Anti-influenza activity of monoterpene-derived substituted hexahydro-2H-chromenes

Article abstract of DOI:10.1016/j.bmc.2016.08.037

The antiviral activity of 4-hydroxy-hexahydro-2H-chromenes and 4-fluorine-hexahydro-2H-chromenes with an aromatic substituent, synthesized from monoterpene (?)-verbenone, was studied for the first time. Five of 11 (45 per cent) of 4-hydroxy-hexahydro-2H-chromene-type compounds have been found to exhibit antiviral activity against influenza A virus of subtype H1N1pdm09. Although a portion of active compounds among 4-fluorine-containing series was fewer, just compound 5i that contains a fluorine substituent exhibited more potent anti-influenza activity along with low cytotoxicity. Thus two new promising types of antiviral compounds were identified.

Full text of DOI:10.1016/j.bmc.2016.08.037

Accepted Manuscript
Anti-influenza activity of monoterpene-derived substituted hexahydro-2H-
chromenes
Oksana S. Patrusheva, Vladimir V. Zarubaev, Anna A. Shtro, Yana R.
Orshanskaya, Sergey A. Boldyrev, Irina V. Ilyina, Svetlana Yu. Kurbakova,
Dina V. Korchagina, Konstantin P. Volcho, Nariman F. Salakhutdinov
PII:
S0968-0896(16)30644-7
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.08.037
BMC 13220
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 July 2016
19 August 2016
20 August 2016
Please cite this article as: Patrusheva, O.S., Zarubaev, V.V., Shtro, A.A., Orshanskaya, Y.R., Boldyrev, S.A., Ilyina,
I.V., Kurbakova, S.Y., Korchagina, D.V., Volcho, K.P., Salakhutdinov, N.F., Anti-influenza activity of
monoterpene-derived substituted hexahydro-2H-chromenes, Bioorganic & Medicinal Chemistry (2016), doi: http://
dx.doi.org/10.1016/j.bmc.2016.08.037
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Anti-influenza activity of monoterpene-derived substituted hexahydro-2H-
chromenes
Oksana S. Patrusheva1, Vladimir V. Zarubaev2,*, Anna A. Shtro2, Yana R. Orshanskaya2, Sergey
A. Boldyrev2, Irina V. Ilyina1,3, Svetlana Yu. Kurbakova1, Dina V. Korchagina1, Konstantin P.
Volcho1,3, Nariman F. Salakhutdinov1,3
1Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of
Sciences, 630090, Novosibirsk, Russia
2Department of Chemotherapy, Influenza Research Institute, 15/17 Prof. Popova St., 197376 St.
Petersburg, Russia
3Novosibirsk State University, Pirogova 2, Novosibirsk, 630090, Russian Federation
Abstract: The antiviral activity of 4-hydroxy-hexahydro-2H-chromenes and 4-fluorine-
hexahydro-2H-chromenes with an aromatic substituent, synthesized from monoterpene (-)-
verbenone, was studied for the first time. Five of 11 (45 per cent) of 4-hydroxy-hexahydro-
2H-chromene-type compounds have been found to exhibit antiviral activity against
influenza A virus of subtype H1N1pdm09. Although a portion of active compounds among
4-fluorine-containing series was fewer, just compound 5i that contains a fluorine
substituent exhibited more potent anti-influenza activity along with low cytotoxicity. Thus
two new promising types of antiviral compounds were identified.
