Synthesis and Biological Activity of Cyanoethyl Derivatives of Fusidic Acid

Article abstract of DOI:10.1134/S1070428018090245

3,11-Dihydroxy and 3,11-dioxo triterpenoids of the fusidane series reacted with acrylonitrile in 1,4-dioxane in the presence of alkali and phase-transfer catalyst to give mono- and bis(2-cyanoethoxy) and 2-cyanoethyl derivatives. The reaction with 3,11-dioxo analog afforded 2,2-disubstituted derivative as a result of addition of two cyanoethyl groups to the α-position with respect to the C³=O carbonyl group. The isolated compounds were screened for antibacterial and antifungal activities.

Full text of DOI:10.1134/S1070428018090245

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 9, pp. 1411–1418. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © E.V. Salimova, A.G. Mamaev, E.V. Tret’yakova, O.S. Kukovinets, A.R. Mavzyutov, K.Yu. Shvets, L.V. Parfenova, 2018, published in
Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 9, pp. 1395–1402.
Synthesis and Biological Activity of Cyanoethyl Derivatives
of Fusidic Acid
a
a
a
b
c
E. V. Salimova ,* A. G. Mamaev , E. V. Tret’yakova , O. S. Kukovinets , A. R. Mavzyutov ,
b, c
a
K. Yu. Shvets , and L. V. Parfenova
a
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
*
e-mail: salimovaev@mail.ru
b
Bashkir State University, ul. Zaki Validi 32, Ufa, 450076 Bashkortostan, Russia
c
Bashkir State Medical University, ul. Lenina 3, Ufa, 450008 Bashkortostan, Russia
Received April 9, 2018
Abstract—3,11-Dihydroxy and 3,11-dioxo triterpenoids of the fusidane series reacted with acrylonitrile in
1
2
,4-dioxane in the presence of alkali and phase-transfer catalyst to give mono- and bis(2-cyanoethoxy) and
-cyanoethyl derivatives. The reaction with 3,11-dioxo analog afforded 2,2-disubstituted derivative as a result
3
of addition of two cyanoethyl groups to the α-position with respect to the C =O carbonyl group. The isolated
compounds were screened for antibacterial and antifungal activities.
DOI: 10.1134/S1070428018090245
A challenging problem in modern medical practice
is therapy of diseases caused by antibiotic-resistant
microorganisms [1–3]. The data published by the US
Centers for Disease Control and Prevention indicated
more than 2 million diseases caused annually by
bacteria and fungi that are resistant to at least several
classes of antibiotics [4]. Development of new anti-
microbial agents remains one of the most important
problems of chemistry and medicine. According to the
statistical data [5], about ~47% of all practically used
drugs created over the past 30 years have been
designed on the basis of natural molecules (natural
compounds, their semisynthetic analogs, and biomi-
metics). More than half of antitumor and antimicrobial
drugs are of natural origin, or they have been designed
by analogy with natural compounds. A huge diversity
of natural compounds, the major part of which is
represented by plant metabolites, provides an abundant
source for rational design of medicines. In this respect,
a great role in the design of new therapeutic agents is
played by the development of efficient methods of
transformations of natural molecules with a view to
obtaining their analogs exhibiting a higher activity and
selectivity for biological targets and possessing the
lowest general toxicity.
Fusidic acid is one of promising natural antibiotics
used in clinical practice. It is a tetracyclic 29-nortriter-
penoid produced by Fusidium coccineum [6] and is
successfully used for the treatment of purulent inflam-
matory diseases of different localizations, caused by
(among others) methicillin-resistant Staphylococcus
spp. [7, 8].
Good results can be achieved by the introduction of
a nitrile functionality into natural molecules; the high
biocompatibility of cyano group is indicated by wide
occurrence of nitriles among pharmaceuticals, as well
as by the results of ongoing clinical studies of potential
drugs [9, 10]. The cyano group is fairly stable and in
most cases is not metabolized in the human organism
[11, 12]. Due to diversity of the mechanisms of inter-
action between the cyano group and biological targets,
nitriles attract increasing attention as promising sub-
strates for the design of various medicinal agents [13].
A simple and convenient method for the introduc-
tion of a cyano group into organic molecules pos-
sessing a labile hydrogen atom is based on cyano-
ethylation with acrylonitrile. With the goal of extend-
ing the set of available antibacterial agents, in the
present work we studied cyanoethylation of fusidic
1
411

1
412
SALIMOVA et al.
Scheme 1.
Me
Me
Me
Me
HO
Me
COOH
OAc
O
O
H C=CHCN
KOH, dioxane
2
NC
O
O
Me
Me
Me
Me
Me
NC
HO
Me
Me
1
2
Me
Me
HO
Me
O
O
+
Me
Me
NC
O
Me
3
acid and its derivatives, and the isolated compounds
were tested for antimicrobial and antifungal activities.
cross-peaks between diastereotopic protons in the
3
β-position with respect to the cyano group and C
11
and/or C . Furthermore, upfield shifts of the 3-H and
1-H signals (δ 3.28 and 3.84 ppm, respectively) were
The reaction of fusidic acid (1) with excess acrylo-
nitrile afforded two products and was accompanied by
cyclization involving the 16-acetoxy group and car-
boxylic acid functionality to form lactone ring. The
product mixture was separated by column chromatog-
raphy to isolate 3,11-bis- and 3-monocyanoethoxy
derivatives 2 and 3 in 50 and 40% yield, respectively
1
1
observed in the H NMR spectrum of 2. In the
1
3
C NMR spectrum of 2, carbon nuclei of the cyano
groups resonated at δ 118.41 and 118.70 ppm, and the
C
3
CN signal of 3 was observed at δ
118.56 ppm. The C
and C signals in the C NMR spectrum of 2 shifted
downfield to δ 79.91 and 75.90 ppm, respectively.
