Influenza antiviral activity of F- and OH-containing isopulegol-derived octahydro-2H-chromenes

Article abstract of DOI:10.1016/j.bmcl.2020.127677

We synthesized fluoro- and hydroxy-containing octahydro-2H-chromenes by the Prins reaction starting from a monoterpenoid (–)-isopulegol and a wide range of aromatic aldehydes in the presence of the BF₃?Et₂O/H₂O system acti

Full text of DOI:10.1016/j.bmcl.2020.127677

Bioorg. Med. Chem. Lett. xxx (xxxx) xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Influenza antiviral activity of F- and OH-containing isopulegol-derived
octahydro-2H-chromenes
Irina V. Ilyinaa, Oksana S. Patrushevaa, Vladimir V. Zarubaevb, Maria A. Misiurinab,
Alexander V. Slitab, Iana L. Esaulkovab, Dina V. Korchaginaa, Yuri V. Gatilova,
,
Sophia S. Borisevichc, Konstantin P. Volchoa *, Nariman F. Salakhutdinova
a Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentjev av.9, 630090 Novosibirsk, Russia
b Pasteur Institute of Epidemiology and Microbiology, 14 Mira str., 197101 St. Petersburg, Russia
c Laboratory of Chemical Physics, Ufa Chemistry Institute of the Ufa Federal Research Center, 71 Octyabrya pr., 450054 Ufa, Russia
A R T I C L E I N F O
A B S T R A C T
Keywords:
Influenza
Antiviral
We synthesized fluoro- and hydroxy-containing octahydro-2H-chromenes by the Prins reaction starting from a
monoterpenoid (–)-isopulegol and a wide range of aromatic aldehydes in the presence of the BF3∙Et2O/H2O
system acting as both an acid catalyst and a fluorine source. Activity of the produced compounds against the
influenza A/Puerto Rico/8/34 (H1N1) virus was studied. The highest activity was demonstrated by fluoro- (11i)
and hydroxy-containing (10i) derivatives of 2,4,6-trimethoxybenzaldehyde. The most pronounced virus-
inhibiting effect of compounds 10i and 11i was observed at an early stage of infection. These compounds
were supposed to be capable of binding to viral hemagglutinin, which is an agreement with data on the effect of
compounds 10i and 11i on the viral fusogenic activity as well as by molecular docking studies.
Fluorine
Monoterpene
Chromene
Seasonal influenza is the most common human infectious disease
resulting in approximately 3–5 million cases of severe acute lower res-
piratory tract infection and about 250,000 to 500,000 deaths worldwide
annually, thus posing a serious public health impact.1,2 The most
effective strategy available for preventing and controlling influenza is
the use of vaccines. Along with vaccination, chemotherapy is an
important method for the prevention and treatment of viral diseases,
especially for immunocompromised patients and during pandemics
when a new virus spreads much faster than vaccine is produced and
epidemically significant population groups are immunized. The
currently marketed anti-influenza medications approved by FDA consist
of drugs from 3 classes: amantadine and rimantadine, which are M2-ion
channel blockers; oseltamivir, zanamivir, laninamivir and peramivir,
which target influenza neuraminidase; and baloxavir marboxil - cap-
dependent endonuclease (CEN) inhibitor.2,3 However, the ada-
mantanes are globally no longer recommended for clinical use because
of widespread resistance among circulating influenza A viruses.4 Influ-
enza virus can also develop resistance to other types of drugs, including
the emergence of oseltamivir-resistant strains.5 The development of
drug-resistant influenza virus mutants can be prevented by using a
combination of two or more agents with different mechanisms of
action.6 Hence, it is necessary to search for novel anti-influenza agents
belonging to new structural types, including those whose targets and
mechanisms of action differ from the currently used ones.