Keywords: Influenza, Monoterpene, Antiviral, Chromene
INTRODUCTION
Influenza A virus is the major cause of seasonal or pandemic flu worldwide. Two major
classes of anti-influenza drugs currently available are adamantane-based M2 protein blockers
(amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir, zanamivir, and
peramivir).1 However, influenza viruses can become resistant to these antiviral drugs. Since the
mid-90s a high incidence of rimantadine resistance in field isolates of influenza viruses has been
reported, and resistance to adamantane drugs are now found in almost all isolates of influenza A
virus.2 A similar trend was observed across seasonal H1N1 strains, which showed an increase in
resistance to oseltamivir from 0% to 100% for the period from November 2007 to March 2009
worldwide.3 Highly pathogenic avian influenza isolates H5N1 and H7N9 can also acquire
* Corresponding author. Tel.: +7-812-499-1527; fax: +7-812-499-1500; e-mail: vladimir.zarubaev@influenza.spb.ru
1

oseltamivir resistance.2,4 There is an evidence demonstrating that influenza virus resistance to
antiviral drugs can emerge during treatment.4 In light of these challenges, it is essential to find
new compounds with an even broader range of activity against influenza A.
The design of low molecular weight substances derived from natural sources has emerged
as an important research area in the field of antiviral drug discovery.5,6 Due to the intrinsic ability
to bind numerous targets in vivo and the presence of abundant sp3 carbon atoms and asymmetric
centers, natural compounds offer a great potential for drug discovery, including antivirals.
Naturally occurring agents and their derivatives find wide application for designing novel
compounds against viral infections, in particular influenza.7,8 Monoterpenoids are pursued as
promising and sustainable sources of bioactive molecules with antiviral activity for
pharmaceutical application. Much emphasis is placed on bicyclic monoterpenes particularly
14-16
pinene,9-12 norbornene13 and camphene
derivatives, however, para-menthane monoterpenes
remain yet to be explored for the treatment of flu. As an example, diol 1 with para-menthane
framework showed minor activity (IC50 = 20 µg/ml, selectivity index SI = 7.5) against influenza
A virus (H1N1) (Scheme 1).17 The addition of an isonicotinic acid residue to the allyl hydroxyl
group (compound 2) increased the SI value to 17.17 The susceptibility of influenza A viruses to
other types of compound 1 derivatives were not studied in this work.
At the same time monoterpenoid 1 can interact with aldehydes 3 in the presence of
heterogeneous catalysts to give heterocyclic compounds 4 with a hexahydro-2H-chromene
framework (Scheme 1).18,19 Similar compounds 5, containing the fluorine atom in place of the
nodal hydroxyl group, could be produced using the BF3·Et2O/H2O reaction (Scheme 1).20
Importantly, the antiviral activity of compounds with oxygen-containing bicyclic frameworks
has been recently proposed.21,22 The objective of this study was the synthesis of hexahydro-2H-
chromene-based compounds from diol 1 and the evaluation of their activity against influenza A
virus.
Scheme 1.
2

Chemistry
Monoterpenoid 1 was prepared from the widespread monoterpenoid (-)-verbenone through
subsequent epoxidation, ketone group reduction and isomerization on K10 clay following
protocols as described (Scheme 2).23,24
Compounds 4a-k were obtained by the reaction of diol 1 with aromatic aldehydes 3a-k in
the presence of K10 clay as previously described (Scheme 2).18 The synthesis of fluorine
containing compounds 5a-i was carried out with the use of BF3·Et2O/H2O as described,20 with
hydroxyl containing compounds 4a-i formed as minor products by side reactions.
Scheme 2. Synthesis of compounds 4a-k and 5a-k.
In addition to these compounds, we also obtained fluorine-containing compounds 5j and
5k by reacting monoterpenoid 1 with 2,4-dimethoxybenzaldehyde 3j and 2,3,4-
trimethoxybenzaldehyde 3k. The reaction was performed under conditions as described20 with
the use of BF3·Et2O and H2O in CH2Cl2 at 2 Co. The interaction of compound 1 with aldehyde 3j
gives compound 5j, which contains a fluorine atom with a yield of 33%. The same reaction
afforded compound 4j containing a hydroxyl group in position C-4 with a yield of 36%. The
addition of another methoxy group in aldehyde 3k increases the yield of the target fluorine-
containing compound (5k) to 52%. Side product 4k was obtained with a yield of 35%. As can be
3

seen from Scheme 2, aldehyde 4k, carrying three electron-donating methoxy groups affords
fluorine-containing compound 5k in greater yield relative to dimethoxybenzaldehyde 3j.
