Synthesis and antiviral activities of cyanoacrylate derivatives containing an α-aminophosphonate moiety

Article abstract of DOI:10.1021/jf800405m

Target compounds 8 were obtained by the reaction of alkyl 2-cyano-3,3-dimethylthioacrylate or cyarylamide (7a-7e) and α- aminobenzylphosphonate (5a-5e) under reflux condition using ethanol as solvent. Their structures were clearly verified by spectroscopic data (IR and ¹H, ¹³C, and ³¹P NMR) and elemental analysis. These compounds were shown to be antivirally active in the bioassay. It was found that title compounds 8d and 8e had the same inactivation effect against tobacco mosaic virus (EC₅₀ = 55.5 and 55.3 μg/mL) as the commercial product ningnanmycin (EC₅₀ = 50.9 μg/mL). To the best of our knowledge, this is the first report on the synthesis and antiviral activity of cyanoacrylate derivatives containing an α-aminophosphonate moiety.

Full text of DOI:10.1021/jf800405m

5242 J. Agric. Food Chem. 2008, 56, 5242–5246
Synthesis and Antiviral Activities of Cyanoacrylate
Derivatives Containing an r-Aminophosphonate
Moiety
NING LONG, XUE-JIAN CAI, BAO-AN SONG,* SONG YANG, ZHUO CHEN,
PINAKI S. BHADURY, DE-YU HU, LIN-HONG JIN, AND WEI XUE
Center for Research and Development of Fine Chemicals, Key Laboratory of Green Pesticide and
Agricultural Bioengineering, Ministry of Education, Guizhou University,
Guiyang 550025, People’s Republic of China
Target compounds 8 were obtained by the reaction of alkyl 2-cyano-3,3-dimethylthioacrylate or
cyarylamide (7a-7e) and R-aminobenzylphosphonate (5a-5e) under reflux condition using ethanol
as solvent. Their structures were clearly verified by spectroscopic data (IR and 1H, 13C, and 31P
NMR) and elemental analysis. These compounds were shown to be antivirally active in the bioassay.
It was found that title compounds 8d and 8e had the same inactivation effect against tobacco mosaic
virus (EC50 ) 55.5 and 55.3 µg/mL) as the commercial product ningnanmycin (EC50 ) 50.9 µg/mL).
To the best of our knowledge, this is the first report on the synthesis and antiviral activity of
cyanoacrylate derivatives containing an R-aminophosphonate moiety.
KEYWORDS: Cyanoacrylate; r-aminophosphonate moiety; antiviral activity; synthesis
INTRODUCTION
involved in induced resistance (11). On the other hand,
R-aminophosphonic acids, bioisosteres of natural amino acids,
have been found to exhibit a wide range of bioactivities. Some
derivatives of R-aminophosphonic acids find application as plant
growth regulators, fungicide, plant virucide, herbicides, and so
on (12–14). A large volume of research on their synthesis and
biological activities has been reported during the last 10
years (15–20).
In our previous work, while many substituted aryl amino-
phosphonate derivatives were shown to have good antiviral
activities (21–26), and carbonylaminophosphonates possessed
better antiviral activities (27). As different aminophosphonates
and their derivatives display potential bioactivities, screening
of cyanoacrylate derivatives bearing various R-amiophosphonate
moieties might produce new lead compounds with more potent
antiviral activities against TMV. Keeping these considerations
in mind, we herein designed and synthesized some novel
cyanoacrylate derivatives containing R-aminophosphonates
(Scheme 1). The synthetic route is shown in Scheme 2. The
bioassay test showed that the new compounds 8 possessed
moderate to good antiviral activities. To the best of our
knowledge, this is the first report on the synthesis and antiviral
2-Cyanoacrylates, a class of highly potent herbicial com-
pounds, are known to disrupt photosynthetic electron transporta-
tion at a common binding domain on the 32 kDa polypeptide
of the photosystem II (PSII) reaction center (1, 2). Due to their
versatile biological activities and promising application in
agrochemistry, a large number of cyanoacrylate derivatives have
been reported to show broad spectrum bioactivities, capable of
acting as herbicides, insecticides, fungicides, plant virucides,
and antitumor agents (3–8). In our previous work, we designed
and synthesized some chiral cyanoacrylates with antiviral
activity by replacing the methylthio moiety of some 2-cyano-
3-methyl-thio-3-substituted-phenylacrylates with (R)- or (S)-1-
phenylethylamine groups. The (E)-configuration of the reported
chiral products was confirmed by X-ray single-crystal structure
analysis. The bioassays showed that a chiral compound contain-
ing a 4-nitrophenyl moiety [(E)-ethyl 3[(S)-1-phenylethylamino]-
3-(4-nitrophenylamino)-2-cyanoacrylate] exhibited good pro-
tection activity against tobacco mosaic virus (TMV) in vivo
(9). Some alkyl 2-cyano-3-methylthio-3-phosphonylacrylates
were found to possess good in vivo curative, protection, and
inactivation effects against TMV with inhibitory rates at 500
mg/L (10). Recently we reported the synthesis and antiviral
activity of (E)-ethyl 3-(R)- or (S)-1-phenylethylamino-3-
(substituted-phenylamino)-2-cyanoacrylate. The objective of our
study was to show the effects of (R)-4p in inducing disease
resistance of tobacco leaves in response to virus pathogen attack
and on the activity of enzymes or metabolites that might be
Scheme 1. Structural Features of Aminophosphonates versus Cyanoacry-
late Analogues Containing Aminophosphonates
* Corresponding author. E-mail: songbaoan22@yahoo.com.