C
11
13
(
Scheme 1). The formation of lactone ring in mole-
C
cules 2 and 3 was confirmed by the upfield shift of the
Taking into account that cyanoethylation of 1 under
the given conditions was accompanied by lactoniza-
tion, we presumed that cyanoethylation of a compound
already containing lactone ring would improve the
selectivity. By alkaline hydrolysis of fusidic acid (1)
we obtained lactone 4 in 95% yield. In fact, the cyano-
ethylation of 4 was characterized by complete con-
version and high chemoselectivity. After purification
1
1
6-H signal (δ 4.96 ppm, d.d) in the H NMR spectra
relative to the corresponding signal of 1, as well as by
the disappearance of signal at δ 1.98 ppm due to
1
6
acetoxy group. In addition, downfield shift of the C
2
1
13
and C signals in the C NMR spectra was observed.
The presence of cyano groups in molecules 2 and 3
followed from the HMBC spectra which displayed
Scheme 2.
Me
Me
HO
Me
O
(
(
1) NaOH–EtOH
2) HCl
H C=CHCN
KOH, dioxane
2
O
1
2
Me
Me
HO
Me
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS AND BIOLOGICAL ACTIVITY OF CYANOETHYL DERIVATIVES
1413
Scheme 3.
Me
Me
Me
Me
HO
Me
COOMe
OAc
COOMe
O
MeI, K CO
H C=CHCN
KOH, dioxane
2
3
2
NC
O
Me CO
2
Me
Me
Me
OAc
1
Me
Me
NC
HO
Me
Me
5
6
Me
Me
Me
Me
HO
Me
COOMe
COOMe
OAc
O
NC
HO
+
Me
OAc
+
Me
Me
Me
Me
NC
O
Me
Me
7
8
by column chromatography, we isolated compound 2
in 90% yield (Scheme 2).
Complete conversion was also achieved in the
cyanomethylation of methyl ester 5 obtained by
alkylation of 1 with methyl iodide in acetone (yield
118.43 ppm, respectively, and the 3-H and 11-H
signals were located in a stronger field relative to those
of initial compound 5 (δ 3.26 and 3.78 ppm, respec-
tively). In the HMBC spectra of 6–8 we observed
cross-peaks between protons of the cyanoethyl group
3
11
and C or/and C , as in the spectra of 2 and 3.
9
7%), but the chemoselectivity was low. Apart from
ester 6 (60%), monosubstituted derivatives at position
or 11 (compounds 7 and 8) were formed (Scheme 3).
The oxidation of methyl ester 5 with chromium(VI)
oxide gave 3,11-dioxo derivative 9 which reacted with
acrylonitrile to afford 85% of 2,2-bis(2-cyanoethyl)
3
We failed to direct the reaction toward selective
formation of one of these products by varying the
amount of acrylonitrile, solvent nature, temperature, or
reaction time.
1
3
derivative 10 (Scheme 4). The C NMR spectrum of
0 showed two signals at δ 118.60 and 119.40 ppm
1
C
2
due to carbon atoms of the cyano groups. The C atom
1
3
The C NMR spectrum of 6 contained two CN
in 10 became quaternary, so that its signal shifted
signals at at δ 118.23 and 118.66 ppm, as well as
downfield (δ 49.71 ppm) relative to the corresponding
signal of initial compound 9. The signals of C and C
C
C
4
12
signals at δ 63.76 and 19.30 ppm belonging to methy-
C
lene carbon atoms of the cyanoethyl substituents. The
C NMR spectra of monosubstituted derivatives 7
and protons attached thereto almost did not change
their position, indicating that these centers were not
involved in the reaction.
1
3
and 8 showed only one CN signal at δ 118.39 and
C
Scheme 4.
Me
Me
Me
Me
O
COOMe
OAc
COOMe
OAc
O
H C=CHCN
KOH, dioxane
NC
2
CrO –AcOH
3
Me
Me
Me
Me
5
Me
Me
NC
O
O
Me
Me
9
10
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

1
414
SALIMOVA et al.
Table 1. Primary evaluation of compounds 1–10 for antimicrobial activity (microorganism growth inhibition percentage)
Compound Staphylococcus Escherichia
Klebsiella
pneumoniae
Pseudomonas Acinetobacter
Candida
albicans
Cryptococcus
neoformans
no.
aureus
coli
aeruginosa
baumannii
0
0
0
0
0
0
0
0
0
1
1
2
3
4
5
6
7
8
9
0
97.86
–0.42
1.30
16.49
–13.03
–40.0
21.12
21.26
–17.67
–3.75
–4.06
14.59
–0.53
14.15
–0.10
7.12
22.72
14.85
11.29
24.06
19.11
6.09
45.16
17.87
21.56
25.95
16.32
–0.03
26.42
220.0
10.53
3.24
4.42
3.18
2.82
5.98
5.54
6.21
4.94
2.09
4.73
3.39
2.11
–23.11
–34.66
–44.20
–18.50
–25.03
–26.07
–27.85
–26.69
–18.37
48.64
27.78
0.40
–1.07
5.88
–3.24
14.59
18.38
2.38
5.55
10.78
14.08
23.41
9.25
12.65
13.50
3.99
–17.21
All compounds synthesized in this work were tested
for antimicrobial and antifungal activities in vitro
against Escherichia coli, Klebsiella pneumoniae,
Acinetobacter baumannii, Pseudomonas aeruginosa,
Staphylococcus aureus, Streptococcus oralis, Strepto-
coccus sobrinus, Candida albicans, and Cryptococcus
neoformans. The primary screening for antimicrobial
activity was performed at the Institute for Molecular
Bioscience (University of Queensland, Australia) by
evaluating growth inhibition of five bacterial strains
dard pulse sequences. The melting points were meas-
ured on a Stuart SMP3 melting point apparatus. The
optical rotations were measured with a Perkin Elmer
341 polarimeter. The mass spectra (MALDITOF/TOF)
were obtained on a Bruker Autoflex TM III Smart
beam mass spectrometer using 3-(4-hydroxy-3,5-dime-
thoxyphenyl)prop-2-enoic (sinapinic) acid as matrix.
Sorbfil plates (Sorbpolimer closed corporation, Russia)
were used for analytical TLC; eluent hexane–ethyl
acetate (4:1); spots were detected by treatment with
10% sulfuric acid, followed by heating for 2–3 min at
100–120°C. Column chromatography was performed
on silica gel (grain size 50–160 μm; Sorbpolimer).