Natural compounds including monoterpenoids that are components
of natural essential oils are important source of novel anti-influenza
agents.7,8 Earlier, we discovered anti-influenza A (H1N1) virus activity
of several compounds with a hydro-2H-chromene scaffold, which were
synthesized by the Prins reaction using p-menthane alcohols and
carbonyl compounds; montmorillonite K10 or a nanosized halloysite
catalyst were used as the reaction catalysts. For example, chromenols 2
and 3 produced from an available monoterpenoid alcohol (–)-isopulegol
1 and aliphatic symmetric ketones, such as acetone and cyclo-
pentanone,9,10 demonstrated high activity in combination with low
toxicity against the influenza virus A (H1N1) (SI = 189 and SI = 96,
respectively).9 The antiviral activity was also detected for substituted 2-
(thiophen-2-yl)octahydro-2H-chromen-4-ol 4 (SI = 25) synthesized by
the reaction of (–)-isopulegol 1 with 5-bromothiophene-2-carbaldehyde
(Scheme 1).11
Another group of compounds with a hydro-2H-chromene scaffold
exhibiting activity against the influenza virus H1N1 was derived from
diol 5, which is synthesized from monoterpenoid (ꢀ )-verbenone 6 in
* Corresponding author.
E-mail address: volcho@nioch.nsc.ru (K.P. Volcho).
https://doi.org/10.1016/j.bmcl.2020.127677
Received 9 September 2020; Received in revised form 8 October 2020; Accepted 2 November 2020
Available online 7 November 2020
0960-894X/© 2020 Published by Elsevier Ltd.
Please cite this article as: Irina V. Ilyina, Bioorg. Med. Chem. Lett., https://doi.org/10.1016/j.bmcl.2020.127677

I.V. Ilyina et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx
atom into organic molecules and expansion of the range of fluorinating
reagents available for synthetic organic chemistry are extremely
important.
The purpose of this study was to develop new anti-influenza agents
by combining two previously found active fragments: an octahydro-2H-
chromene scaffold synthesized from (–)-isopulegol 1 as well as aromatic
Scheme 1. (–)-Isopulegol
1
derived compounds with anti-influenza
Scheme 4. Interaction of (–)-isopulegol 1 with aromatic aldehydes 9a-s cata-
activity.9,11.
lyzed by BF3*Et2O/H2O.
three stages.12 Thus, by using starting diol 5 and aromatic aldehydes as
well as the BF3∙Et2O/H2O system as a catalyst of the reaction, we syn-
thesized a large set of heterocyclic compounds with a hexahydro-2H-
chromene scaffold, which contained a hydroxy group at position C-4, as
well as compounds fluorinated at this position (Scheme 2). A number of
substances thus obtained showed high antiviral activity, for example
compound 7 with the hexahydro-2H-chromene framework synthesized
from 5 and p-chlorobenzaldehyde and 2,4,6-trimetoxybenzaldehyde-
derived fluorine-containing compound 8, which combines high anti-
viral potency (IC50 = 5 µM) and low cytotoxicity with good selectivity
index SI value of 55.13
Table 1
Synthesis of compounds 10 and 11.
Ar
Yielda ((4R)/(4S))
10
11
a
b
c
d
e
f
C6H5
20% (4.5:1)
14 (35:1)
70% (0:1)
4-MeO-C6H4
2,3-MeO-C6H3
2,4-MeO-C6H3
2,5-MeO-C6H3
3,4-MeO-C6H3
2,3,4-MeO-C6H2
2,4,5-MeO-C6H2
2,4,6-MeO-C6H2
3,4,5-MeO-C6H2
2-OH-C6H4
58 (1:1.3)
25% (5:1)
60% (1:1.7)
35% (2.5:1)
60% (1:1.7)
52% (1:1.3)
53% (1.7:1)
42% (5:1)
51% (24.5:1)
27% (8:1)
20% (4:1)
g
h
i
24% (60:1)
35% (˃99: traces)
60% (10:1)
20% (4:1)
The only examples of transformation of monoterpenoid alcohols via
the Prins reaction in the presence of BF3∙Et2O reported before our work
are the reactions of (–)-isopulegol 114 or geraniol15 with aldehydes;
however, olefin products lacking the fluorine atom are formed in both
cases (Scheme 3). At the same time, the introduction of the fluorine atom
into the molecule is an important strategy in the development of new
biologically active compounds, which enables changing lipophilicity
and electrostatic interactions and increasing the metabolic stability of
compounds16 and, as a result, affects their physiological activity.17–19 It
should be mentioned that some of the top-selling drugs on the current
pharmaceutical market contain fluorine atoms in their structures.20 In
this regard, the development of methods for introducing the fluorine
31% (1:4)
j
62% (1:2)
k
l
46% (10.5:1)
30% (1:0)
19% (0:1)
4-OH-C6H4
42% (1:1)
m
n
o
p
q
r
3-OH,4-MeO-C6H3
3-MeO,4-OH-C6H3
4-OH,3,5-MeO-C6H2
4-F-C6H4
26% (5.5:1)
27% (12.5:1)
23% (6.6:1)
8% (3:1)
64% (1:1.5)
56% (1:1.2)
51% (1:1.4)
55% (1:5.9)
51% (1:8.2)
65% (traces:1)
60% (0:1)
4-Cl-C6H4
13% (2:1)
4-Br-C6H4
10% (2:1)
s
4-NO2-C6H4
25 (1:1.5)
a
Reaction conditions: (–)-isopulegol 1 (3.3 mmol), aldehyde (3.3 mmol),
BF3*Et2O (4.9 mmol) and H2O (24.4 mmol)
Scheme 2. Diol 5 derived compounds with anti-influenza activity.
