Discovery of a New Class of Inhibitors of Vaccinia Virus Based on (?)-Borneol from Abies sibirica and (+)-Camphor

Article abstract of DOI:10.1002/cbdv.201800153

A series of the bornyl ester/amide derivatives with N-containing heterocycles were designed and synthesized as vaccinia virus (VV) inhibitors. Bioassay results showed that among the designed compounds, derivatives 6, 13, 14, 34, 36 and 37 showed the best inhibitory activity against VV with the IC₅₀ values of 12.9, 17.9, 3.4, 2.5, 12.5 and 7.5 μm, respectively, and good cytotoxicity. The primary structure–activity relationship (SAR) study suggested that the combination of a saturated N-heterocycle, such as morpholine or 4-methylpiperidine, and a 1,7,7-trimethylbicyclo[2.2.1]heptane scaffold was favorable for antiviral activity.

Full text of DOI:10.1002/cbdv.201800153

Article Type: Full Paper
Discovery of a new class of inhibitors of Vaccinia virus based on (-)-borneol
from Ábies sibírica and (+)-camphor
Anastasiya S. Sokolova*a, Olga I. Yarovaya a,b, Nikolay I. Bormotovc, Larisa N. Shishkinac, Nariman F.
Salakhutdinova,b
a Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch Russian Academy of Sciences, 9, Lavrent’ev ave., Novosibirsk 630090, Russian
Federation,
e-mail asokolova@nioch.nsc.ru
b Laboratory of new medicines, Novosibirsk State University, 2, Pirogova Str., Novosibirsk 630090, Russian Federation
c Department of prevention and treatment of especially dangerous infections, State Research Center of Virology and Biotechnology
VECTOR, Koltsovo, Novosibirsk Region, 630559, Russian Federation
A series of the bornyl ester/amide derivatives with N-containing heterocycles were designed and
synthesised as Vaccinia virus (VV) inhibitors. Bioassay results showed that among the designed
compounds, derivatives 6, 13, 14, 34, 36 and 37 showed the best inhibitory activity against VV with
IC50 values of 12.9, 17.9, 3.4, 2.5, 12.5 and 7.5 µM, respectively, and good cytotoxicity. The primary
structure–activity relationship (SAR) study suggested that the combination of a saturated N-
heterocycle, such as morpholine or 4-methylpiperidine, and a 1,7,7-trimethylbicyclo[2.2.1]heptan
scaffold was favorable for antiviral activity.
Keywords: borneol • N-heterocycles • antiviral activity • orthopoxviruses • monoterpenoids
Introduction
Poxviruses and poxvirus-associated diseases have had long-standing attention from the scientific
community for a multitude of reasons. Firstly, the poxvirus family is genetically diverse and its
members are capable of causing infections in a wide array of vertebrate and invertebrate taxa with
high morbidity and mortality. The Orthopoxvirus genus, which includes the variola, cowpox,
monkeypox and Vaccinia viruses, has the greatest relevance to human health. Of the
orthopoxviruses, Variola virus is the most dangerous, and smallpox was responsible for serious illness
and death until the development of a successful vaccine [1]. After completion of the "global
elimination of smallpox" program, vaccination against smallpox was abolished in 1980 [2], leading to
a dangerous situation in which more than half of the world population do not have immunity against
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orthopoxvirus infections. Variola virus belongs to category A of potentially dangerous biological
agents, posing a significant threat in a bioterrorist attack. There are two orally administered
bioavailable antiviral drugs currently in clinical trials that were developed in the USA: ST-246
(Tecovirimat) [3] and CMX001 (Brincidofovir, 1-0-hexadecyloxypropyl-cidofovir) [4]. CMX001 is a
lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to Cidofovir
(CDV). CDV (Vistide®) is an antiviral drug approved for the treatment of cytomegalovirus retinitis [5]
and has shown activity in lethal models of poxvirus infection using mice and monkeys [6]. Although
CDV is the only antiviral drug currently available for use in the event of a smallpox outbreak, it has
low oral bioavailability and can be toxic to the kidneys [7] .Tecovirimat (TPOXX®) was developed by
SIGA Technologies, Inc., under the FDA “Animal Rule”. Its mechanism of action is distinct from that of
CDV that inhibits viral DNA replication. The target of Tecovirimat is a highly conserved virally
encoded protein p37 present in all orthopoxviruses [8].
Figure 1. Chemical structure of inhibitors of orthopoxvirus replication
Due to the increased urgency to protect people from orthopoxvirus infections together with the
emergence of drug resistant strains, it is necessary to search for new chemical compounds with
different mechanisms of action in order to create a new generation of antiviral agents.
Monoterpenoids are important natural products, and have been used in drug design due to their
anticancer, antibacterial, analgesic, anti-inflammatory and antiviral activity [9]. In recent years, our
research group has been widely involved in the development of novel antiviral drugs based on the
bicyclic monoterpenoids camphor and borneol. Of the camphor derivatives synthesised, imines
showed promising activity against the influenza virus [10], [11]. Of the borneol derivatives, N-
heterocyclic bornyl esters demonstrated high antiviral activity against influenza virus A/Puerto
Rico/8/34 (H1N1)[12]. Moreover, we have shown some bornyl esters are able to specifically inhibit
Marburg virus entry into the target cell [13].Thus, the 1,7,7-trimethylbicyclo[2.2.1]heptan scaffold is
an important pharmacophore for exhibiting high inhibitory activity.
Following on from this, we investigated the antiviral activity of a large number of borneol derivatives
against Vaccinia virus. Overall, 31 compounds, incorporating the 1,7,7-trimethylbicyclo[2.2.1]heptan
scaffold and several functionalities, have been evaluated in cell-based assays for cytotoxicity and
antiviral activity against a panel of Vaccinia viruses.
