuan Xieli Pharmaceutical Co., Ltd. (Chi-

na), and locally produced chemicals of the chemically pure 

grade. 

Camphecene – 2-(E)-((1R,4R)-1,7,7-trimethylbicyclo 

[2.2.1] heptan-2-ylidene-aminoethanol was synthesized at 

the Novosibirsk Institute of Organic Chemistry (NIOCH SB 

RAS) (Fig. 2): а mixture of (1R)-(+)-camphor (1.0 equiv.), 

the appropriate amine (2.5 equiv.), and anhydrous ZnCl2 

(0.1% mol on camphor) was reflux for 5–12 h. Diethyl 

ether was added to the reaction mixture, after completion 

of the reaction. The organic layer was washed with brine, 

dried (Na2SO4), and evaporated. The crude product was 

subjected to vacuum distillation [12]. 

The complex of Camph and Qu and Rut was formed by 

mixing 96% alcohol solution. The process of complex for-

mation between Qu and Rut and Camph was analyzed us-

ing electron-optical UV-Vis spectroscopy (a SPEKS 

SSP 705-PC spectrometer (CJSC Spectroscopic Systems, 

Russia). 

The complexes of Qu/Rut and Camph were formed by 

mixing an alcohol solution of Qu/Rut and Camph at the 

molar ratio of 1:1 and 2:1 (using ethanol as alcohol). The 

stoichiometry of the complex was evaluated by the de-

pendence of optical density of a Camph solution (meas-

ured at 201 nm) on Qu/Rut concentration. A contribution 

of Qu/Rut to absorbance was corrected by subtracting the 

absorbance spectrum of Qu/Rut from the total absorbance 

spectrum. Measurements were carried out in a quartz cell. 

3. Results and Discussion

Following the objectives of the work, sets of complexes of 

bioflavonoids Qu and Rut with an antiviral drug Cam-

phecene at different molar ratios "guest: host" were syn-

thesized. 

For a detailed study of the processes of complexation 

of Qu and Camph, the absorption spectra of Camph in a 

mixture with different concentrations of Qu were investi-

gated. In the first step, complexes of Qu with Camph were 

obtained at molar ratios: 1:1 and 2:1 and studied by UV/Vis 

spectroscopy. The binding of Camph and Qu after mixing 

of their solutions was accompanied by changes in the  

(+)-Camphor 2-Aminoethanol Scaffold monoterpenoid–Camphecene 

Fig. 2 Scheme of obtaining the scaffold monoterpenoid – 
Camphecene [12] 



Chimica Techno Acta 2021, vol. 8(2), № 20218202 ARTICLE 

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absorbance spectrum of Camph indicating the complex 

formation of these compounds (Fig. 3). The UV-VIS spec-

trophotometric analysis of the mixture of Camph and Qu 

has shown that the increase in Qu concentration is accom-

panied by the change in the shape of the Camph spectrum 

due to complex formation (its maximum of absorbance 

becomes lower). As demonstrated in Fig. 3, with an in-

crease in the concentration of Qu from 0 to 0.125 mM, a 

bathochromic shift of the absorption maximum of Camph 

(201  215 nm) is recorded in the UV/Vis spectra, and a 

decrease in optical density is observed. 

Fig. 3 shows the Camph spectra, which are the differ-

ence absorption spectra of the mixture of Camph and Qu 

and the spectrum of Qu at a given concentration. 

An increase in the concentration of Qu (from 0.25 mM 

and higher) leads to the disappearance of the maximum 

absorption of Camph, which indicates the complete bind-

ing of Camph molecules in the presence of Qu (Fig. 4). 

Fig. 4 demonstrates from the dependence of the optical 

density on the concentration of Qu at the value of the max-

imum absorption band of Camph λmax1= 201 nm: the opti-

cal density sharply decreases its values depending on the 

concentration of Qu in the mixture. 

The study of Rut (Fig. 5) demonstrated similar changes 

in the UV/Vis spectra of the obtained complexes. When the  

Fig. 3 Absorption spectrum of Camphecene (CCamph = 0.5 mM) at 
different concentrations of Qu* (in 96% alcohol solution). The 
upper spectrum line corresponds to the absorbance spectrum of 
Camph in the absence of Qu (C= 0.0 mM). 

Fig. 4 Dependence of optical density on the concentration of 
quercetin 

Fig. 5 Absorption spectrum of Camphecene (CCamph = 0.5 mM)  
at different concentrations of Rut (*Rut 0.01 mM – standard solu-

tion of rutin) 

Rut concentration changes in the range from 0.05 to 

0.275 mM, a bathochromic shift of the absorption maxi-

mum of Camph is recorded (201  213 nm). 

