1042 0009-3130/13/4806-1042
©
2013 Springer Science+Business Media New York
Chemistry of Natural Compounds, Vol. 48, No. 6, January, 2013 [Russian original No. 6, November–December, 2012]
SEARCH FOR COMPOUNDS WITH ANTIVIRAL ACTIVITY
AMONG SYNTHETIC ()-CYTISINE DERIVATIVES
I. P. Tsypysheva,
1*
A. V. Kovalskaya,
1
A. N. Lobov,
1
UDC 547.94:834.2
V. V. Zarubaev,
2
L. A. Karpinskaya,
2
I. A. Petrenko,
1
E. A. Nikolaeva,
1
A. A. Shtro,
2
and M. S. Yunusov
1
The antiviral activity of several amides and thio- and carboxamides of ()-cytisine in addition to bromination
and nitration products of its 2-pyridone core was studied. Compounds with a selectivity index close to 10
were found.
Keywords: ()-cytisine, H1N1 flu virus.
Some plants that exhibit antiviral properties are known to bear alkaloids. Thus, several genera of the family Fabaceae,
e.g., Sophora, Acacia, and Caragana, yield extracts that are highly active against hepatitis C (HCV), hepatitis B (HBV),
Herpes simplex 1 (HSV-1), and several other viruses [1–5].
The search for new antiviral agents should be conducted among representatives of the most common structural
groups of quinolizidine alkaloids, including ()-cytisine, because plants of the family Fabaceae are the principal producers of
them [6] and the aforementioned antiviral properties may be associated with them.
The pharmacological profiles of ()-cytisine itself and its derivatives are very broad. Neuropharmacological, anti-
inflammatory, analeptic, and antidiabetic activity was established for them [7]. An example of a study of the antiviral properties
of ()-cytisine itself and several of its synthetic derivatives was published [8].
We synthesized two groups of derivatives of ()-cytisine and N-methylcytisine that contained substituents on the
secondary N atom and in the 2-pyridone core in order to discover compounds with antiviral activity and to establish the
structure–activity relationship.
The transformation products of the ( )-cytisine secondary amine were amides of m-fluoro-, m-bromo-, and
p-chlorobenzoic acids (1–3) that were prepared by the hydroxysuccinimide method as before [9]. The syntheses of thio- and
carboxamides 4 and 5, substituted ureas 6 and 7, nitro derivatives 9 and 10, carbamide 12, and dibromo derivative 8 were
described by us previously [10, 11]. Dinitro derivative 11 was synthesized by repeated nitration of 9.
Table 1 summarizes results from the study of the toxicity and antiviral activity of cytisine derivatives 1–12.
According to the results, starting alkaloid ()-cytisine had low toxicity and antiviral activity. Transformation products
of the ()-cytisine secondary amine, i.e., amides of m-fluoro-, m-bromo-, and p-chlorobenzoic acids 1–3, differed in toxicity
and activity. This indicated that the nature of the corresponding acid and the halogen atom and its position on the aromatic ring
affected the antiviral properties.
1) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, Prosp. Oktyabrya,
71, e-mail: tsipisheva@anrb.ru; 2) Research Institute of the Flu, Ministry of the Russian Federation for Health and Social
Development, 197376 St. Petersburg, Ul. Prof. Popova, 15/17. Translated from Khimiya Prirodnykh Soedinenii, No. 6,
November–December, 2012, pp. 920–923. Original article submitted April 13, 2012.
N
N
O
R
1
X
1 - 6
H H
N
N
O
N
O
N
N
O
N
O
6
N
N
O
Me
R
2
R
1
7 8 - 12
13
11
14
3
5
8
10
1: R
1
= 3-F-Ph, X = O; 2: R
1
= 3-Br-Ph, X = O; 3: R
1
= 4-Cl-Ph, X = O; 4: R
1
= NH
2
, X = S
5: R
1
= NH
2
, X = O; 6: R
1
= NHPh, X = O; 8: R
1
= R
2
= Br; 9: R
1
= NO
2
, R
2
= H
10: R
1
= H, R
2
= NO
2
; 11: R
1
= R
2
= NO
2
; 12: R
1
= NHCONHPh, R
2
= H