However, under the same reaction conditions we observed no effect of the number of methoxy
groups in the aldehyde aromatic ring on the yield of hydroxyl containing compounds 4j,k
(Scheme 2).
Compounds 4j,k and 5j,k, like compounds 4a-i and 5a-i, were formed as a mixture of
diastereomers at the C-4 position, favoring the (S)-configured products 4 and (R)-configured
products 5 (Scheme 2).
Biology
The antiviral activity of the synthesized compounds was studied against the pandemic
influenza virus A/California/07/09 (H1N1)pdm09 cultivated in cell culture by the technique
described.25 Cytotoxicity of the compounds was evaluated in uninfected MDCK cells as
described previously.25 Based on the data obtained, selectivity index was calculated for each
derivative. The compounds with SI=10 and higher were considered active.
Table 1. Antiviral activity and cytotoxicity of compounds 4a-k and 5a-k against influenza virus
A/California/07/09 (H1N1)pdm09 in MDCK cells
Compounds of type 4
Compounds of type 5
IC50, μM
Substituents in
aromatic ring
b
IC50 , μM
SIc
SI
a
CC50 , μM
803 51
425 22
1199 64
354 19
987 65
2593 174
1670 82
2000 102
>824
CC50, μM
a
131 20
26 3
6.1
16.3
5.5
1.2
3
880 65
129 8
361 18
>935
152 18
97 11
>340
5.8
1.3
1
b, R4=Cl
c, R4=F
d, R4=NO2
e, R4=OMe
f, R3=R4=OMe
g, R3=R4=R5=OMe
h, R2=R4=R5=OMe
i, R2=R4=R6=OMe
j, R2=R4=OMe
k, R2=R3=R4=OMe
Rimantadine
219 31
288 38
>329
312 43
18 3
3.0
36.3
3.8
4.5
1
>654
213 33
63 8
12.2
26.5
12.7
2.4
1
>893
232 35
309 42
820 91
5 1
1404 116
>820
157 19
343 22
898 93
187 21
44 6
>273
54.6
2.3
1
>898
893 71
>820
387 42
>820
1995 96
350 26
10.7
8.0
a CC50 is the median cytotoxic concentration, i.e. the concentration causing 50% cell death.
IC50 is the 50% inhibiting concentration, i.e. the concentration causing 50% decrease of
b
virus replication.
c SI is the selectivity index, which is the CC50/IC50 ratio.
4

CC50’s and IC50’s are presented as mean standard deviation. The values are calculated
from three independent experiments.
Table 1 shows that compound 4a with an unsubstituted aromatic ring failed to exhibit
significant antiviral activity. However, compound 4b, containing a fluorine atom in the para-
position of the aromatic ring, had moderate antiviral effects (IC50 = 26 μM) and low cytotoxicity,
thus increasing the SI value to over 16. Compounds 4c-e, containing other electron withdrawing
and donating substituents in the para-position (NO2, F, OMe) proved to be less potent.
An increase in the number of methoxy groups contributes to antiviral activity, with the
methoxy group in the meta-position (compounds 4f-h,k) playing an essential role. The lack of
this substituent (compounds 4i,j) eliminates the antiviral effect. The greatest activity was
detected for compound 4g with three methoxy substituents in the ortho-, meta- and para-
positions. Compound 4g showed low cytotoxicity and a high SI value of over 26.
In contrast, compounds of type 5 that carry a fluorine atom in place of the hydroxyl group
displayed dramatically different biological properties. The antiviral activity was observed in only
5e and 5i that contain the methoxy group in the para-position while lacking the one in the meta-
position. Interestingly, compound 5j with close configuration of methoxy groups to 5e and 5i
failed to show antiviral activity. Compound 5i seems to be a promising one combining high
antiviral potency (IC50 = 5 μM) and low cytotoxicity and the SI value of 55.