(
Escherichia coli, Klebsiella pneumoniae, Acineto-
bacter baumannii, Pseudomonas aeruginosa, and
Staphylococcus aureus) and two fungal strains
(
(
Candida albicans and Cryptococcus neoformans)
Table 1). The concentration of 1–10 was 32 μg/mL.
Compounds 2, 3, 6–8, and 10 (general procedure).
A mixture of 1 mmol of fusidic acid (1), lactone 4,
methyl ester 5, or methyl ester 9, 8 mL (122 mmol) of
acrylonitrile, 0.3 mL of 40% aqueous potassium hy-
droxide, and 0.1 g (0.44 mmol) of benzyl(triethyl)-
ammonium chloride in 15 mL of dioxane was stirred
for 4 h at room temperature. The mixture was poured
into a mixture of 100 g of ice and 5 mL of concen-
trated aqueous HCl, the precipitate was filtered off and
washed with water until neutral washings, dried in air,
and extracted with chloroform (3×30 mL) on heating.
The combined extracts were evaporated under reduced
pressure, and the residue was subjected to silica gel
column chromatography using hexane–EtOAc (40:1)
as eluent to isolate compounds 2, 3, and 10 or CHCl3–
MeCN (15:1) to isolate compounds 6–8.
All tests were carried out in duplicate. Compound was
believed to be active if the inhibition percentage was
equal to or higher than 80% in at least one test.
The results showed that cyanoethyl derivatives 2, 3,
–8, and 10 possess no antibacterial activity; more-
6
over, in some cases, they favored bacterial growth. The
transformation of carboxy group to ester or lactone
ring leads to reduction of antibacterial activity, which
is consistent with published data [14], and introduction
of a cyanoethyl fragment does not increase the activity.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on
a Bruker Avance 400 spectrometer at 400.13 and
1
5
tively, using standard 5-mm NMR ampules. One- and
two-dimensional NMR experiments (COSY, HSQC,
HMBC, NOESY) were carried out according to stan-
3,3′-{[(1S,2R,4aS,5R,9aS,10aS,10bS)-1,4a,10a,10b-
Tetramethyl-7-(4-methylpent-3-en-1-yl)-8-oxo-
2,3,4,4a,4b,5,6,6a,8,9a,10,10a,10b,11,12,12a-hexa-
decahydro-1H-naphtho[2′,1′:4,5]indeno[2,1-b]-
furan-2,5-diyl]bis(oxy)}dipropanenitrile (2). Yield
00.62 MHz, respectively, and on a Bruker Ascend
00 instrument at 500.17 and 125.78 MHz, respec-
2
0
0.28 g (50%), white crystals, mp 60–62°C, [α]D
=
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS AND BIOLOGICAL ACTIVITY OF CYANOETHYL DERIVATIVES
1415
1
3
13
+
40.3° (c = 0.782, CHCl ). H NMR spectrum
11.0 Hz), 5.10 t (1H, 24-H, J = 5.7 Hz). C NMR
3
28
27
(
CDCl ), δ, ppm: 0.80 s (3H, 18-H), 0.92 d (3H, 28-H,
J = 6.5 Hz), 0.95 s (3H, 19-H), 1.04–1.13 m (1H,
-H), 1.13–1.19 m (1H, 7-H) 1.21 d.d (1H, 15-H, J =
.3, J = 14.8 Hz), 1.22–1.30 m (1H, 1-H), 1.45 s (3H,
spectrum (CDCl ), δ , ppm: 15.98 (C ), 17.78 (C ),
3 C
19.40 (C ), 19.99 (C ), 20.90 (C ), 23.10 (C ), 23.35
(C ), 24.00 (C ), 25.34 (C ), 25.67 (C ), 27.40 (C ),
30.51 (C ), 31.67 (C ), 31.59 (C ), 34.02 (C ), 36.43
3
3
32
18
6
30
3
19
22
2
26
23
6
4
3
1
1
1
2
2
2
2
3
3
(
(
1
5
(
(
2
(
3
(
(
(
2
1
7
12
15
5
4
10
13
8
0-H), 1.48–1.59 m (1H, 4-H), 1.49–1.53 m (1H, 9-H),
.52–1.63 m (3H, 2-H, 7-H, 12-H), 1.61 s (3H, 27-H),
.64–1.72 m (1H, 6-H), 1.69 s (3H, 26-H), 1.83–
.90 m (1H, 2-H), 2.14–2.23 m (1H, 5-H), 2.18–
.24 m (2H, 23-H), 2.19–2.22 m (1H, 22-H), 2.21–
.31 m (1H, 1-H), 2.23–2.34 m (1H, 15-H), 2.24–
.30 m (1H, 12-H), 2.32–2.39 m (1H, 22-H), 2.57–
.66 m (2H, 35-H), 2.65–2.75 m (2H, 32-H), 3.27–
.29 m (1H, 3-H), 3.39–3.46 m (1H, 13-H), 3.40–
.47 m (1H, 31-H), 3.45–3.50 m (1H, 34-H), 3.66 t.d
(C ), 36.59 (C ), 36.91 (C ), 38.12 (C ), 40.76 (C ),
9
14
31
11
50.41 (C ), 55.17 (C ), 63.32 (C ), 67.79 (C ), 79.64
3
16
33
24
(C ), 81.90 (C ), 118.56 (C ), 123.30 (C ), 132.73
2
5
20
17
21
(C ), 133.47 (C ), 170.18 (C ), 176.67 (C ). Mass
spectrum, m/z (I , %): 532 (40.9) [M + Na] , 548
+
rel
+
(100) [M + K] .