Scheme 3. Prince reaction of (–)-isopulegol 1 and geraniol.14,15.
2

I.V. Ilyina et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx
Table 2
Antiviral activity and cytotoxicity of compounds 10 и 11.
Ar
Compounds of type 10
Compounds of type 11
SIc
CC50
,
IC50 ,
SIc
a
b
a b
CC50
,
IC50
,
μM
μ
M
μM
μM
a
b
c
d
e
f
C6H5
580 ±
31
100 ±
11
6
65 ± 5
>38
2
4-MeO-C6H4
2,3-MeO-C6H3
2,4-MeO-C6H3
2,5-MeO-C6H3
3,4-MeO-C6H3
2,3,4-MeO-C6H2
689 ±
45
29 ± 4
24
1
171 ± 8
>103
2
>937
>937
78 ± 5
>312
180 ±
11
43 ± 4
4
>937
12
2
379 ±
29
155 ±
21
2
512 ±
36
37 ± 2
>31
1
>937
344 ±
40
3
20 ± 2
>9
2
g
>857
717 ±
76
1
133 ±
11
6 ± 1
22
h
i
2,4,5-MeO-C6H2
2,4,6-MeO-C6H2
>857
856 ±
49
>857
19 ± 2
1
78 ± 5
851 ±
62
6 ± 1
13
35
Fig. 1. Molecular structure of (4S)-11r (50% probability thermal ellipsoids
45
24 ± 3
are shown).
j
3,4,5-MeO-C6H2
405 ±
24
>285
1
568 ±
46
199 ±
23
3
aldehyde moieties in the presence of the BF3∙Et2O/H2O system as an
acid catalyst and a fluorine source.
k
l
2-OH-C6H4
4-OH-C6H4
3-OH,4-MeO-
C6H3
>1086
127 ± 8
738 ±
46
>1086
87 ± 10
118 ±
19
1
1
6
44 ± 3
95 ± 4
136 ± 9
>36
>36
>32
1
3
4
The synthesis of octahydro-2H-chromene-based compounds was
carried out according to the procedure described previously13,21 in one
preparative step via the reaction between (–)-isopulegol 1 and aromatic
aldehydes 9a-s in the presence of BF3∙Et2O/H2O in CH2Cl2 and at a
temperature of 2 ◦C for 2.5 h within which complete conversion of
(–)-isopulegol 1 was reached. The progress of the reaction was moni-
tored by GLC. The boron trifluoride etherate acted as both an acid
catalyst and a fluorine source, leading, as in the case of similar reactions
of diol 5,13,21 to the formation of two pairs of epimers containing either
hydroxy group or fluorine atom at position C-4 (10a-s and 11a-s,
respectively; Scheme 4). The obtained results are summarized in
Table 1.
m
n
o
3-MeO,4-OH-
C6H3
411 ±
28
>327
1
2
642 ±
36
>324
2
3
4-OH,3,5-MeO-
C6H2
473 ±
31
235 ±
30
158 ±
11
59 ± 7
p
q
r
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
65 ± 2
62 ± 2
132 ±
10
>36
>37
>89
2
2
1
68 ± 4
57 ± 4
>882
>36
2
2
2
29 ± 4
391 ±
44
s
4-NO2-C6H4
Rimantadine
Ribavirin
>982
393 ±
29
3
>976
>976
1
326 ±
21
69 ± 9
5
The total yield of octahydro-2H-chromenes 10 and 11 in the re-
actions was 70–90%, with the predominant formation of fluorides 11,
except reactions with 2,4-dimethoxybenzaldehyde 9d, 2,4,5- and 2,4,6-
trimethoxybenzaldehyde 9 h and 9i, and 2-hydroxybenzaldehyde 9 k
where the main products were compounds 10 or both types of products
formed in equal amounts. The structure of isomer (4S)-11r was addi-
tionally verified by the XRD data (Fig. 1).