In this study, the stability constants for the complex of 

Camph and Qu/Rut were analyzed by changes of optical 

density of Camph solutions (with its constant concentra-

tion, CCamph = 0.5 mM) with variable concentrations of 

Qu/Rut. To calculate the stability constant of the complex-

es, we used the Benesi-Hildebrand plot (1) [13]. Eq. (1) is 

applicable for certain experimental conditions (Camph 

concentration < Qu/Rut concentration). 

The stability constant of the nQu-Camph complex was 

estimated from the change in the optical density of Camph 

(λmax1 = 201 nm) at its fixed concentration in solutions in 

which the Qu (or Rut) concentration was varied. Eq. (1) 

allows, within the framework of one experiment, not only 

to estimate the stability constant of the complex (K) but 

also to determine the stoichiometry ratio "host: guest" (n) 

in the complex: 

∆𝐷 𝐷⁄ − 1 = 1 [Qu]𝑛⁄ ∙ 1 𝐾⁄  (1) 

where ∆𝐷 = ∆𝜀 ∙ [Camph] – change in the optical density of 

the solution, К – the constant of stability of the complex, 

determined for the reaction Camph + nQu ⇄ Camph-nQu: 

𝐾 =
[Camph − nQu]

[Camph] ∙ [nQu]
 (2) 

The absorption spectrum of Camph was recorded at a 

wavelength of 201 nm, while the Camph concentration  

Fig. 6 Dependence of the slope of the straight line D/D on 
1/[Qu]

2
 



Chimica Techno Acta 2021, vol. 8(2), № 20218202 ARTICLE 

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was constant and amounted to 0.5 mM. The obtained de-

pendence of the absorption intensity of Camphecene 

(λ = 201 nm) on the concentration of Qu is shown in 

Fig. 6. 

From the slope of the straight line ∆𝐷 𝐷⁄  depending on 

1/[Qu]
2
 (Fig. 6), the stability constant of the complex was 

calculated using Eq. (1). The stability constant for the 

Camph+Qu complex is 1/K = 3 10
-9

 M
2
 or K = 3.3 10

8
 M

-2
. 

Recognizing the value of the binding constant, the 

change in the Gibbs energy was calculated. Obtained from 

the binding constant, the change in Gibbs’s energy  

∆G = -47.8 kJ. Based on the obtained negative value, it can 

be concluded that the reaction proceeds spontaneously 

during the formation of Qu and Camph complexes. Simi-

larly, according to Eq. (1), the stability constant of the 

complex Camph+Rut was calculated, 1/K = 3 10
-9

 M
2
 or  

K = 3.3 10
8
 M

-2
. Using the value of the binding constant, 

the change in Gibbs’s energy was calculated. The change in 

the Gibbs energy ∆G =-47.8 kJ, which allows us to con-

clude that the reaction proceeds spontaneously during the 

formation of a complex of Rut with Camph. 

Thus, the values of the binding constant Camph for Qu 

and Rut are comparable, and the same conclusion can be 

drawn about the change in the Gibbs energy ∆G = -47.8 kJ. 

Comparison of the binding constants of the obtained 

complexes shows that the efficiency of Camphecene’s 

complexation with the participation of flavonoids is more 

efficient (K = 3.3 10
8
 M

-2
 for the Camph+2Qu; 

Camph+2Rut complexes) than with the participation of 

triterpenoids (K = 6.94 10
6
 M

-2
 for Camph+2GA) [14]. Al-

so, it was found that the complexes of Camphecene with 

the quercetin and rutin are soluble in water, in contrast to 

the complexes with triterpenoids, which makes it possible 

to increase the bioavailability of both Camphecene and 

flavonoids. 

4. Conclusions 

For the first time, the complexation of the Plant’s Flavo-

noids (Quercetin (Qu) and its glycoside - Rutin (Rut)) with 

the novel Russian antiviral drug Camphecene (Camph) 

was investigated.  

The complexes obtained at different molar ratios "host: 

guest" - 1:1 and 2:1 were studied using UV/Vis spectrosco-

py. 

Formation of the "host: guest" complexes were regis-

tered: Qu and Rut molecular complexes (Camph+2Qu; 

Camph+2Rut) with a stability constant K = 3.3 10
8
 M

-2
. 

The obtained results demonstrate the high potential of 

flavonoids Qu and Rut to the development of novel phar-

maceutical forms using the Camphecene in the form of 

molecular complexes, as the novel forms of delivery. 

Acknowledgements 

This work was supported by the Ministry of Science and 

Higher Education of the Russian Federation (State assign-

ment in the field of scientific activity, project No 0852-

2020-0031) and the Russian Foundation for Basic Re-

search (RFBR, grant no. 19-33-90211-Aspiranty). 

The authors are grateful to the Corresponding Member 

of the RAS, Doctor of Chemical Sciences, Professor of 

NIOCH SB RAS Salakhutdinov N.F. for the kindly provided 

scaffold monoterpenoid Camphecene. 

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