Methyl (2Z)-2-[16β-acetoxy-3α,11α-bis(2-cy-
anoethoxy)-4α,8α,10β,14β-tetramethylgonan-17-
ylidene]-6-methylhept-5-enoate (6). Yield 0.38 g
60%), white crystals, mp 70–72°C, [α] = –17.8° (c =
.469, CHCl ). H NMR spectrum (CDCl ), δ, ppm:
3 3
.87 s (3H, 18-H), 0.88 d (3H, 28-H, J = 5.2 Hz),
.92 s (3H, 19-H), 0.95–1.09 m (1H, 6-H), 1.05–
1.16 m (1H, 7-H), 1.19–1.29 m (2H, 1-H, 15-H), 1.27 s
3H, 30-H), 1.47–1.56 m (1H, 4-H), 1.49–1.55 m (1H,
-H), 1.50–1.60 m (1H, 2-H), 1.51–1.61 m (1H, 12-H),
.54–1.67 m (1H, 6-H), 1.57 s (3H, 27-H), 1.58–
.68 m (1H, 7-H), 1.65 s (3H, 26-H), 1.79–1.89 m (1H,
-H), 1.94 s (3H, 32-H), 1.98–2.13 m (2H, 23-H),
.12–2.24 m (3H, 1-H, 5-H, 15-H), 2.34–2.52 m (2H,
2-H), 2.41–2.50 m (1H, 12-H), 2.50–2.65 m (4H,
5-H, 38-H), 2.89 d (1H, 13-H, J = 12.0 Hz), 3.23–
3.28 m (1H, 3-H), 3.34–3.41 m (1H, 34-H), 3.40–
.47 m (1H, 37-H), 3.58–3.66 m (1H, 34-H), 3.61 s
2
0
(
D
3
2
3
1
1H, 31-H, J = 4.8, J = J = 8.1 Hz), 3.72–3.78 m
1H, 34-H), 3.82–3.85 m (1H, 11-H), 4.95 d.d (1H,
6-H, J = 4.3, J = 11.0 Hz), 5.12 t (1H, 24-H, J =
1
0
0
3
3
2
3
13
.8 Hz). C NMR spectrum (CDCl ), δ , ppm: 15.92
3
C
2
8
27
32
35
18
C ), 17.90 (C ), 19.40 (C , C ), 19.89 (C ), 21.18
(
6
30
19
22
12
C ), 22.34 (C ), 23.88 (C ), 24.10 (C ), 25.37 (C ),
9
1
1
2
2
2
3
2
26
23
1
5.43 (C ), 25.73 (C ), 27.31 (C ), 29.60 (C ), 30.94
7
15
5
10
4
C ), 33.97 (C ), 35.84 (C ), 36.71 (C ), 37.04 (C ),
1
3
8
9
14
8.33 (C ), 40.79 (C ), 50.91 (C ), 55.11 (C ), 62.72
3
1
34
11
3
C ), 63.86 (C ), 75.90 (C ), 79.91 (C ), 81.84
C ), 118.41 (C ), 118.70 (C ), 123.29 (C ), 123.37
C ), 132.77 (C ), 169.70 (C ), 176.53 (C ). Mass
spectrum, m/z (I , %): 585 (60.6) [M + Na] , 601
1
6
33
36
24
2
0
25
17
21
3
+
rel
+
(
100) [M + K] .
3
(
(
1
3H, 33-H), 3.67–3.75 m (1H, 37-H), 3.76–3.79 m
3
-{[(1S,2R,4aS,5R,9aS,10aS,10bS)-5-Hydroxy-
3
1H, 11-H), 5.05 t (1H, 24-H, J = 6.5 Hz), 5.81 d (1H,
1
8
,4a,10a,10b-tetramethyl-7-(4-methylpent-3-en-1-yl)-
-oxo-2,3,4,4a,4b,5,6,6a,8,9a,10,10a,10b,1,12,12a-
hexadecahydro-1H-naphtho[2′,1′:4,5]indeno[2,1-b]-
furan-2-yl]oxy}propanenitrile (3). Yield 0.21 g
40%), white crystals, mp 58–60°C, [α] = +25.7° (c =
.326, CHCl ). H NMR spectrum (CDCl ), δ, ppm:
3 3
3
13
6-H, J = 8.3 Hz). C NMR spectrum (CDCl ), δ ,
3 C
2
8
18
27
38
ppm: 15.88 (C ), 17.75 (C , S ), 19.30 (C ), 19.33
(
2
(
3
(
7
1
(
3
5
6
32
30
19
C ), 20.90 (C ), 20.94 (C ), 23.24 (C ), 23.42 (C ),
2
26
23
22
2
0
5.41 (C ), 25.74 (C ), 28.27 (C ), 28.98 (C ), 29.02
(
D
1
2
1
7
5
10
1
C ), 29.75 (C ), 31.52 (C ), 35.90 (C ), 36.50 (C ),
0
0
0
1
1
1
1
2
1
2
2
2
2
3
4
15
8
13
3
6.65 (C ), 38.92 (C ), 39.42 (C ), 44.03 (C ), 48.51
.80 s (3H, 18-H), 0.93 d (3H, 28-H, J = 6.5 Hz),
.96 s (3H, 19-H), 1.02–1.15 m (1H, 6-H), 1.11–
1
4
9
33
34
37
C ), 49.69 (C ), 51.39 (C ), 62.86 (C ), 63.76 (C ),
1
6
11
3
36
3
2
4.35 (C ), 76.33 (C ), 79.97 (C ), 118.23 (C ),
.18 m (1H, 7-H), 1.21 d.d (1H, 15-H, J = 4.4, J =
4.5 Hz), 1.45–1.51 m (1H, 9-H), 1.46–1.54 m (1H,
-H), 1.49 s (3H, 30-H), 1.50–1.61 m (1H, 4-H), 1.52–
.66 m (1H, 2-H), 1.58–1.72 m (1H, 6-H), 1.59 s (3H,
7-H), 1.60–1.67 m (1H, 7-H), 1.67 s (3H, 26-H),
.76–1.86 m (1H, 12-H), 1.85–1.92 m (1H, 2-H),
.08 d.t (1H, 12-H, J = 2.6, J = 13.6 Hz), 2.11–
.20 m (1H, 1-H), 2.09–2.19 m (1H, 5-H), 2.16–
.24 m (2H, 23-H), 2.20–2.40 m (2H, 22-H), 2.22–
.32 m (1H, 15-H), 2.56–2.71 m (2H, 32-H), 3.30–
3
9
24
20
18.66 (C ), 122.89 (C ), 130.16 (C ), 132.64
2
5
17
21
31
C ), 148.24 (C ), 170.23 (C ), 170.62 (C ). Mass
+
spectrum, m/z (I , %): 659 (51.6) [M + Na] , 675
(
rel
+
100) [M + K] .