>2130
35 ± 5
61
a
CC50 is the median cytotoxic concentration, i.e., the concentration causing
50% cell death.
b
IC50 is the 50% inhibiting concentration, i.e., the concentration causing 50%
decrease of virus replication.
c
SI is the selectivity index, which is the CC50/IC50 ratio. CC50′s and IC50′s are
presented as mean ± standard deviation. The values are calculated from three
It should be noted that, as we showed earlier,13,21 the reactions of
diol 5 with aromatic aldehydes in the presence of BF3∙Et2O/H2O led to
the predominant formation of (S)-isomers with the axially located
methyl group in the case of hydroxy-2H-chromene derivatives and (R)-
isomers with the equatorial methyl group at C-4 in the case of fluori-
nated products. A similar pattern is observed for the diastereomeric
distribution of 4-hydroxy-containing products 10 formed from (–)-iso-
pulegol 1. The major isomers of hydroxyl-containing compounds 10 are
independent experiments.
isomers with the axial methyl group, i.e. (R)-isomers, except reactions
with 4-NO2-benzaldehyde 9 s. Among fluoro-2H-chromene derivatives
11, the diastereomeric distribution is not unambiguous, but in most
cases compounds 11 were formed mainly as isomers with the equatorial
methyl group, i.e. as (S)-isomers.
Previously, for the reactions of diol 5 with aromatic aldehydes in the
Scheme 5. Presumable scheme of 10 and 11 formation.
3

I.V. Ilyina et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx
Fig. 2. Activity of 10i and 11i against influenza virus A/Puerto Rico/8/34 (H1N1) according to time-of-addition experiment.
presence of BF3∙Et2O/H2O, we showed that the fluoro- and hydroxy-
chromene ratio may be affected by many factors, such as reaction
temperature, reagent ratio (amounts of aldehyde, BF3∙Et2O, water), and
conversion degree of the starting diol 5, as well as demonstrated the
conversion of fluoro-chromene derivatives into hydroxy-containing an-
alogs.21 In addition, investigation of reactions of (–)-isopulegol 1 with
thiophene-2-carboxaldehyde22 and acetone10 catalyzed by heteroge-
neous acid aluminosilicate catalysts revealed that the stereoselectivity of
octahydro-2H-chromenol formation (ratio of (R)- and (S)-diastereomers)
depended on the concentration of acid sites, reaction temperature, and
initial concentrations of reagents. The produced hydroxy-compounds 10
may probably also partially convert, as we showed earlier,21 into fluo-
rides 11 via interaction with a fluorine source by the SN2 mechanism or
via protonation and dehydration leading to the formation of carbocation
12 (Scheme 5). Thus, to correctly understand regio- and stereoselectivity
of the formation of fluoro- and hydroxy-substituted octahydro-2H-
chromenes in each case, detailed investigation of the Prins reactions
catalyzed by the BF3∙Et2O/H2O system is required.
previously.23 Based on the data obtained, selectivity index (SI) was
calculated for each derivative. The compounds with SI = 10 and higher
were considered as active.
The results of an in vitro study of cytotoxic and anti-viral properties of
obtained compounds are summarized in Table 2.
Compound 10a with a hydroxy group at position C-4 and an
unsubstituted aromatic ring did not exhibit significant antiviral activity
(Table 2). The introduction of a methoxy group into the para-position of
the aromatic ring generally increased activity against the influenza A
(H1N1) virus and decreased cytotoxicity; on the contrary, the intro-
duction of methoxy groups into meta-positions reduced the antiviral
effect. The role of ortho-methoxy groups was not unambiguous.