In general, the studied group of compounds possessed moderate anti-influenza activity. Of
22 substances, 7 (32%) had SI’s higher than 10. Nevertheless, compound 5i with SI = 55
demonstrated low toxicity and high activity (IC50 in low micromolar range). This allows one to
consider it prospective for further optimization and development as a potential antiviral.
Experimental part
General methods: All the chemicals were of commercial reagent grade. CH2Cl2 was
passed through calcined Al2O3. (1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol
1 ([α]D31= -49.1 (c = 2.6, CHCl3)) was synthesized according to23 from (–)-verbenone (Aldrich),
the content of the main substance was not less than 98.0%. Column chromatography (CC): silica
gel (SiO2; 60-200 μ; Macherey-Nagel). GC/MS (purity control and products analysis): Agilent
7890A with a quadrupole mass spectrometer Agilent 5975C as a detector, HP-5MS quartz
column, 30000x0.25 mm, He (1 atm) as carrier gas. Optical rotation: polAAr 3005 spectrometer,
CHCl3 soln. HR-MS: DFS-Thermo-Scientific spectrometer in a full scan mode (15-500 m/z, 70
1
13
eV electron-impact ionization, direct sample introduction). H and C NMR: Bruker DRX-500
apparatus at 500.13 MHz (1H) and 125.76 MHz (13C) in CDCl3 or CDCl3/CD3OD (10:1 v/v);
chemical shifts δin ppm rel. to residual CHCl3 (δ(H) 7.24, δ(C) 76.90 ppm), J in Hz; structure
5

1
1
1
determinations by analyzing the H NMR spectra, including H – H double resonance spectra
1
1
13
13
1
and H – H 2D homonuclear correlation, J-modulated C NMR spectra (JMOD), and C – H
2D heteronuclear correlation with one-bond and long-range spin-spin coupling constants (C – H
COSY, 1J(C,H) = 160 Hz, COLOC, 2,3J(C,H) = 10 Hz).
General procedure for compounds 4a, e-k: An appropriate aldehyde (3 a, e-k) was added
to a suspension of clay K10 in CH2Cl2 (10 ml). A solution of para-mentha-1,8-diene-5,6-diol 1
in CH2Cl2 (20 ml) was added dropwise with stirring. The solvent was distilled off under reduce
pressure. The mixture was stored at r.t. for required time. Then EtOAc (20 ml) was added. The
catalyst was filtered off, the reaction mixture was concentrated and residue was separated on a
SiO2 column. Spectral characteristics of compounds 4a, e-k were described in the works.26,27,28
General procedure for compounds 4b-d and 5a-k: Para-mentha-1,8-diene-5,6-diol 1 (2.4
mmol) and aldehyde (2.9 mmol) were dissolved in CH2Cl2 (5 ml) and cooled to 2 °C. Then water
(17.8 mmol) was added to the BF3·Et2O (3.6 mmol) solution in CH2Cl2 (5 ml) under vigorous
stirring. Resulting cloudy solution of BF3·Et2O was added dropwise to the mixture of aldehyde
and monoterpenoid, and then the reaction mixture was stirred for 8 or 72 hours at 2 °C. Then 10
% NaHCO3 solution was added, the layers were separated and the aqueous phase was extracted
with CH2Cl2 (2 x 15 ml). The combined organic layers were dried over Na2SO4, filtered and
concentrated. Reaction mixture was separated on a SiO2 column (hexane : EtOAc 100:0 – 0:100
as eluent). Spectral characteristics of compounds 4b-d and 5a-i were described in the work.20
(2S,4S,4aR,8R,8aR)-2-(2,4-dimethoxyphenyl)-4-fluoro-4,7-dimethyl-3,4,4a,5,8,8a-
hexahydro-2H-chromen-8-ol ((S)-5j) and (2S,4R,4aR,8R,8aR)-2-(2,4-dimethoxyphenyl)-4-
fluoro-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromen-8-ol ((R)-5j).