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Results and Discussion
The synthetic routes to borneol esters 4–25 include two steps that are depicted in Scheme 1. We use
(-) borneol, obtained from natural material by the method described in a patent [14]. In the first
reaction between the (-)-borneol and different acid chlorides, (1S,2R,4S)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-yl 2-chloroacetat 1, -3-chloropropanoat 2, -4-chlorobutanoate 3 are
formed. Then, after nucleophilic substitution reactions involving different nitrogen or sulphur-
containing nucleophiles, esters 1–3 were transformed into target compounds 4–25.
Scheme 1. Reagents and conditions: (i) 2-chloroacetyl chloride/3-chloropropanoyl chloride/4-chlorobutanoyl chloride, Et3N, CH2Cl2 (dry), 25 °C; (ii) for
compounds 4–7, the corresponding heterocycle, DBU, CH3CN, reflux; (ii) for compounds 8–25, the corresponding amine, CH2Cl2, Et3N.
In order to investigate how the chemical structure of the bicyclic scaffold affected their ability to
inhibit virus replication, a series of esters based on different monoterpenoids were synthesised
(Scheme 2). Fenchol and nopol derivatives 28–29 were synthesised using a method similar to
compounds 4–25, starting from (+)-fenchol, (-)-nopol and chloroacetyl chloride.
Scheme 2. Reagents and conditions: (i) 2-chloroacetyl chloride, monoterpenoid alcohol, CH2Cl2,
Et3N, 15–25 °C; (ii) morpholine, CH2Cl2, Et3N, 25 °C.
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We further investigated the importance of the ester group for inhibitory activity. Amides 34–40 were
prepared as illustrated in Scheme 3. Combining 2-bornyl amine 31, synthesised from camphor oxime
39, with the corresponding chlorinated acid chloride led to the formation of the key intermediates
32–33, which were converted into amides 34–40 under basic conditions.
Scheme 3. Reagents and conditions: (i) NH2OH·HCl, NaOAc, microwave radiation; (ii) NiCl2, NaBH4, MeOH, –30 °C; (iii) 2-chloroacetyl/3-
chloropropanoyl chloride CH2Cl2, Et3N, 25 °C; (iv) the corresponding heterocycle, CH2Cl2, Et3N, reflux.
The antiviral activity and cytotoxicity of the synthesised derivatives against VV were evaluated using
an adapted method [15] (Table 1). The commercially available agent Cidofovir was used as a positive
control and the results are listed in Table 1.
Table 1. Antiviral activity of target derivatives 4–40 against Vaccinia virus.
Compound
TC50a, µM
IC50b, µM
SIc
(-)-borneol
>650
NA
-
4
34.68 9.44
20.19 6.7
NA
1.7
-
5
35.70 6.86
6
474.79 33.55
216.36 37.74
272.85 57.77
479.96 37.62
118.48 20.36
179.27 37.37
81.74 13.70
1010.63 119.90
168.61 25.95
182.88 24.86
16.48 3.46
12.89 0.58
42.33 11.13
161.58 26.85
120.71 11.06
NA
36
5
7
8
1.7
4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
-
NA
-
NA
-
17.88 4.55
3.45 0.10
7.95 2.04
NA
56
48
23
-
53.76 13.99
156.07 37.44
103.38 22.73
117.86 25.30
104.96 21.75
72.66 15.31
19.39 4.45
64.87 16.89
NA
2.7
2
-
NA
-
NA
-
21.17 11.66
3
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23
61.72 14.10
21.05 3.99
19.07 2.87
NA
3
24
-
25
71.04 12.80
229.61 32.94
120.69 21.61
134.99 33.37
88.42 14.16
501.80 16.90
473.36 61.61
583.44 39.12
743.39 227.86
1625.16 590.17
475.27 74.97
NA
-
28
138.21 17.20
NA
1.7
-
29
34
2.50 0.17
13.87 1.89
12.55 4.24
7.47 1.09
109.35 19.05
33.50 3.58
NA
54
6
35
36
40
63
5
37
38
39
22
-
40
Cidofovir
40.01 2.87
11.8
aTC50=50% toxicity concentration, at which 50% of cells in uninfected monolayers are destroyed.
bIC50=50% inhibitory concentration, at which 50% of cells in infected monolayers are preserved.
cSI=selectivity index, ratio TC50/IC50.
The structure–activity analysis showed that bornyl ester derivatives 13, 14, 15, 36 and 37 bearing the
morpholine fragment exhibited strong antiviral activity, with IC50 values of 17.9, 3.5, 7.9, 12.5 and 7.5
µM, respectively. Moreover, their toxicity was low and, as a consequence, the selectivity indices SIs
were high. Similar to the morpholine derivatives, ester 6 with a 4,5-dihydrothiazole-2-thiol fragment,
had an IC50 value of 12.9 µM and low toxicity (TC50=475 µM). Of note, morpholine derivatives of (+)-
fenchol 28 and (-)-nopol 29 showed no antiviral activity. Incorporation of the non-cyclic amine into
the terpene (24 and 25) resulted in a lack of virus suppression. SAR analysis of the synthesised
amides indicated that for several derivatives the amide group was favorable for the cytotoxicity while
retaining high inhibitory activity. These findings were evidenced by the cytotoxicity order of 37 (583
µM)>14 (168 µM) and 39 (743 µM)>18 (156 µM). In addition, bornyl based amides 34 and 39
containing 4-methylpiperidine and methylpiperazine heterocycles, exhibited good antiviral activity,
with IC50 values of 2.5 and 33.5, respectively. The strong dependence of antiviral activity on the linker
length was not observed. In order to confirmed specificity of antiviral activity against VV we
evaluated anti-HSV-1 activity of derivatives 14, 34, 36. The results showed that these derivatives did
not exhibit antiviral activity.