Accordingly, the highest activity was demonstrated by compounds 10b
and 10i with a methoxy group in the para-position and without meta-
substituents, which, in combination with low cytotoxicity, resulted in
good SI amounting to 24 and 45, respectively. A selectivity index of>10
was also found for compound 10d with a methoxy group in the para-
position but in this case a relatively high selectivity index was associated
mainly with low toxicity and not with high activity. Note that previously
diol 5 derivatives did not exhibit a clear dependence of the antiviral
activity on the location of methoxy groups in the aromatic ring.13 Sub-
stitution of methoxy groups in the aromatic ring by hydroxy groups,
halogen atom, or a nitro group decreased the antiviral activity and/or
increased cytotoxicity, which led to low selectivity indexes.
Thus, a large set of new compounds with an octahydro-2H-chromene
scaffold was produced. By using silica gel column chromatography, we
were able to individually isolate the main (R)-isomers of compounds
10b, 10d–h, and 10 k–p, but could not separate diastereomers of fluo-
rinated product 11 with the chromene scaffold. Therefore, the antiviral
activity of compounds 10b, 10d–h, and 10 k–p was studied for their (R)-
isomers; the activity of compounds 11 k, 11r, and 11 s was studied for
(S)-isomers. In other cases, the biological activity was investigated for a
diastereomeric mixture at ratios indicated in Table 1.
Comparison of the antiviral activity of octahydro-2H-chromenes 10
with that of the appropriate compounds 11 reveals that the replacement
of the hydroxy substituent with a F atom in position C-4 usually leads to
an increase in the antiviral activity (decrease in IC50), but at the same
time, there is also an increase in cytotoxicity of chromenols 11, which
generally results in low SI values. However, three fluoro-derivatives, 11
g, 11 h, and 11i, having three methoxy groups in the aromatic ring
For biological testing, we used reference laboratory strain of H1N1
subtype (A/Puerto Rico/8/34). The antiviral activity of the synthesized
compounds was studied by the technique described earlier.23 Cytotox-
icity of the compounds was evaluated in MDCK cells as described
Fig. 3. Anti-fusogenic activity of 10i (orange) and 11i (blue) against hemagglutinin activity of influenza virus A/Puerto Rico/8/34 (H1N1).
4

I.V. Ilyina et al.
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx
Table 3
The docking results for compounds 10i and 11i. Energy characteristics are given in kcal/mol.
HOAa, %
PCacob, nm/sec
> 500 is great
(R)-
(S)-
> 80 is high
Docking score
IFD score
Interaction with amino acids
K558 ꢀ -cation stacking; K551 – H-bridge
Docking score
IFD score
Interaction with amino acids
10i
11i
100
100
4467.3
9906.0
ꢀ 10.0
ꢀ 9.5
ꢀ 3041.6
ꢀ 3038.5
π
×
×
×
S554 ꢀ H-bridge
ꢀ 8.5
ꢀ 3036.4
only hydrophobic
a
HOA ꢀ Predicted human oral absorption on 0 to 100% scale. The prediction is based on a quantitative multiple linear regression model;
b
PCaco ꢀ Predicted apparent Caco-2 cell permeability in nm/sec. Caco-2 cells are a model for the gut-blood barrier. These predictions are for non-active transport
Fig. 4. Hemagglutinin and the binding site of potential inhibitors:
yellow line.
π-cation stacking interactions are shown by the green dashed line, hydrogen bridges by the
showed both good antiviral activity and moderate cytotoxicity, which
resulted in high selectivity indexes of 22, 13 and 35, respectively.
Thus, the best selectivity indices were found for both hydroxy-
octahydro-2H-chromene (10i) and fluoro-octahydro-2H-chromene (11i)
derivatives synthesized from 2,4,6-trimethoxybenzaldehyde. Interest-
ingly, fluorine-containing derivative 8, which was produced earlier from
diol 5 and 2,4,6-trimethoxybenzaldehyde 9i, also showed significant
antiviral activity.13
the time of addition experiment, evaluation of the leader compound
effect on the fusogenic activity of viral hemagglutinin, and previously
obtained data for structurally similar compounds.9 The docking results
are shown in Table 3.
In general, affinity of the ligands is comparable. The compounds are
located between two
α-helices, forming a series of non-covalent in-
teractions with the surrounding amino acids (Fig. 4). This binding of
potential HA inhibitors complicates separation of
α-helices and may
Compounds 10i and 11i demonstrating high anti-influenza activity
and the highest selectivity index were tested for antiviral activity
depending on the time of addition to infected cells. In both cases,
compounds 10i and 11i exhibited the most pronounced virus-inhibiting
activity at an early stage of infection (Fig. 2).
impede further conformational transition from pre- to post-fusion.24
We have estimated ADME parameters, which would predict whether
the synthesized compounds can be applied as medicines (for details see
SI). According to calculation results (Table 3) the compounds would
have 100% human oral availability and high membrane permeability.