Methyl (2Z)-2-[16β-acetoxy-3α-(2-cyanoethoxy)-
3
2
11α-hydroxy-4α,8α,10β,14β-tetramethylgonan-17-
ylidene]-6-methylhept-5-enoate (7). Yield 0.06 g
(15%), white crystals, mp 64–66°C, [α] = –9.2° (c =
2
0
D
1
0.578, CHCl ). H NMR spectrum (CDCl ), δ, ppm:
3
3
3
.36 m (1H, 3-H), 3.44–3.52 m (1H, 31-H), 3.52 d.d
1H, 13-H, J = 2.6, 13.6 Hz), 3.71–3.79 m (1H, 31-H),
.33–4.39 m (1H, 11-H), 4.94 d.d (1H, 16-H, J = 4.4,
0.92 s (3H, 18-H), 0.94 d (3H, 28-H, J = 6.8 Hz),
0.99 s (3H, 19-H), 1.01–1.10 m (1H, 6-H), 1.10–
1.18 m (1H, 7-H), 1.23–1.31 m (1H, 15-H), 1.38 s (3H,
3
(
4
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

1
416
SALIMOVA et al.
3
4
3
16
11
3
1
1
7
1
2
0-H), 1.47–1.54 m (1H, 1-H), 1.54–1.57 m (1H, 9-H),
.55–1.67 m (2H, 4-H, 6-H), 1.61 s (3H, 27-H), 1.62–
.69 m (1H, 2-H), 1.69 s (3H, 26-H), 1.71–1.79 m (1H,
-H), 1.79–1.89 m (1H, 12-H), 1.85–1.93 m (1H, 2-H),
.99 s (3H, 32-H), 2.00–2.08 m (1H, 23-H), 2.06–
.15 m (1H, 1-H), 2.11–2.19 m (1H, 23-H), 2.13–
(C ), 71.29 (C ), 74.34 (C ), 76.77 (C ), 118.43
3
6
24
20
25
(C ), 122.89 (C ), 130.25 (C ), 132.72 (C ), 148.03
1
7
21
31
(C ), 170.27 (C ), 170.67 (C ). Mass spectrum, m/z
+
+
(I , %): 606 (9.1) [M + Na] , 622 (100) [M + K] .
rel
Methyl (2Z)-2-[16β-acetoxy-2,2-bis(2-cyano-
ethyl)-4α,8α,10β,14β-tetramethyl-3,11-dioxogonan-
7-ylidene]-6-methylhept-5-enoate (10). Yield 0.54 g
85%), white crystals, mp 110–112°C, [α] = +46.2°
c = 1.082, CHCl ). H NMR spectrum (CDCl ), δ,
ppm: 0.83 s (3H, 19-H), 1.04–1.16 m (1H, 6-H), 1.20 s
3H, 18-H), 1.21 d (3H, 28-H, J = 6.4 Hz), 1.22–
.36 m (1H, 7-H), 1.23 s (3H, 30-H), 1.46 d (1H,
5-H, J = 14.3 Hz), 1.52–1.60 m (1H, 6-H), 1.59–
1.70 m (1H, 34-H), 1.62 s (3H, 27-H), 1.69 s (3H,
6-H), 1.91 d (1H, 1-H, J = 14.6 Hz), 1.94–2.04 m
1H, 37-H), 1.95–2.12 m (2H, 23-H), 1.99–2.07 m
1H, 34-H), 1.99–2.07 m (2H, 35-H), 2.03 s (3H,
2-H), 2.05–2.13 m (1H, 7-H), 2.06–2.18 m (1H, 5-H),
.08–2.16 m (1H, 37-H), 2.11–2.20 m (1H, 4-H),
.22 d.d (1H, 15-H, J = 8.9, J = 14.3 Hz), 2.24–
.41 m (2H, 38-H), 2.31–2.47 m (2H, 22-H), 2.56–
.59 m (1H, 9-H), 2.70 d.d (1H, 12-H, J = 12.8, J =
14.6 Hz), 2.86–2.92 m (1H, 13-H), 2.89 d (1H, 1-H,
2
2
.22 m (2H, 5-H, 15-H), 2.33 d.t (1H, 12-H, J = 3.1,
1
3
2
0
J = 13.1 Hz), 2.39–2.55 m (2H, 22-H), 2.56–2.66 m
(
(
D
3
1
(
2H, 35-H), 3.05 d (1H, 13-H, J = 11.2 Hz), 3.32–
3
3
3
3
.37 m (1H, 3-H), 3.50 d.t (1H, 34-H, J = 6.5,
2
3
J = 9.2 Hz), 3.66 s (3H, 33-H), 3.77 d.t (1H, 34-H,
J = 6.5, J = 9.2 Hz), 4.31–4.36 m (1H, 11-H), 5.10 t
(
3
2
1
1
3
3
2
(
1H, 24-H, J = 6.6 Hz), 5.86 d (1H, 16-H, J =
13
8
.4 Hz). C NMR spectrum (CDCl ), δ , ppm: 15.98
3 C
2
8
27
18
35
6
2
(
C ), 17.76 (C ), 17.82 (C ), 19.35 (C ), 20.69 (C ),
2
3
2
19
30
2
2
0.99 (C ), 22.86 (C ), 24.07 (C ), 25.49 (C ), 25.74
(
(
2
6
23
22
1
7
(
C ), 28.28 (C ), 28.92 (C ), 30.65 (C ), 32.40 (C ),
1
2
4
5
10
3
5.49 (C ), 36.21 (C ), 36.67 (C ), 36.84 (C ), 39.04
3
2
2
2
2
1
5
8
13
14
9
(
C ), 39.40 (C ), 43.90 (C ), 48.68 (C ), 49.23 (C ),
3
3
34
11
16
3
2
5
1.41 (C ), 63.51 (C ), 68.28 (C ), 74.43 (C ), 79.91
3
36
24
20
(
(
C ), 118.39 (C ), 123.05 (C ), 130.39 (C ), 132.58
C ), 148.18 (C ), 170.41 (C ), 170.78 (C ).
2
5
17
21
31
3
2
+
Mass spectrum, m/z (I , %): 606 (9.1) [M + Na] , 622
rel
+
2
3
2
(
100) [M + K] .