Conclusions
In summary, 31 esters/amides containing a monoterpenoid fragment were synthesised and their
antiviral activity was studied in vitro against VV. Preliminary SAR studies suggest that the
incorporation of the N-heterocyclic unit into the 1,7,7-trimethylbicyclo[2.2.1]heptan scaffold resulted
in a significant improvement to antiviral activity. Esters 6, 13, 14 and 15 exhibited high anti-VV
activity and low cytotoxicity. Of the synthesised amides, derivatives 34 and 37, with 4-
methylpiperidine and morpholine fragments, respectively, showed the best antiviral activity together
with low toxicity. It is notable that (-)-borneol showed no activity against VV. Thus, the presence of
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both a heterocyclic unit and 1,7,7-trimethylbicyclo[2.2.1]heptan scaffold is responsible for the
antiviral activity against VV. The results are comparable to the reference drug Cidofovir, suggesting
the compounds’ potential as anti-VV drug candidates.
Experimental Section
General
Reagents and solvents were purchased from commercial suppliers and used as received. Dry solvents
were obtained according to the standard procedures. Optical rotation: PolAAr 3005 spectrometer;
CHCl3 soln. 1H and 13C NMR spectra were recorded with a Bruker AV-300 (1H: 300.13 MHz, 13C: 75.47
MHz), AV-400 (1H: 400.13 MHz, 13C: 100.78 MHz) and DRX-500 (1H: 500.13 MHz, 13C: 125.76 MHz) in
CDCl3; chemical shifts δ in ppm relative to residual [δ(CHCl3) 7.24, δ(CDCl3) 76.90. Spin multiplicities
are given as s (singlet), d (doublet), t (triplet) and m (multiplet) as well as b (broad). Coupling
constants (J) are given in hertz. HR-MS: DFS Thermo Scientific spectrometer in full scan mode (15–
500 m/z, 70 eV electron impact ionization, direct sample administration) and Agilent 7200
Quadrupole Time-of-Flight GC/MS system. The purity of the target compounds was determined by
gas chromatography methods. All of the target compounds reported in this paper have a purity of no
less than 95%. Column chromatography (CC) was performed on silica gel (60–200 l, Macherey-Nagel).
Numeration of atoms in the compounds is given for assigning the signals in the NMR spectra and
does not coincide with that for the names according to the nomenclature of compounds. Specific
rotation is expressed as (deg ml) (g dm)−1; concentraꢀon is expressed as (g) (100 ml)−1.
Previously, we described the synthesis of several compounds according to the references 1, 2, 8, 9,
11, 13, 14, 16-18, 20, 22-25 [12], 4-7 [16] .
Synthesis of (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-chlorobutanoate (3)
To the solution of 4-chlorobutanoic acid in dry CH2Cl2, excess oxalyl chloride and N,N-
dimethylformamide (one drop) were added. The mixture was stirred at room temperature for 4 h in
an Ar atmosphere. The excess oxalyl chloride was removed on a rotary evaporator. The resulting 4-
chlorobutanoyl chloride was used in a further reaction immediately.
To the solution of (−)-borneol (30 mmol) in CH2Cl2 was added the 4-chlorobutanoyl chloride (30
mmol) in CH2Cl2 (5 ml) and Et3N (30 mmol) at 0–5 °C, and the mixture was stirred at room
temperature for 24 h in an atmosphere of Ar. The reaction mixture was washed with brine and
extracted with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4 and the
solvent was removed. The crude product was purified by flash CC (silica gel, eluent: hexane–ethyl
1
acetate). Yield: 62%, yellow oil. H NMR (δ, ppm, J/Hz): 0.77 (3H, s, Me-9), 0.82 (3H, s, Me-10), 0.85
2
(3H, s, Me-8), 0.90 (1H, dd, J=13.7, J2endo, 1exo=3.4, H-2endo), 1.13-1.28 (2H, m, H-4endo, H-5exo),
1.62 (1H, dd, J3,2exo=J3,4exo=4.6, H-3), 1.64-1.74 (1H, m, H-4exo), 1.82-1.90 (1H, m, H-5endo), 2.04 (2H,
p, J=7.7, H-13), 2.29 (1H, m, H-2exo), 2.46 (2H, t, J=7.2, H-12), 3.55 (2H, t, J=6.1, H-14), 4.84 (1H, m,
H-1exo). 13C NMR (δ, ppm): 172.70 s (C-11), 79.85 d (C-1), 48.52 s (C-6), 47.57 s (C-7), 44.62 d (C-3),
43.92 t (C-14), 36.57 t (C-2), 31.38 t (C-12), 27.80 t (C-4), 27.57 t (C-13), 26.87 t (C-5), 19.47 q (Me-9),
[α]24
18.60 q (Me-10), 13.30q (Me-8).
found: 258.1383.
= -38.5 (СHCl3, c=0.8). HRMS: calcd for C14H23O235Cl1: 258.1381
D
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General synthetic procedure for compounds 10, 12, 15, 19, 21
A mixture of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-chlorobutanoate (3) (2 mmol), the
corresponding amine (2.2 mmol), Et3N (2.2 mmol) and 15 ml CH2Cl2 were refluxed for 12 h. After
completion, the mixture was concentrated in a vacuum. Brine and CHCl3 were added to the residue,
and then the mixture was extracted twice with CHCl3. The combined organic phase was dried over
Na2SO4 and the solvent was removed in vacuo. The crude product was purified by silica gel CC
(eluent: hexane–ethyl acetate).