Thus, the compounds could be considered as bioavailable. Based on the
calculations, it seems that the bioavailability of fluorine containing
compound 11i could be higher than that of 10i.
Previously,9 given the activity spectrum of compound 2 against
different influenza virus strains, its predominant effect at an early stage
of infection, and molecular modeling, it was suggested that a potential
target of the compound might be hemagglutinin enabling the virus to
attach to a host cell. Taking into account the high activity of compounds
10i and 11i at an early stage of infection and their structural similarity
to compound 2, hemagglutinin might also be proposed as one of the
potential targets. To verify this suggestion, we studied the effect of
compounds 10i and 11i on the fusogenic activity of viral hemagglutinin.
As can be seen from the results obtained, both 10i and 11i demon-
strate strong dose-dependent inhibiting activity against influenza virus
hemagglutinin (Fig. 3).
Noteworthy, docking of the (S)-isomer of compound 10i failed. In the
case of 11i, the (S)-isomer also bind poorer than the (R)-isomer. The
docking score that characterizes binding of the (S)-11i ligand in a hy-
drophobic pocket and the IDF score that evaluates the total energy of the
ligand–protein system exceed the values describing the interaction be-
tween (R)-11i and hemagglutinin. Thus, among the isomers, the (R)-
stereoisomer is likely to exhibit biological activity. The (R)- and (S)-
isomer ratio is 10 : 1 for 10i; in the case of 11i, the ratio shifts toward
(S)-isomers and is 1 : 4 ((R)- and (S)-, Table 1). The weighted mean
values characterizing affinity of 11i for the protein, with allowance for
the (R) and (S) ratios, amount to –8.7 kcal/mol (docking score) and
–3036.8 kcal/mol (IFD score). Thus, 11i is characterized by lower
Molecular docking of potential HA inhibitors to the binding site was
performed for leader compounds 10i and 11i for both 4R- and 4S-di-
astereomers. The biological target was selected based on the results of
5

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Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx
6 Moghadas SM, Bowman CS, Rost G, Wu J. Population-wide emergence of antiviral
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affinity for the HA binding site compared to 10i. These data correlate
with the results of biological tests (Table 3), according to which 10i
inhibits the influenza virus at a lower concentration than 11i.
7 Salakhutdinov NF, Volcho KP, Yarovaya OI. Monoterpenes as a renewable source of
biologically active compounds. Pure Appl Chem. 2017;89:1105–1117. https://doi.
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Therefore, we synthesized F- and OH-containing isopulegol-derived
octahydro-2H-chromenes and studied their activity against the influenza
A/Puerto Rico/8/34 (H1N1) virus. The most active compounds were 10i
and 11i containing a 2,4,6-trimethoxybenzyl substituent. Given the re-
sults of time addition experiments, investigation of the effect of these
compounds on the viral fusogenic activity, and molecular docking,
hemagglutinin is suggested as a possible molecular target.
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activity of isopulegol-derived substituted octahydro-2 H -chromen-4-ols against
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Declaration of Competing Interest
11 Nazimova EV, Shtro AA, Anikin VB, Patrusheva OS, Il′ina IV, et al. Influenza
Antiviral Activity of Br-Containing [2R,4R(S),4aR,7R,8aR]-4,7-Dimethyl-2-
(Thiophen-2-YL)Octahydro-2H-Chromen-4-Ols Prepared from (–)-Isopulegol. Chem
Nat Compd. 2017;53(2):260–264.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
12 Il’ina I, Volcho K, Korchagina D, Barkhash V, Salakhutdinov N. Reactions of Allyl
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Research Center SB RAS for spectral and analytical measurements. All
calculations were performed on a cluster supercomputer of the Ufa
Institute of Chemistry of the Ufa Federal Research Centre of the Russian
Academy of Sciences. Molecular docking and quantum chemical calcu-
lations were performed under Government Contract AAAA-A17-
117011910028-7. The authors are grateful to Ministry of Science and
Higher Education of the Russian Federation for the financial support
(grant N 075-15-2020-777).
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