J = 14.6 Hz), 2.95 d.d (1H, 12-H, J = 4.6, J =
4.6 Hz), 3.69 s (3H, 33-H), 5.08 t (1H, 24-H, J =
.1 Hz), 5.92 d (1H, 16-H, J = 8.2 Hz). C NMR
spectrum (CDCl ), δ , ppm: 12.53 (C ), 12.38 (C ),
3
1
7
Methyl (2Z)-2-[16β-acetoxy-11α-(2-cyano-
3
13
ethoxy)-3α-hydroxy-4α,8α,10β,14β-tetramethyl-
gonan-17-ylidene]-6-methylhept-5-enoate (8). Yield
0
–
3
8
35
3
C
2
8
18
27
32
2
0
1
2
(
3
(
6.87 (C ), 17.39 (C ), 17.74 (C ), 20.90 (C ),
.12 g (20%), white crystals, mp 64–66°C, [α]
=
D
6
30
19
26
1
1.12 (C ), 24.43 (C ), 23.38 (C ), 25.74 (C ), 27.79
8.7° (c = 0.334, CHCl ). H NMR spectrum (CDCl ),
3
3
2
3
22
34
7
37
3
C ), 29.03 (C ), 31.98 (C ), 33.13 (C ), 36.41 (C ),
δ, ppm: 0.93 s (3H, 18-H), 0.94 d (3H, 28-H, J =
1
5
10
8
1
8.05 (C ), 36.41 (C ), 40.88 (C ), 42.78 (C ), 43.42
6
1
1
1
1
2
1
2
2
2
6
3
3
3
5
.7 Hz), 0.98 s (3H, 19-H), 1.05–1.20 m (1H, 6-H),
.10–1.21 m (1H, 7-H), 1.22–1.32 m (1H, 15-H),
.24–1.35 m (1H, 1-H), 1.33 s (3H, 30-H), 1.47–
.61 m (1H, 4-H), 1.56–1.68 m (1H, 12-H), 1.57–
.61 m (1H, 9-H), 1.60–1.72 m (1H, 6-H), 1.61 s (3H,
7-H), 1.63–1.72 m (1H, 7-H), 1.69 s (3H, 26-H),
.69–1.92 m (2H, 2-H), 1.99 s (3H, 32-H), 2.03–
.20 m (2H, 23-H), 2.12–2.24 m (1H, 5-H), 2.14–
.32 m (1H, 15-H), 2.21–2.33 m (1H, 1-H), 2.37–
5
12
4
13
14
C ), 44.32 (C ), 44.71 (C ), 46.35 (C ), 48.71 (C ),
2
33
9
16
4
9.71 (C ), 51.61 (C ), 57.75 (C ), 73.99 (C ), 118.60
3
9
36
24
20
(
(
(
(
C ), 119.40 (C ), 122.46 (C ), 132.10 (C ), 133.19
2
5
17
31
21
C ), 144.88 (C ), 169.87 (C ), 170.17 (C ), 209.63
11
3
C ), 216.24 (C ). Mass spectrum, m/z (I , %): 655
rel
+
+
100) [M + Na] , 671 (61) [M + K] .
(1S,2R,4aS,5R,9aS,10aS,10bS)-2,5-Dihydroxy-
1,4a,10a,10b-tetramethyl-7-(4-methylpent-3-en-1-
yl)-1,2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12,12a-
hexadecahydro-8H-naphtho[2′,1′:4,5]indeno[2,1-b]-
furan-8-one (4). A 0.1 N solution of sodium hydroxide
in ethanol, 44 mL, was added dropwise to a solution of
1 g (1.92 mmol) of fusidic acid (1) in 10 mL of
ethanol. The mixture was stirred for 3 h at room tem-
perature and neutralized with 2 N aqueous HCl
(20 mL). Ethanol was distilled off under reduced pres-
sure, and the residue was extracted with chloroform.
3
.56 m (3H, 12-H, 22-H), 2.59 t (2H, 35-H, J =
3
.0 Hz). 2.93 d (1H, 13-H, J = 11.7 Hz), 3.40 d.t (1H,
3
2
4-H, J = 6.8, J = 8.0 Hz), 3.65 s (3H, 33-H), 3.67–
.75 m (1H, 34-H), 3.69–3.76 m (1H, 3-H), 3.82–
3
.87 m (1H, 11-H), 5.09 t (1H, 24-H, J = 6.8 Hz),
3
13
.85 d (1H, 16-H, J = 8.5 Hz). C NMR spectrum
2
8
18
(CDCl ), δ , ppm: 15.85 (C ), 17.58 (C ), 17.78
3 C
2
7
35
32
6
30
(
C ), 19.52 (C ), 20.97 (C ), 21.05 (C ), 23.24 (C ),
1
9
26
23
22
2
2
3.51 (C ), 25.76 (C ), 28.30 (C ), 29.02 (C ),
1
2
1
2
7
9.14 (C ), 29.33 (C ), 29.88 (C ), 31.36 (C ), 35.36
The organic extract was dried over CaCl and evapo-
rated, and the residue was dried under reduced pres-
sure. Yield 0.84 g (95%), white crystals, mp 112°C,
2
5
10
4
15
8
(
C ), 36.69 (C ), 36.97 (C ), 38.94 (C ), 39.59 (C ),
1
3
14
9
33
4
4.06 (C ), 48.55 (C ), 49.76 (C ), 51.44 (C ), 62.99
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS AND BIOLOGICAL ACTIVITY OF CYANOETHYL DERIVATIVES
1417
2
0
1
28
18
[
α] = +31.1° (c = 0.65, CHCl ). H NMR spectrum
spectrum (CDCl ), δ , ppm: 15.95 (C ), 17.74 (C ),
D
3
3
C
6
2
7
32
19
(
CDCl ), δ, ppm: 0.79 s (3H, 18-H), 0.92 d (3H, 28-H,
J = 6.7 Hz), 0.96 s (3H, 19-H), 1.06–1.18 m (2H, 6-H,
17.75 (C ), 20.84 (C ), 20.99 (C ), 22.94 (C ), 23.99
3
3
30
26
23
22
2
(C ), 25.73 (C ), 28.33 (C ), 28.93 (C ), 29.92 (C ),
3
2
1
7
12
5
7
1
1
7
(
1
-H), 1.21 d.d (1H, 15-H, J = 4.1, J = 14.6 Hz), 1.46–
.52 m (1H, 1-H), 1.47–1.58 m (1H, 4-H), 1.48–
.52 m (1H, 9-H), 1.50 s (3H, 30-H), 1.54–1.67 m (1H,
-H), 1.58 s (3H, 27-H), 1.60–1.72 m (1H, 6-H), 1.66 s
3H, 26-H), 1.68–1.88 m (2H, 2-H), 1.74–1.87 m (1H,
2-H), 2.03–2.14 m (2H, 12-H, 5-H), 2.13–2.23 m
2H, 22-H), 2.17–2.42 m (2H, 23-H), 2.18–2.26 m
1H, 1-H), 2.21–2.32 m (1H, 15-H), 3.54 d (1H, 13-H,
J = 11.4 Hz), 3.70–3.74 m (1H, 3-H), 4.36–4.39 m
30.18 (C ), 32.22 (C ), 35.53 (C ), 36.00 (C ), 36.35
4
10
15
8
13
(C ), 36.96 (C ), 39.03 (C ), 39.50 (C ), 43.91 (C ),
14
9
33
11
48.67 (C ), 49.26 (C ), 51.39 (C ), 68.24 (C ), 71.39
(C ), 74.41 (C ), 123.06 (C ), 130.35 (C ), 132.56
(C ), 148.17 (C ), 170.40 (C ), 170.76 (C ). Mass
spectrum, m/z (I , %): 553 (18.3) [M + Na] , 569
3
16
24
20
2
5
17
21
31
+
rel
+
(
(100) [M + K] .