(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-(piperidin-1-yl)butanoate (10)
Yield: 71%, yellow oil. 1H NMR (δ, ppm, J/Hz): 0.79 (3H, s, Me-10), 0.84 (3H, s, Me-8), 0.87 (3H, s, Me-
9), 0.92 (1H, dd, 2J=13.7, J2endo, 1exo=3.5, H-2endo), 1.14-1.31 (2H, m, H-4endo, H-5exo), 1.35-1.44 (2H,
m, H-17), 1.48-1.59 (4H, m, 2H-16, 2H-18), 1.61-1.65 (1H, m, H-3), 1.65-1.74 (1H, m, H-4exo), 1.79
(2H, p, J=7.4, H-13), 1.85-1.94 (1H, m, H-5endo), 2.24-2.36 (9H, m, H-2exo, 2H-12, 2H-14, H-15, H-19),
4.85 (1H, ddd, J1exo, 2endo=10.0, J1exo, 2endo=3.5, J1exo,5exo=2.2, H-1exo). 13C NMR (δ, ppm): 173.68 s (C-11),
79.51 d (C-1), 58.34 t (C-14), 54.34 t (C-15, C-19), 48.52 s (C-6), 47.57 s (C-7), 44.67 d (C-3), 36.60 t (C-
2), 32.56 t (C-12), 27.83 t (C-4), 26.90 t (C-5), 25.70 t (C-16, C-18), 24.19 t (C-17), 22.12 t (C-13), 19.49
q (Me-9), 18.63 q (Me-10), 13.32 q (Me-8). [α]30 =-38.6 (СHCl3, c=0.8). HRMS: calcd for C19H33O2N1:
D
307.2506; found: 307.2504.
(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-(4-methylpiperidin-1-yl)butanoate (12)
Yield: 57%, yellow oil. 1H NMR (δ, ppm, J/Hz): 0.80 (3H, s, Me-10), 0.84 (3H, s, Me-8), 0.87 (3H, s, Me-
2
9), 0.88 (3H, d, J=12.1, Me-20), 0.93 (1H, dd, J=13.7, J2endo, 1exo=3.5, H-2endo), 1.15-1.33 (5H, m, H-
4endo, H-5exo, H-17a, H-19, H-18a), 1.54-1.60 (2H, m, H-17e, H-18e), 1.64 (1H, m, H-3), 1.65-1.90
(6H, m, H-4exo, H-5endo, H-15a, H-16a, H-13), 2.25-2.36 (7H, m, H-2exo, H-12, H-13), 2.81-2.87 (2H,
m , H-15e, H-16e), 4.84 (1H, m, H-1exo). 13C NMR (δ, ppm): 173.69 s (C-11), 79.64 d (C-1), 57.96 t (C-
14), 53.81 t (C-15, C-16), 48.62 s (C-6), 47.66 s (C-7), 44.76 d (C-3), 36.70 t (C-2), 33.92 t (C-17, C-18),
32.57 t (C-12), 30.58 d (C-19), 27.92 t (C-4), 27.00 t (C-5), 22.17 t (C-13), 21.71 q (Me-20), 19.58 q
[α]25
(Me-9), 18.71 q (Me-10), 13.41 q (Me-8).
321.2662; found: 321.2660.
=-35.7 (СHCl3, c=0.6). HRMS: calcd for C20H35O2N1:
D
(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-morpholinobutanoate (15)
Yield: 76%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.79 (3H, s, Me-9), 0.83 (3H, s, Me-10), 0.86 (3H, s,
2
Me-8), 0.91 (1H, dd, J=13.7, J2endo, 1exo=3.5, H-2endo), 1.14-1.30 (2H, m, H-4endo, H-5exo), 1.63 (1H,
dd, J3, 2exo=J3, 4exo=4.6, H-3), 1.66-1.74 (1H, m, H-4exo), 1.78 (2H, p, J=7.3, H-13), 1.85-1.93 (1H, m, H-
5endo), 2.27-2.35 (5H, m, 2H-12, 2H-14, H-2exo), 2.40 (4H, b, 2H-15, 2H-17), 3.67(4H, t, J=4.7, 2H-16,
2H-18), 4.85 (1H, ddd, J1exo,2exo=10.0, J1exo,2endo=3.5, J1exo,5exo=2.2, H-1exo). 13C NMR (δ, ppm): 173.68 s
(C-11), 79.65 d (C-1), 66.85 t (C-16, C-18), 57.97 t (C-14), 53.52 t (C-15, C-17), 48.60 s (C-6), 47.65 s (C-
7), 44.72 d (C-3), 36.70 t (C-2), 32.34 t (C-12), 27.92 t (C-4), 26.98 t (C-5), 21.79 t (C-13), 19.57 q (Me-
9), 18.70 q (Me-10), 13.42 q (Me-8). [α]25 =-31.3 (СHCl3, c=0.6). HRMS: calcd for C18H31O3N1:
D
309.2299; found: 309.2301.
(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-(4-methylpiperazin-1-yl)butanoate (19)
Yield: 56%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.77 (3H, s, Me-10), 0.82 (3H, s, Me-8), 0.85 (3H, s,
2
Me-9), 0.90 (1H, dd, J=13.7, J2endo, 1exo=3.5, H-2endo), 1.13-1.28 (2H, m, H-4endo, H-5exo), 1.62 (1H,
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dd, J3, 2exo=J3, 4exo=4.6, H-3), 1.64-1.73 (1H, m, H-4exo), 1.77 (2H, p, J=7.4, H-13), 1.84-1.92 (1H, m, H-
5endo), 2.23 (3H, s, Me-19), 2.25-2.56 (12H, m, H-2exo, 2H-12, 2H-14, 2H-15, 2H-16, 2H-17, 2H-18),
4.83 (1H, ddd, J1exo, 2exo=10.0, J1exo, 2endo=3.5, J1exo, 5exo=2.2, H-1exo). 13C NMR (δ, ppm): 173.67 s (C-11),
79.59 d (C-1), 57.55 t (C-14), 54.96 t (C-16, C-18), 52.98 t (C-15, C-17), 48.59 s (C-6), 47.63 s (C-7),
45.91 q (Me-19), 44.71 d (C-3), 36.68 t (C-2), 32.47 t (C-12), 27.90 t (C-4), 26.97 t (C-5), 22.15 t (C-13),
[α]29
19.56 q (Me-9), 18.69 q (Me-10), 13.41 q (Me-8).
C19H34O2N2: 322.2615; found: 322.2622.