Reaction of 1 with 2,4-dimethoxybenzaldehyde 3j for 8 hours at 2 °C gave products 4j
(S:R = 5:1, 36%) and 5j (S:R = 1:1, 33%).
3
Compound (S)-5j. 1H NMR (CDCl3, δ ): 1.64 (3H, dd, J17,F = 23.6, J17,4a = 0.8 Hz, H-
H
17), 1.82 (3H, m, all J ≤2.5 Hz, H-18), 1.86 (1H, dddd, J4e,4a = 13.1, J4e,3a = 2.6, J4e,F = J4e,6a = 1.1
Hz, He-4), 1.96-2.07 (2H, m, Ha-4, Ha-6), 2.17 (1H, dm, J7e,7a = 18.3 Hz, anothers J < 6.4 Hz,
He-7), 2.25 (1H, dddqd, J7a,7e = 18.3, J7a,6a = 10.9, J7a,8 = J7a,18 = 2.5, J7a,10e = 1.5 Hz, Ha-7), 3.71
(1H, m, all J ≤2.5 Hz, He-1), 3.76 (3H, s, H-20), 3.78 (3H, s, H-19), 3.90 (1H, br.s, He-10), 4.69
(1H, dd, J3a,4a = 11.9, J3a,4e = 2.6 Hz, Ha-3), 5.63-5.67 (1H, m, H-8), 6.41 (1H, d, J13,15 = 2.4 Hz,
H-13), 6.46 (1H, dd, J15,16 = 8.5, J15,13 = 2.4 Hz, H-15), 7.26 (1H, d, J16,15 = 8.5 Hz, H-16). 13C
NMR (CDCl3, JC,F, δ ): 20.69 (C-18), 22.59 (d, 3J = 6.0 Hz, C-7), 24.72 (d, 2J = 25.8 Hz, C-17),
C
37.88 (d, 2J = 18.9 Hz, C-6), 39.64 (d, 2J = 20.0 Hz, C-4), 55.23, 55.29 (C-19, C-20), 70.22 (d, 4J
3
3
1
= 2.0 Hz, C-10), 71.61 (d, J = 11.9 Hz, C-3), 77.81 (d, J = 7.7 Hz, C-1), 95.39 (d, J = 175.9
6

Hz, C-5), 98.21 (C-13), 104.46 (C-15), 122.47 (C-11), 124.46 (C-8), 127.06 (C-16), 131.26 (C-
9), 156.64 (C-12), 160.12 (C-14). HR-MS: 336.1735 (M+, C19H25O4F; calcd 336.1731).
3
Compound (R)-5j. 1H NMR (CDCl3, δ ): 1.32 (3H, d, J17,F = 22.3 Hz, H-17), 1.68 (1H,
H
3
ddd, J4a,F = 40.9, J(4a,4e) = 14.6, J4a,3a = 11.6 Hz, Ha-4), 1.94 (1H, ddd, J4e,4a = 14.6, J4e,F
=
10.6, J4e,3a = 2.7 Hz, He-4), 1.82 (3H, m, all J ≤2.5 Hz, H-18), 1.95-2.03 (3H, m, Ha-6, 2H-7),
3.76, 3.77 (6H, 2s, H-19, H-20), 3.90 (1H, br.s, He-10), 4.13 (1H, m, all J ≤2.5 Hz, He-1), 5.04
(1H, dd, J3a,4a = 11.6, J3a,4e = 2.7 Hz, Ha-3), 5.55-5.59 (1H, m, H-8), 6.40 (1H, d, J13,15 = 2.4 Hz,
13
H-13), 6.44 (1H, dd, J15,16 = 8.5, J15,13 = 2.4 Hz, H-15), 7.24 (1H, d, J16,15 = 8.5 Hz, H-16). C
NMR (CDCl3, JC,F, δ ): 20.80 (C-18), 24.09 (d, 3J = 9.6 Hz, C-7), 24.74 (d, 2J = 24.4 Hz, C-17),
C
36.19 (d, 2J = 21.0 Hz, C-6), 38.97 (d, 2J = 21.5 Hz, C-4), 55.19, 55.22 (C-19, C-20), 70.00 (C-
3), 70.14 (C-10), 75.28 (C-1), 95.27 (d, 1J = 168.5 Hz, C-5), 98.17 (C-13), 104.43 (C-15), 123.14
(C-11), 123.18 (C-8), 132.19 (C-9), 126.98 (C-16), 156.81, 159.94 (C-12, C-14). HR-MS:
336.1735 (M+, C19H25O4F; calcd 336.1731).