(
Methyl (2Z)-2-(16β-acetoxy-4α,8α,10β,14β-
tetramethyl-3,11-dioxogonan-17-ylidene)-6-methyl-
hept-5-enoate (9). Chromium(VI) oxide, 0.6 g, was
added to a solution of 1 g (1.88 mmol) of methyl ester
5 in 20 mL of acetic acid. The mixture was stirred for
0 min at room temperature, poured into water, and
extracted with ethyl acetate. The extract was washed
with water and dried over CaCl , and the solvent was
distilled off under reduced pressure. Yield 0.94 g
95%), white crystals, mp 148–150°C, [α] = +74.0°
c = 1.62, CHCl ). H NMR spectrum (CDCl ), δ,
ppm: 1.05 d (3H, 28-H, J = 6.3 Hz), 1.06 s (3H,
9-H), 1.09–1.20 m (1H, 6-H), 1.15 s (3H, 30-H),
.17–1.27 m (1H, 7-H), 1.19 s (3H, 18-H), 1.42 d (1H,
3
3
(
5
(
(
2
(
3
(
(
(
[
1H, 11-H), 4.94 d.d (1H, 16-H, J = 4.1, 10.8 Hz),
.10 t (1H, 24-H, J = 5.7 Hz). C NMR spectrum
3
13
2
8
27
CDCl ), δ , ppm: 16.03 (C ), 17.78 (C ), 19.84
3 C
1
8
6
30
19
23
C ), 21.21 (C ), 22.76 (C ), 23.70 (C ), 24.01 (C ),
3
2
6
22
2
1
5.68 (C ), 27.46 (C ), 29.79 (C ), 29.89 (C ), 31.18
7
12
15
5
10
C ), 31.65 (C ), 33.97 (C ), 35.54 (C ), 36.87 (C ),
2
4
13
8
9
6.96 (C ), 38.20 (C ), 40.83 (C ), 50.51 (C ), 55.19
1
4
11
3
16
2
0
C ), 67.74 (C ), 71.33 (C ), 81.92 (C ), 123.31
(
(
D
2
4
20
25
17
1
C ), 123.39 (C ), 132.71 (C ), 170.23 (C ), 176.72
3
3
2
1
3
C ). Mass spectrum, m/z (I , %): 479 (70.8)
rel
+
+
M + Na] , 495 (100) [M + K] .
1
1
1
Methyl (2Z)-2-(16β-acetoxy-3α,11α-dihydroxy-
α,8α,10β,14β-tetramethylgonan-17-ylidene)-
-methylhept-5-enoate (5). Methyl iodide, 0.38 mL
2
5-H, J = 14.3 Hz), 1.52–1.62 m (1H, 6-H), 1.59 s
3H, 27-H), 1.66 s (3H, 26-H), 1.81 t (1H, 5-H, J =
4
6
3
(
1
2
2
2
2
2
2
2
2.0 Hz), 1.94–2.03 m (1H, 2-H), 1.95–2.12 m (2H,
3-H), 2.01 s (3H, 32-H), 2.00–2.08 m (1H, 7-H),
.13–2.27 m (2H, 4-H, 15-H), 2.31–2.45 m (2H,
2-H), 2.34–2.44 m (1H, 1-H), 2.46–2.55 m (1H, 1-H),
.59–2.62 m (1H, 9-H), 2.63–2.74 m (1H, 12-H),
.70–2.79 m (1H, 2-H), 2.84–2.94 m (1H, 13-H),
.85–2.95 m (1H, 12-H), 3.66 s (3H, 33-H), 5.06 t (1H,
(
6.1 mmol), was added to a mixture of 1 g (1.92 mmol)
of fusidic acid (1) and 0.19 g (1.37 mmol) of freshly
calcined potassium carbonate in 35 mL of anhydrous
acetone. The mixture was refluxed for 2 h and cooled,
the solvent was distilled off under reduced pressure,
the residue was dissolved in chloroform, the precipitate
of K CO was filtered off, the filtrate was evaporated,
and the residue was dried under reduced pressure.
Yield 0.99 g (97%), white crystals, mp 152°C, [α] =
–
2
3
3
3
4-H, J = 7.0 Hz), 5.89 d (1H, 16-H, J = 8.4 Hz).