=-30.36 (СHCl3, c=1.1). HRMS: calcd for
D
(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-(4-ethylpiperazin-1-yl)butanoate (21)
Yield: 65%, yellow oil. 1H NMR (δ, ppm, J/Hz): 0.78 (3H, s, Me-10), 0.83 (3H, s, Me-8), 0.86 (3H, s, Me-
2
9), 0.91 (1H, dd, J=13.7, J2endo, 1exo=3.5, H-2endo), 1.05 (3H, t, J=7.25, Mе-20), 1.14-1.30 (2H, m, H-
4endo, H-5exo), 1.64 (1H, dd, J3, 2exo=J3, 4exo=4.6, H-3), 1.65-1.74 (1H, m, H-4exo), 1.79 (2H, p, J=7.4, H-
2
13), 1.85-1.92 (1H, ddd, J=12.9, J5endo, 4endo=9.3, J5endo, 4exo=4.4, H-5endo), 2.24-2.57 (14H, m, H-2exo,
2H-12, 2H-14, 2H-15, 2H-16, 2H-17, 2H-18, 2H-19), 4.84 (1H, ddd, J1exo,2exo=10.0, J1exo,2endo=3.5,
J
1exo,5exo=2.2, H-1exo). 13C NMR (δ, ppm): 173.68 s (C-11), 79.60 d (C-1), 57.63 t (C-14), 53.02 t (C-15,
C-17), 52.67 t (C-16, C-18), 52.19 (C-20), 48.60 s (C-6), 47.65 s (C-7), 44.74 d (C-3), 36.69 t (C-2), 32.53
t (C-12), 27.91 t (C-4), 26.99 t (C-5), 22.19 t (C-13), 19.56 q (Me-9), 18.70 q (Me-10). 13.41 q (Me-8),
11.84 q (Me-20). [α]25 =-30.3 (СHCl3, c=0.6). HRMS: calcd for C20H35O2N1: 321.2662; found: 321.2530.
D
Synthesis of chlorides 26 and 27
To the mixture of (+)-fenchol or (-)-nopol (0.02 mol) and Et3N (0.02 mol) in 15 ml dry CH2Cl2 at 15–18
°С in an Ar atmosphere was added chloroacetyl chloride (0.05 mol), and the mixture was stirred at
23–25 °С for 12 h. The organic layers were washed with brine and extracted with CH2Cl2. The
combined organic phase was dried over anhydrous Na2SO4 and the solvent was removed. The crude
product was purified by silica gel CC (eluent: hexane–ethyl acetate).
(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl 2-chloroacetate (26)
Yield: 72%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.76 (3H, s, Me-10), 1.02 (3H, s, Me-8), 1.08 (3H, s,
Me-9), 1.05-1.12 (1H, m), 1.17 (1H, dd, J=10.5, 1.5), 1.37-1.47 (1H, m), 1.55 (1H, m), 1.60-1.76 (3H,
m), 4.06 (2H, s, H-12), 4.40 (1H, d, J=2.0). 13C NMR (δ, ppm): 167.61 s (C-11), 88.10 d (C-2), 48.22 s (C-
1), 48.11 d (C-4), 41.15 t (C-7), 40.88 t (C-12), 39.44 s (C-3), 29.49 q (Me-9). 26.32 t (C-5), 25.60 t (C-
6), 19.89 q (Me-10), 19.18 q (Me-8). [α]25=43.9 (СHCl3, c=0.9). The spectral characteristics of
D
compound 26 coincide with the literature data [17].
2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl 2-chloroacetate (27)
Yield: 49%, yellow oil. 1H NMR (δ, ppm, J/Hz): 0.79 and 1.25 (each 3H, s, Me-8 or Me-9), 1.11 (1H, d,
J=8.6, H-7a), 1.99-2.09 (2H, m, H-1, H-5), 2.17-2.23 (2H, m, H-4), 2.30 (2H, m, H-10), 2.33-2.36 (1H, m,
H-7b), 4.04 (2H, s, H-13), 4.13-4.25 (2H, m, H-11), 5.29 (1H, m, H-3). 13C NMR (δ, ppm): 167.16 s (C-
12), 143.47 s (C-2), 119.15 d (C-3), 64.34 t (C-11), 45.57 d (C-1), 40.89 t (С-13), 40.61 d (C-5), 35.62 t
(C-10), 31.54 t (C-7), 31.25 t (C-4), 26.16 q (Me-8), 20.99 q (Me-9).
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General synthetic procedure for compounds 28-29
A mixture of the corresponding chloride 26 or 27 (2 mmol), morpholine (2.2 mmol), Et3N (2.2 mmol)
and 15 ml CH2Cl2 were stirring for 12 h. After completion, the mixture was concentrated in a vacuum.
Brine and CHCl3 were added to the residue, and then the mixture was extracted twice with CHCl3.
The combined organic phase was dried over Na2SO4 and the solvent was removed in vacuo. The
crude product was purified by silica gel CC (eluent: hexane–ethyl acetate).
(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl 2-morpholinoacetate (28)
Yield: 68%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.74 (3H, s), 1.01 (3H, s), 1.07 (3H, s), 1.02-1.10
(1H, m), 1.16 (1H, dt, J=1.3, 10.3), 1.37-1.47 (1H, m), 1.55 (1H, m), 1.60-1.71 (3H, m), 2.56 (4H, t,
J=4.4, H-13, H-14), 3.22 (2H, s, H-12), 3.72 (4H, t, J=4.4, H-15, H-16), 4.37 (1H, d, J=1.7). 13C NMR (δ,
ppm): 170.52 s (C-11), 86.46 d (C-2), 66.70 t (C-15, C-16), 59.27 t (C-12), 53.13 t (C-13, C-14), 48.11 d
(C-4), 48.02 s (C-1), 41.18 t (C-7), 39.31 s (C-3), 29.44 q (Me-9). 26.44 t (C-5), 25.63 t (C-6), 20.05 q
(Me-10), 19.25 q (Me-8). [α]24 =38.7 (СHCl3, c=0.6). The spectral characteristics of compound 28
D
coincides with the literature data [17].