(2S,4S,4aR,8R,8aR)-2-(2,3,4-trimethoxyphenyl)-4-fluoro-4,7-dimethyl-3,4,4a,5,8,8a-
hexahydro-2H-chromen-8-ol ((S)-5k) and (2S,4R,4aR,8R,8aR)-2-(2,3,4-trimethoxyphenyl)-
4-fluoro-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromen-8-ol ((R)-5k).
Reaction of 1 with 2,3,4-trimethoxybenzaldehyde 3k for 8 hours at 2 °C gave products 4k
(S:R = 3:2, 35%) and 5k (S:R = 2:32, 52%).
3
Compound (S)-5k. 1H NMR (CDCl3, δ ): 1.64 (3H, dd, J17,F = 23.5, J17,4a = 0.6 Hz, H-
H
17), 1.74-1.81 (1H, m, He-4), 1.80 (3H, m, all J ≤2.5 Hz, H-18), 2.02-2.07 (1H, m, Ha-6), 2.12-
2.31 (3H, m, Ha-4, 2H-7), 3.72 (1H, m, all J ≤2.5 Hz, He-1), 3.81 (3H, s, H-21), 3.82 (3H, s, H-
20), 3.86 (3H, s, H-19), 3.87 (1H, br.s, He-10), 4.62 (1H, dd, J3a,4a = 12.0, J3a,4e = 2.5 Hz, Ha-3),
5.62-5.66 (1H, m, H-8), 6.63 (1H, d, J15,16 = 8.7 Hz, H-15), 7.01 (1H, d, J16,15 = 8.7 Hz, H-16).
13C NMR (CDCl3, JC,F, δ ): 20.66 (C-18), 22.57 (d, 3J = 6.0 Hz, C-7), 24.68 (d, 2J = 25.8 Hz, C-
C
17), 37.75 (d, 2J = 18.9 Hz, C-6), 39.72 (d, 2J = 20.4 Hz, C-4), 55.88 (C-21), 60.58 (C-20), 61.20
3
3
(C-19), 70.14 (d, 4J = 2.1 Hz, C-10), 72.47 (d, J = 11.9 Hz, C-3), 77.87 (d, J = 7.7 Hz, C-1),
1
95.27 (d, J = 176.2 Hz, C-5), 107.47 (C-15), 121.10 (C-16), 124.41 (C-8), 127.27 (C-11),
131.22 (C-9), 141.91 (C-13), 150.80 (C-12), 153.22 (C-14). HR-MS: 366.1836 (M+, C20H27O5F;
calcd 366.1837).