10.1021/jf800405m CCC: $40.75  2008 American Chemical Society
Published on Web 06/12/2008

Cyanoacrylates Containing R-Aminophosphonate Moiety
J. Agric. Food Chem., Vol. 56, No. 13, 2008 5243
Scheme 2. Synthetic Route to Cyanoacrylate Analogues 8 Containing R-Aminophosphonate
νmax 3062.9, 3030.1, 2983.8, 2953.0, 2208.4, 1643.3, 1566.2, 1556.5,
activity of cyanoacrylate derivatives containing an R-amino-
phosphonate moiety.
1514.1, 1494.8, 1440.8, 1384.8, 1257.5, 1161.1, 1045.4, 1020.3, 975.9,
1
840.9, 781.1, 748.3, 698.2, 561.2. H NMR (500 MHz, DMSO-d6): δ
1.28-1.29 (m, 3H, C-CH3), 1.31-1.32 (m, 3H, C-CH3), 2.54 (s, 3H,
S-CH3), 3.82 (s, 3H, O-CH3), 4.05-4.91 (m, 2H, O-CH), 5.59-5.64
(m, 1H, Ar-CH), 7.34-7.40 (m, 5H, Ar-H), 10.94 (s, 1H, C-NH).
13C NMR (CDCl3, 125 MHz): δ 172.26, 172.18, 171.18, 168.45, 129.08,
128.76, 127.66, 127.63, 117.93, 63.89, 58.16, 56.94, 52.22, 18.49, 16.47,
16.43, 16.37. 31P NMR (CDCl3, 500 MHz) δ: 19.21. Anal. Calcd for
C19H27N2O5SP (440.15): C, 51.25; H, 5.82; N, 7.03. Found: C, 51.01;
H, 5.90; N, 6.81.
MATERIALS AND METHODS
Instruments. The melting points of the products were determined
on a XT-4 binocular microscope (Beijing Tech Instrument Co., China)
and were not corrected. The IR spectra were recorded on a Bruker
VECTOR 22 spectrometer with KBr disk. 1H, 13C, and 31P NMR
(solvent DMSO-d6 and CDCl3) spectra were performed on a JEOL-
ECX 500 NMR spectrometer at room temperature using TMS as AN
internal standard. Elemental analysis was performed on an Elementar
Vario-III CHN analyzer. Analytical TLC was performed on silica gel
GF254. Column chromatographic purification was carried out using
silica gel. All reagents were of analytical reagent grade or chemically
pure. All solvents were dried, deoxygenated, and redistilled before
use.
Synthetic Procedures. Diethyl phosphite and di-n-propyl phosphite
were prepared according to literature method as described (28).
Intermediates 5a-f, 6a-e, and 7a-e were prepared according to the
reported methods (29) and a detailed procedure can be found in the
Supporting Information.
General Procedure for the Preparation of Title Compounds
8a-8x. A mixture of alkyl (imido) 2-cyano-3,3-dimethylthioacrylate
(7a-e) (0.1 mmol) and R-aminobenzylphosphonate (5a-e) (0.1 mmol)
in ethanol (10 mL) was refluxed for 4 h. Upon completion of the
reaction, the solvent was removed under reduced pressure and the
residue was washed with water, filtered off, and purified by silica gel
column chromatography (petroleum ether-ethyl acetate, 2:1, v:v) to
give the title compounds 8a-x in 25.6-70.0% yields. The reperesen-
tative data for 8a is shown below, while data for 8b-8x can be found
in the Supporting Information.