2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl 2-morpholinoacetate (29)
Yield: 60%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.78 (3H, s, Me-8), 1.09 (1H, d, J=8.6, H-7a), 1.23
(3H, s, Me-9), 1.99-2.07 (2H, m, H-1, H-5), 2.15-2.21 (2H, m, H-4), 2.26 (2H, m, H-10), 2.29-2.35 (1H,
m, H-7b), 2.54 (4H, t, J=4.6, H-14, H-17), 3.15 (2H, s, H-13), 3.71 (2H, t, J=4.6, H-15, H-16), 4.07-4.13
(2H, m, H-11), 5.25 (1H, m, H-3). 13C NMR (δ, ppm): 169.95 s (C-12), 143.74 s (C-2), 118.77 d (C-3),
66.64 t (C-15, C-16), 62.74 t (C-11), 59.56 t (C-13), 53.16 t (C-14, C-17), 45.41 d (C-1), 40.49 d (C-5),
35.72 t (C-10), 31.47 t (C-7), 31.18 t (C-4), 26.10 q (Me-8), 20.63 q (Me-9). [α]2D5 =-29.7 (СHCl3, c=0.6).
HRMS: calcd for C17H27O3N: 293.1986; found: 293.1981.
2-Chloro-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)acetamide (32)
To the mixture of amine 31 (0.012 mol) which has been synthesized by a procedure described
previously [18], and Et3N (0.012 mol) in 20 ml dry CH2Cl2 at 15–18 °С in an Ar atmosphere was
added chloroacetyl chloride (0.017 mol), and the mixture was stirred at room temperature for 24 h.
The organic layers were washed with brine and extracted with CHCl3. The combined organic phase
was dried over anhydrous Na2SO4 and the solvent was removed. The resulting residue was used in
next step without any further purification. Yield: 65%, pale yellow solid, m.p. 72 C. 1H NMR (δ, ppm,
J/Hz): 0.82 (6H, s, Me-8, Me-10), 0.92 (3H, s, Me-9), 1.10-1.18 (1H, m, H-4endo), 1.23-1.30 (1H, m, H-
5endo), 1.55-1.63 (2H, m, H-5exo, H-4exo), 1.65-1.72 (1H, m, H-4exo), 1.76 (1H, t, J3,2exo= J3,4exo
=4.3, H-3), 1.85 (1H, dd, J=9.0, 14.0, H-2exo), 3.86 (1H, dt, J=4.9, 9.2, H-1exo), 4.02 (2H, AB-d, J=2.7,
H-11), 6.27 (1H, N-H). 13C NMR (δ, ppm): 164.73 s (C-11), 56.85 d (C-1), 48.42 s (C-6), 46.96 s (C-7),
44.73 d (C-3), 42.75 d (C-12), 38.74 t (C-2), 35.68 t (C-5), 26.84 t (C-4), 20.07 q, 19.93 q (Me-8, Me-9),
11.59 q (Me-10). [α]2D7= -41.7 (СHCl3, c=0.6). HRMS: calcd for C12H20O1N1Cl1: 229.1228 found:
229.1225.
3-Chloro-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)propanamide (33)
To the solution of 3-chloropropanoic acid in dry CH2Cl2, excess oxalyl chloride and N,N-
dimethylformamide (one drop) were added. The mixture was stirred at room temperature for 4 h in
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an Ar atmosphere. The excess oxalyl chloride was removed on a rotary evaporator. The resulting 3-
chloropropanoyl chloride was used in a further reaction immediately.
To the solution of amine 1 (15 mmol) in CH2Cl2 was added the 3-chloropropanoyl chloride (20 mmol)
in CH2Cl2 (5 ml) and Et3N (15 mmol) at 0–5 °C, and the mixture was stirred at room temperature for
24 h in an atmosphere of Ar. The organic layer was washed with brine and extracted with CH2Cl2.
The combined organic phase was dried over anhydrous Na2SO4 and the solvent was removed. The
resulting residue was used in next step without any further purification. Yield: 62%, pale yellow oil.
1H NMR (δ, ppm, J/Hz): 0.80 (3H, s, Me-9), 0.82 (3H, s, Me-10), 0.89 (3H, s, Me-8), 1.08-1.15 (1H, m,
H-4endo), 1.20-1.28 (1H, m, H-5endo), 1.49-1.61 (2H, m, H-2endo, H-5exo), 1.62-1.69 (1H, m, H-
4exo), 1.70-1.74 (1H, m, H-3), 1.83 (1H, dd, J=9.0, 14.0, H-2exo), 2.81 (2H, t, J=6.7, H-12), 3.72 (2H, t,
J=6.7, H-13), 3.88 (1H, dt, J=5.0, 9.2, H-1exo). 13C NMR (δ, ppm): 174.49 s (C-11), 57.01 d (C-1), 48.36
s (C-6), 46.93 s (C-7), 44.61 d (C-3), 40.38 t (C-13), 39.71 d (C-12), 38.72 t (C-2), 35.69 t (C-5), 26.77 t
[α]25
(C-4), 20.11 q, 20.05 q (Me-8, Me-9), 11.59 q (Me-10).
C13H22O1N1Cl1: 243.1384; found: 243.1385.
= -27.1 (СHCl3, c=0.7). HRMS: calcd for
D
General synthetic procedure for compounds 34–40
A mixture of acetamide 2 or 3 (2 mmol), the corresponding amine (2.2 mmol), Et3N (2.2 mmol) and
10 ml CH2Cl2 was refluxed for 12 h. After completion, the mixture was washed brine and extracted
twice with CHCl3. The combined organic phase was dried over Na2SO4 and the solvent was removed
in vacuo. The crude product was purified by silica gel CC (eluent: hexane–ethyl acetate).