Compound (R)-5k. 1H NMR (CDCl3, δ ): 1.34 (3H, d, 3J17,F = 22.5 Hz, H-17), 1.80 (3H,
H
3
m, all J ≤2.5 Hz, H-18), 1.81-1.88 (1H, m, He-4), 1.90 (1H, ddd, J4a,F = 38.9, J(4a,4e) = 14.6,
J4a,3a = 11.5 Hz, Ha-4), 1.95-2.03 (3H, m, Ha-6, 2H-7), 3.80 (3H, s, H-21), 3.83 (3H, s, H-20),
3.85 (3H, s, H-19), 3.89 (1H, br.s, He-10), 4.15 (1H, m, all J ≤2.5 Hz, He-1), 4.91-4.95 (1H, m,
7

Ha-3), 5.55-5.59 (1H, m, H-8), 6.62 (1H, d, J15,16 = 8.7 Hz, H-15), 6.98 (1H, d, J16,15 = 8.7 Hz,
H-16). 13C NMR (CDCl3, JC,F, δ ): 20.78 (C-18), 24.10 (d, 3J = 9.5 Hz, C-7), 24.78 (d, 2J = 24.5
C
Hz, C-17), 36.10 (d, 2J = 20.9 Hz, C-6), 38.91 (d, 2J = 21.4 Hz, C-4), 55.88 (C-21), 60.58 (C-20),
61.23 (C-19), 70.12 (C-10), 71.36 (C-3), 75.28 (d, 3J = 1.1 Hz, C-1), 95.17 (d, 1J = 168.6 Hz, C-
5), 107.41 (C-15), 121.34 (C-16), 123.22 (C-8), 127.95 (C-11), 132.17 (C-9), 142.12 (C-13),
151.13 (C-12), 153.10 (C-14). HR-MS: 366.1836 (M+, C20H27O5F; calcd 366.1837).
Acknowledgments
This work was supported by Russian Scientific Foundation (grant 15-13-00017). Authors
would like to acknowledge the Multi-Access Chemical Service Center SB RAS for spectral and
analytical measurements.
References
1. Shen, Z.; Lou, K.; Wang, W. Acta Pharm. Sin. B 2015, 5, 419.
2. Govorkova, E. A.; Baranovich, T.; Seiler, P.; Armstrong, J.; Burnham, A.; Guan, Y.;
Peiris, M.; Webby, R. J.; Webster, R.G. Antiviral Res. 2013. 98, 297.
3. Dixit, R.; Khandaker, G.; Ilgoutz, S.; Rashid, H.; Booy, R. Infect. Disord. Drug Targets
2013, 13, 34.
4. Hay, A. J.; Hayden, F. G. Lancet. 2013, 381, 2230.
5. Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311.
6. Harvey, A. L.; Edrada-Ebel, R. A.; Quinn R. J. Nat. Rev. Drug Discov. 2015, 14, 111.
7. Martinez, J. P.; Sasse, F.; Bronstrup, M.; Diez, J.; Meyerhans, A. Nat. Prod. Rep. 2015,
32, 29.
8. Gogineni, V.; Schinazi, R. F.; Hamann, M. T. Chem. Rev. 2015, 115, 9655.
9. Dong, J.; Chen, S.; Li, R.; Cui, W.; Jiang, H.; Ling, Y.; Yang, Z.; Hu, W. Eur. J. Med.
Chem. 2016, 108, 605.
10. Zhao, X.; Li, C.; Zeng, S.; Hu, W. Eur. J. Med. Chem. 2011, 46, 52.
11. Teplov, G. V.; Suslov, E. V.; Zarubaev, V. V.; Shtro, A. A.; Karpinskaya, L. A.;
Rogachev, A. D.; Korchagina, D. V., Volcho, K. P.; Salakhutdinov, N. F.; Kiselev, O. I.
Lett. Drug Des. Discov. 2013, 6, 477.
12. Zhao, X.; Jie, Y.; Rosenberg, M. R.; Wan, J.; Zeng, S.; Cui, W.; Xiao, Y.; Li, Z.; Tu, Z.;
Casarotto, M. G.; Hu, W. Antiviral Res. 2012, 96, 91.
13. Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Cerero, S.; Rodriguez
Herrero, M. E.; Martinez Ruiz, P.; Subramanian, L. R.; Garcia Gancedo, A. J. Med.