1
3
28
2
0
C NMR spectrum (CDCl ), δ , ppm: 14.05 (C ),
3
C
D
1
8
27
32
6
1
1
6.92 (C ), 17.71 (C ), 20.90 (C ), 21.18 (C ), 22.45
10.0° (c = 0.93, CHCl ). H NMR spectrum (CDCl ),
3
3
1
9
30
26
23
3
(
C ), 23.94 (C ), 25.70 (C ), 27.83 (C ), 28.95
δ, ppm: 0.91 s (3H, 18-H), 0.92 d (3H, 28-H, J =
2
2
2
7
10
1
(
C ), 32.38 (C ), 33.32 (C ), 36.57 (C ), 36.70 (C ),
6
1
1
1
1
.7 Hz), 0.98 s (3H, 19-H), 1.05–1.15 m (1H, 6-H),
1
5
8
12
4
2
3
8.12 (C ), 40.75 (C ), 44.40 (C ), 44.77 (C ), 46.22
.10–1.19 m (1H, 7-H), 1.27 d (1H, 15-H, J =
5
13
14
33
9
(
C ), 46.63 (C ), 48.63 (C ), 51.54 (C ), 58.25 (C ),
4.1 Hz), 1.38 s (3H, 30-H), 1.48–1.54 m (1H, 1-H),
.54–1.66 m (2H, 4-H, 6-H), 1.56–1.58 m (1H, 9-H),
.60 s (3H, 27-H), 1.67 s (3H, 26-H), 1.68–1.79 m
1
6
24
20
25
7
1
2
4.08 (C ), 122.54 (C ), 131.82 (C ), 133.05 (C ),
1
7
31
21
11
45.22 (C ), 169.94 (C ), 170.16 (C ), 209.62 (C ),
3
15.58 (C ). Mass spectrum, m/z (I , %): 549 (100)
(
1H, 7-H), 1.72–1.78 m (1H, 2-H), 1.79–1.89 m (1H,
rel
+
+
[
M + Na] , 565 (97.9) [M + K] .
1
2
2
2-H), 1.82–1.91 m (1H, 2-H), 1.96–2.08 m (1H,
3-H), 1.98 s (3H, 32-H), 2.07–2.16 m (1H, 5-H),
.09–2.20 m (1H, 23-H), 2.13–2.22 m (1H, 15-H),
Evaluation of antibacterial activity. The antibac-
terial activity of compounds 1–10 was assayed by the
serial dilution method at the Institute for Molecular
Bioscience (University of Queensland, Australia).
Samples were prepared by dissolution in DMSO to
a concentration of 32 μg/mL. All bacterial cultures
were grown overnight on Müller Hinton agar at 37°C.
3
2
.15–2.21 m (1H, 1-H), 2.32 d.t (1H, 12-H, J = 3.1,
2
J = 12.9 Hz), 2.37–2.53 m (2H, 22-H), 3.04 d (1H,
3
1
(
3-H, J = 11.2 Hz), 3.64 s (3H, 33-H), 3.73–3.77 m
1H, 3-H), 4.33–4.37 m (1H, 11-H), 5.09 t (1H, 24-H,
3
3
13
J = 7.2 Hz), 5.85 d (1H, 16-H, J = 8.6 Hz). C NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

1
418
SALIMOVA et al.
A sample of each bacterial culture was then diluted by
a factor of 40, incubated for 1.5–3 h at 37°C, and
added to wells of a 384-well microplate, containing
for Antimicrobial Drug Discovery under financial
support by the Welcome Trust (United Kingdom) and
University of Queensland (Australia), as well as by the
Bashkir State Medical University.
a DMSO solution of compound 1–10 (concentration
5
5
×10 CFU/mL, overall volume 50 μL). All micro-
plates were covered and incubated for 18 h at 37°C
without shaking. Bacterial growth inhibition was
evaluated by measuring the absorbance at λ 600 nm
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1
2
. Anderson, A.C., Pollastri, M.P., Schiffer, C.A., and
Peet, N.P., Drug Discovery Today, 2011, vol. 16, p. 755.
. Hurdle, J.G., O’Neill, A.J., Chopra, I., and Lee, R.E.,
Nat. Rev. Microbiol., 2011, vol. 9, p. 62.
. Wright, G.D., Chem. Commun., 2011, vol. 47, p. 4055.
. Silva, L.N., Zimmer, K.R., Macedo, A.J., and
Trentin, D.S., Chem. Rev., 2016, vol. 116, p. 9162.
. Newman, D.J. and Cragg, G.M., J. Nat. Prod., 2016,
(
OD ) with a Tecan M1000 Pro microplate reader.
600
The inhibition percentage was calculated for each well
using negative (nutrition medium) and positive con-
trols (bacteria without inhibitors) on the same micro-
plate. The inhibitory activity was also estimated by
modified Z-factors calculated from the median abso-
lute deviations (MAD) for samples without control on
the same plate. Compounds that inhibited bacterial
growth by 80% and more with a Z-factor of higher
than 2.5 in two runs were considered to be active,
and those with an inhibition percentage of 50 to 80%
and a Z-factor of higher than 2.5 in two runs, partially
active.
3
4
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8
9
The antibacterial activity of compounds 1–10 in
vitro against Streptococcus oralis and Streptococcus
sobrinus was also estimated by the agar diffusion
method at the Bashkir State Medical University.
A 14-mg sample of each compound 1–10 was dis-
solved in 1 mL of dimethyl sulfoxide to obtain stock
solutions with a concentration of 14 mg/mL. The stock
solutions were subjected to ten-fold serial dilutions
–
1
–2
–3
–4
1
0. Markus, B. and Kwon, C.-H., J. Pharm. Sci., 1994,
(
1
14 × 10 , 14 × 10 , 14 × 10 , 14 × 10 , and 14×
–5
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0 μg/L). The antibacterial activity was evaluated by
1
1. Boyd, M.J., Crane, S.N., Robichaud, J., Scheigetz, J.,
the diameter (mm) of inhibition zone. Each test was
carried out in triplicate.
Black, W.C., Chauret, N., Wang, Q., Masse, F., and
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This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 17-43-020021 r_a), as well as in the framework of
state assignment no. AAAA-A17-117012610057-7.
The spectral studies were performed at the Agidel Joint
Center (Institute of Petrochemistry and Catalysis,
Russian Academy of Sciences). The antimicrobial
screening in vitro was carried out by the Community
1
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