X-ray Diffraction. Colorless blocks of 8v (0.29 mm × 0.24 mm ×
0.21 mm) were counted on a quartz fiber with protection oil. Cell
dimensions and intensities were measured at 273 K on a Bruker
SMART CCD area detector diffractometer with graphite-monochro-
mated Mo KR radiation (λ ) 0.710 73 Å), θmax ) 25.00, 19 767
measured reflections, and 3232 independent reflections (Rint ) 0.1763)
of which 4767 had I > 2δ(I). Data were corrected for Lorentz and
polarization effects and for absorption (Tmin ) 0.7680, Tmax ) 0.8237).
The structure was solved by direct methods using SHELXS-97; all other
calculations were performed with Bruker SAINT System and Bruker
2
SMART programs. Full-matrix least-squares refinement based on F
using the weight of 1/[σ2(Fo ) + (0.0703P)2 + 0.0000P] gave final
2
values of R ) 0.0558, ωR ) 0.1610, and GOF(F) ) 1.052 for 307
variables and 4767 contributing reflections. The maximum shift/error
) 0.001, and max/min residual electron density ) 0.400/-0.322 e Å-3
.
Hydrogen atoms were observed and refined with a fixed value of their
isotropic displacement parameter.
Antiviral Biological Assay. Purification of Tobacco Mosaic Virus.
Using Gooding’s method (30), the upper leaves of Nicotiana tabacum
L inoculated with TMV were selected, ground in phosphate buffer,
and then filtered through a double-layer pledget. The filtrate was
centrifuged at 10 000g, treated twice with PEG, and centrifuged again.
Data for Methyl 2-Cyano-3-methylthio-3-(diethyl aminoben-
zylphosphonyl)acrylate (8a). Colorless liquid; 51.3% yield. IR (KBr):

5244 J. Agric. Food Chem., Vol. 56, No. 13, 2008
Long et al.
The whole experiment was carried out at 4 °C. Absorbance values were
estimated at 260 nm using an ultraviolet spectrophotometer.
0.1%,260nm
1cm
virus concn ) (A260 × dilution ratio) / E
(1)
Protective Effects of Compounds against TMV in Vivo. The
compound solution was smeared on the left side while the solvent served
as the control on the right side of growing N. tabacum L. leaves of the
same ages. The leaves were then inoculated with the virus after 12 h.
A brush was dipped in tobacco mosaic virus of 6 × 10-3 mg/mL to
inoculate the leaves, which were previously scattered with silicon
carbide. The leaves were then washed with water and rubbed softly
along the nervature once or twice. The local lesion numbers appearing
3-4 days after inoculation were counted (9). Three repetitions were
conducted for each compound.
Inactivation Effect of Compounds against TMV in Vivo. The virus
was inhibited by mixing with the compound solution at the same volume
for 30 min. The mixture was then inoculated on the left side of the
leaves of N. tabacum L., while the right side of the leaves was
inoculated with the mixture of solvent and the virus for control. The
local lesion numbers were recorded 3-4 days after inoculation (9).
Three repetitions were conducted for each compound.
Curative Effect of Compounds against TMV in Vivo. Growing
leaves of N. tabacum. L of the same ages were selected. The tobacco
mosaic virus (concentration of 6 × 10-3 mg/mL) was dipped and
inoculated on the whole leaves. Then the leaves were washed with water
and dried. The compound solution was smeared on the left side and
the solvent was smeared on the right side for control. The local lesion
numbers were then counted and recorded 3-4 days after inoculation
(9). For each compound, three repetitions were measured. The inhibition
rate of the compound was then calculated according to the following
formula (av means average, and controls were not treated with
compound).
Figure 1. Molecular structure of 8v.
Antiviral Activity and Structure-Activity Relationship.
To make a judgment of the antiviral potency of the synthesized
compounds 8a-8x, the commercially available plant virucide
Ningnanmycin (31), perhaps the most successful registered
antiplant viral agent available in China, was used as the control.
The antiviral bioassay against TMV is assayed by the reported
method (9, 30) and the antiviral results of all the compounds
against TMV are listed in Table 1. The results showed that
most of our designed compounds had moderate antiviral
activities at 500 mg/L against TMV in vivo.