2-(4-Methylpiperidin-1-yl)-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)acetamide (34)
1
Yield: 45%, yellow oil. H NMR (δ, ppm, J/Hz): 0.79 (3H, s, Me-10), 0.82 (3H, s, Me-8), 0.89 (3H, d,
J=6.3, Me-18), 0.91 (3H, s, Me-9), 1.08-1.4 (5H, m, H-4endo, H-5endo, H-14a, H-15, H-16a), 1.49-1.67
(4H, m, H-5exo, H-4exo, H-14e, H-16e), 1.72 (1H, m, H-3), 1.82 (1H, dd, J=9.0, 14.0, H-2exo), 1.85-1.94
(2H, H-13e, H-17e), 2.68-2.80 (2H, m, H-13e, H-17e), 2.90 (2H, AB-d, H-12), 3.84 (1H, m, H-1exo), 7.49
(1H, N-H).13C NMR (δ, ppm): 169.56 s (C-11), 61.61 t (C-12), 55.57 d (C-1), 54.24 t (C-13, C-17), 48.24 s
(C-6), 46.89 s (C-7), 44.71 d (C-3), 39.06 t (C-2), 35.70 t (C-5), 34.60 t (C-14, C-16), 29.88 d (C-15),
[α]24
26.88 t (C-4), 21.67 q (Me-18), 20.08 q, 19.90 q (Me-8, Me-9), 11.84 q (Me-10).
c=1.1). HRMS: calcd for C18H32O1N2: 292.2509 found: 292.2514.
D = -27.6 (СHCl3,
3-(4-Methylpiperidin-1-yl)-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)propanamide (35)
Yield: 45%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.80 (3H, s, Me-8), 0.81 (3H, s, Me-10), 0.89 (3H, d,
J=6.3, Me-18), 0.91 (3H, s, Me-9), 1.08-1.30 (5H, m, H-4endo, H-5endo, H-16a, H-18, H-17a), 1.46-
1.73 (6H, m, H-5exo, H-2endo, H-4exo, H-3, H-16e, H-17e), 1.78-1.89 (3H, m, H-2exo, H-14a, H-15a),
2.30-2.40 (2H, m, H-12), 2.41-2.53 (2H, m, H-13), 2.86-2.93 (2H, m, H-14e, H-15e), 3.84 (1H, dt, J=4.9,
9.2, H-1exo), 8.52 (1H, N-H).13C NMR (δ, ppm): 171.51 s (C-11), 55.65 d (C-1), 54.37 t (C-14, C-15),
53.14 t (C-13), 47.88 s (C-6), 46.55 s (C-7), 44.50 d (C-3), 38.82 t (C-2), 35.62 t (C-5), 33.44 t (C-16, C-
17), 31.53 t (C-12), 30.21 d (C-18), 26.62 t (C-4), 21.39 q (Me-19), 20.27 q, 19.81 q (Me-8, Me-9),
11.46 q (Me-10). [α]27 =-28.2 (СHCl3, c=0.6). HRMS: calcd for C19H34O1N2: 306.2666; found: 306.2667.
D
2-Morpholino-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)acetamide (36)
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Yield: 59%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.78 (3H, s, Me-10), 0.82 (3H, s, Me-8), 0.90 (3H, s,
Me-9), 1.09-1.17 (1H, m, H-4endo), 1.23-1.31 (1H, m, H-5endo), 1.48-1.58 (2H, m, H-5exo, H-2endo),
1.63-1.70 (1H, m, H-4exo), 1.73 (1H, t, J3,2exo= J3,4exo =3.8, H-3), 1.83 (1H, dd, J=9.0, 14.0, H-2exo), 2.49-
2.55 (4H, m, H-13, H-14), 2.95 (2H, AB-d, J=1.5, H-12), 3.66-3.74 (4H, m, H-15, H-16), 3.85 (1H, dt,
J=4.9, 9.2, H-1exo), 7.33 (1H, N-H).13C NMR (δ, ppm): 168.6 s (C-11), 67.02 t (C-15, C-16), 61.65 t (C-
12), 55.74 d (C-1), 53.73 t (C-13, C-14), 48.30 s (C-6), 46.95 s (C-7), 44.75 d (C-3), 39.12 t (C-2), 35.71 t
(C-5), 26.88 t (C-4), 20.08 q, 19.96 q (Me-8, Me-9), 11.93 q (Me-10). [α]24= -29.8 (СHCl3, c=1.1).
D
HRMS: calcd for C16H28O2N2: 280.2145; found: 280.2139.
3-Morpholino-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)propanamide (37)
Yield: 43%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.80 (3H, s, Me-10), 0.81 (3H, s, Me-8), 0.91 (3H, s,
Me-9), 1.07-1.15 (1H, m, H-4endo), 1.20-1.29 (1H, m, H-5endo), 1.45-1.56 (2H, m, H-5exo, H-2endo),
1.61-1.71 (2H, m, H-4exo, H-3), 1.82 (1H, dd, J=9.0, 14.0, H-2exo), 2.33-2.37 (2H, m, H-12), 2.40-2.47
(4H, br. s., H-14, H-15), 2.50-2.57 (2H, m, H-13), 3.63-3.73 (4H, m, H-16, H-17), 3.84 (1H, dt, J=4.9, 9.2,
H-1exo), 8.10 (1H, N-H).13C NMR (δ, ppm): 171.2 s (C-11), 66.37 t (C-16, C-17), 55.96 d (C-1), 54.78 t
(C-13), 52.93 t (C-14, C-15), 48.10 s (C-6), 46.86 s (C-7), 44.68 d (C-3), 39.16 t (C-2), 35.81 t (C-5),
31.27 t (C-12), 26.83 t (C-4), 20.56 q, 20.03 q (Me-8, Me-9), 11.81 q (Me-10). [α]26= 27.4 (СHCl3,
D
c=0.6). HRMS: calcd for C17H30O2N2: 294.2302 found: 294.2300.