Chem. 1995, 38, 4474.
8

14. Sokolova, A. S.; Yarovaya, О. I.; Korchagina, D. V.; Zarubaev, V. V.; Tretiak, T. S.;
Anfimov, P. M.; Kiselev, O. I.; Salakhutdinov, N. F. Bioorg. Med. Chem. 2014, 22, 2141.
15. Zarubaev, V. V.; Garshinina, A. V.; Tretiak, T. S.; Fedorova, V. A.; Shtro, A. A.;
Sokolova, A. S.; Yarovaya, O. I.; Salakhutdinov, N. F. Antiviral Res. 2015, 120, 126.
16. Sokolova, A. S.; Yarovaya, O. I.; Shernyukov, A. V.; Gatilov, Y. V.; Razumova, Y. V.;
Zarubaev, V. V.; Tretiak, T. S.; Pokrovsky, A. G.; Kiselev, O. I.; Salakhutdinov, N. F.
Eur. J. Med. Chem. 2015, 105, 263.
17. Ardashov, O. V.; Zarubaev, V. V.; Shtro, A. A.; Korchagina, D. V.; Volcho, K. P.;
Salakhutdinov, N. F.; Kiselev, O. I. Lett. Drug Des. Discov. 2011, 8, 375.
18. Il’ina, I.; Mikhalchenko, O.; Pavlova, A.; Korchagina, D.; Tolstikova, T.; Volcho, K.;
Salakhutdinov, N.; Pokushalov E. Med. Chem. Res. 2014, 23, 5063.
19. Stekrova, M.; Mäki-Arvela, P.; Kumar, N.; Behravesh, E.; Aho, A.; Balme, Q.; Volcho,
K.; Salakhutdinov, N., Murzin, D. Yu. J. Mol. Catal. A: Chem. 2015, 410, 260.
20. Mikhalchenko, O. S.; Korchagina, D. V.; Volcho, K. P.; Salakhutdinov, N. F. Beilstein J.
Org. Chem. 2016, 12, 648.
21. Chen, B.-L.; Wang, Y.-J.; Guo, H.; Zeng, G.-Y. Eur. J. Med. Chem. 2016, 109, 199.
22. Batool, S.; Mushtaq, G.; Kamal, W.; Kamal, M. A. Med. Chem. 2016, 12, 63.
23. Il’ina, I. V.; Volcho, K. P.; Korchagina, D. V.; Barkhash, V. A.; Salakhutdinov, N. F.
Helv. Chim. Acta 2007, 90, 353.
24. Ardashov, O. V.; Il’ina, I. V.; Korchagina, D. V.; Volcho, K. P.; Salakhutdinov, N. F.
Mendeleev Commun. 2007, 17, 303.
25. Sokolov, D. N.; Zarubaev, V. V.; Shtro, A. A; Polovinka, M. P.; Luzina, O. A.;
Komarova, N. I.; Salakhutdinov, N. F.; Kiselev, O. I. Bioorg. Med. Chem. Lett. 2012, 22,
7060.
26. Il’ina, I. V.; Volcho, K. P.; Korchagina, D. V.; Barkhash, V. A.; Salakhutdinov, N. F.
Helv. Chim. Acta. 2007, 90, 353.
27. Il'ina, I. V.; Volcho, K. P.; Mikhalchenko, O. S.; Korchagina, D. V.; Salakhutdinov, N. F.
Helv. Chim. Acta, 2011, 94, 502.
28. Mikhalchenko, O. S.; Korchagina, D. V.; Volcho, K. P.; Salakhutdinov, N. F. Helv.
Chim. Acta 2014, 97, 1406.
29. Mikhalchenko, O.; Il’ina, I.; Pavlova, A.; Morozova, E.; Korchagina, D.; Tolstikova, T.;
Pokushalov, E.; Volcho, K.; Salakhutdinov, N. Med. Chem. Res. 2013, 22, 3026.
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