2-(4-Methylpiperazin-1-yl)-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)acetamide (38)
Yield: 63%, yellow oil. 1H NMR (δ, ppm, J/Hz): 0.75 (3H, s, Me-10), 0.78 (3H, s, Me-8), 0.86 (3H, s, Me-
9), 1.05-1.12 (1H, m, H-4endo), 1.19-1.27 (1H, m, H-5endo), 1.45-1.54 (2H, m, H-5exo, H-2endo),
1.59-1.66 (1H, m, H-4exo), 1.66-1.70 (1H, m, H-3), 1.78 (1H, dd, J=9.0, 14.0, H-2exo), 2.21 (3H, s, Me-
17), 2.29-2.55 (8H, m, H-13, H-14, H-15, H-16), 2.91 (2H, AB-d, J=3.8, H-12), 3.80 (1H, dt, J=4.9, 9.2, H-
1exo), 7.33 (1H, N-H).13C NMR (δ, ppm): 168.89 s (C-11), 60.99 t (C-12), 55.58 d (C-1), 55.16 t (C-13, C-
14), 53.19 t (C-16, C-15), 48.18 s (C-6), 46.86 s (C-7), 45.74 q (Me-17), 44.64 d (C-3), 39.01 t (C-2),
35.62 t (C-5), 26.80 t (C-4), 20.00 q, 19.98 q (Me-8, Me-9), 11.83 q (Me-10). [α]24= -26.7 (СHCl3,
D
c=0.9). HRMS: calcd for C17H31O1N3: 293.2462; found: 293.2460.
3-(4-Methylpiperazin-1-yl)-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)propanamide (39)
Yield: 53%, pale yellow oil. 1H NMR (δ, ppm, J/Hz): 0.80 (3H, s, Me-8), 0.81 (3H, s, Me-10), 0.91 (3H, s,
Me-9), 1.08-1.17 (1H, m, H-4endo), 1.21-1.30 (1H, m, H-5endo), 1.45-1.56 (2H, m, H-5exo, H-2endo),
1.61-1.71 (2H, m, H-4exo, H-3), 1.82 (1H, dd, J=9.0, 14.0, H-2exo), 2.26 (3H, s, Me-18), 2.27-2.69 (8H,
br.s., H-14, H-15, H-16, H-17), 2.35 (2H, m, H-12), 2.48-2.60 (2H, m, H-13), 3.84 (1H, dt, J=4.9, 9.2, H-
1exo), 8.24 (1H, N-H).13C NMR (δ, ppm): 171.58 s (C-11), 56.02 d (C-1), 54.58 t (C-13), 54.33 t (C-14, C-
15), 52.50 t (C-16, C-17), 48.21 s (C-6), 46.93 s (C-7), 45.87 q (Me-18), 44.76 d (C-3), 39.14 t (C-2),
[α]25
35.88 t (C-5), 31.63 t (C-12), 26.92 t (C-4), 20.92 q, 20.13 q (Me-8, Me-9), 11.89 q (Me-10).
D
=18.5 (СHCl3, c=0.7). HRMS: calcd for C18H33O1N3: 307.2618; found: 307.2619.
3-(4-Ethylpiperazin-1-yl)-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)propanamide (40)
Yield: 62%, yellow oil. 1H NMR (δ, ppm, J/Hz): 0.80 (3H, s, Me-10), 0.81 (3H, s, Me-8), 0.91 (3H, s, Me-
9), 1.05 (3H, t, J=7.3, Me-19), 1.08-1.14 (1H, m, H-4endo), 1.21-1.29 (1H, m, H-5endo), 1.43-1.54 (2H,
m, H-5exo, H-2endo), 1.59-1.69 (2H, m, H-4exo, H-3), 1.79 (1H, dd, J=9.0, 14.0, H-2exo), 2.26-2.75
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(14H, m, H-12, H-13, H-14, H-15, H-16, H-17, H-18), 3.82 (1H, dt, J=4.9, 9.2, H-1exo), 8.22 (1H, N-
H).13C NMR (δ, ppm): 171.59 s (C-11), 56.00 d (C-1), 54.31 t (C-13), 52.44 t (C-14, C-15), 52.22 t (C-16,
C-17), 48.18 s (C-6), 46.90 s (C-7), 44.73 d (C-3), 39.12 t (C-2), 35.87 t (C-5), 31.59 t (C-18), 26.90 t (C-
4), 20.90 q, 20.10 q (Me-8, Me-9), 11.87 q (Me-10), 11.77 q (Me-19). [α]25 =-31.3 (СHCl3, c=0.6).
D
HRMS: calcd for C19H35O1N3: 321.2775; found: 321.2777.
Determination of cytotoxicity and anti-orthopoxviral activities of compounds
To determine the cytotoxicity and antiviral activities of agents against Vaccinia virus (VV), we
adapted a method using 96 well plates [15]. The Emax plate spectrophotometer (Molecular Devices,
USA) and the SoftMax 4.0 Software (Molecular Devices, USA), which automatically calculated the
TC50 and IC50 concentrations of the agents were used to evaluate the results: TC50 - the substance
concentration at which 50 % of cells in uninfected monolayer are destroyed, IC50 - the substance
concentration at which 50 % of cells in infected monolayer are preserved. The selectivity index (SI)
was determined by the ratio of TC50 and IC50 values.
Supplementary Material
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/MS-number.
Acknowledgements
This work was supported by the Russian Foundation Research 17-73-10153. Authors would like to
acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical
measurements.
Author Contribution Statement
Anastasiya S. Sokolova and Olga I. Yarovaya carried out chemical transformation, structure
elucidation and prepared the manuscript. Nikolay I. Bormotov and Larisa N. Shishkina carried out
biological assay. Larisa N. Shishkina and Nariman F. Salakhutdinov designed the experiments. All
authors read and approved the manuscript.
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