The title compounds 8a-8x exhibited protection activities
of 29.6-56.5% at 500 mg/L. Compounds 8d (R1 is H, R2 is
OCH3, and R3 is n-Bu), 8h (R1 is H, R2 is OC2H5, and R3 is
n-Bu), 8o (R1 is H, R2 is NH2, and R3 is Et), 8q (R1 is H, R2 is
NH2, and R3 is i-Pr), and 8t (R1 is H, R2 is PhCH2NH2, and R3
is Et) have the same protection activity (55.9%, 56.5%, 55.6%,
54.4% and 55.1%, respectively) as that of the standard reference
(59.9%). In addition, compounds 8b, 8c, 8e, 8f, 8i, 8j, 8k, 8m,
8n, 8p, 8r, 8s, 8u, 8w, and 8x showed 40.8-48.3% protection
activities at 500 mg/L. From the data presented in Table 1, it
can be observed that the title compounds 8a-8x possess
potential inactivation bioactivities, with values of 64.1%, 47.1%,
45.7%, 92.8%, 92.1%, 71.0%, 37.8%, 84.0%, 74.1%, 46.8%,
51.5%, 55.9%, 80.6%, 70.0%, 60.8%, 63.0%, 5.7%, 9.6%,
70.7%, 51.9%, 50.0%, 51.5%, 11.0%, and 73.4% at 500 µg/
mL, respectively. Among these compounds, 8d and 8e are
appreciably more active than the rest, with the inactivation rate
of 92.8% and 92.1%, respectively, which are similar to that of
Ningnanmycin (99.5%) against TMV at 500 µg/mL. The data
also indicate that a change in the substituent might also affect
the curative activity of title compounds 8a-8x. Compound 8a
(R1 is H, R2 is OCH3, and R3 is Et), 8d, 8e (R1 is 2-F, R2 is
OCH3, and R3 is Et), 8f (R1 is H, R2 is OC2H5, and R3 is n-Pr),
8h, 8i (R1 is 2-F, R2 is OC2H5, and R3 is Et), 8j (R1 is H, R2 is
OC2H5OC2H5, and R3 is Et), 8m (R1 is H, R2 is OC2H5OC2H5,
and R3 is n-Bu), 8n (R1 is 2-F, R2 is OC2H5OC2H5, and R3 is
Et), 8o, 8p (R1 is H, R2 is NH2, and R3 is n-Pr), 8t, 8u (R1 is
H, R2 is PhCH2NH2, and R3 is n-Pr), and 8v (R1 is H, R2 is
PhCH2NH2, and R3 is i-Pr) have curative activities against TMV
of up to 56.7%, 60.2%, 58.4%, 50.5%, 55.8%, 50.7%, 55.2%,
51.8%, 52.7%, 54.4%, 53.9%, 55.0%, 53.8%, and 52.9%,
respectively, at 500 µg/mL. The other compounds have a
relatively lower curative activity than those of 8a, 8d, 8e, 8f,
8h, 8i, 8j, 8m, 8n, 8o, 8p, 8t, 8u, and 8v. Comparison of
biological activities among 8a-8x shows functional groups R2
) OMe, OEt and R3 ) n-Bu to be potentially more active than
R2 ) NH2, PHCH2NH2, OC2H5OC2H5 and R3 ) n-Pr, i-Pr, Et.
inhibn rate (%) )
av local lesion no. of control -
av local lesion no. of drug-treated
× 100% (2)
av local lesion no. of control
RESULTS AND DISCUSSION
Synthesis. R-Benzylphosphonates 5a-5e were synthesized
from dialkyl phosphites and benzaldehyde in accordance with
Scheme 2. addition of p-toluenesulfonic acid into the imine is
highly exothermic and may cause an undesired side reaction.
Controlling the reaction temperature near 0 °C during its addition
is the most important factor in the synthesis of R-benzylphos-
phonates.
Esters 6a-6c were prepared conveniently from cyanoacetic
acid and primary alcohols in the presence of a catalytic amount
of anhydrous H2SO4. Amides 6d and 6e were synthesized from
ethyl cyanoacetate and the corresponding amine in excellent
yields. Intermediate 2-cyano-3,3-dimethylthioacrylate 7 was
achieved by treating the corresponding ester (amide) 6a-6e with
carbon disulfide and 2 mol of dimethyl sulfate in a one-pot
reaction using sodium hydroxide as alkali.
The desired products (8a-8x) were then obtained in moderate
yields (Scheme 2) by a nucleophilic substitution reaction
involving intermediates 7 and R-aminobenzylphosphonate
5a-5e in refluxing ethanol. This reaction is assumed to be
initiated by a nucleophilic attack followed by expulsion of SCH3.
The Michael-type attack of the R-aminophosphonate at the R,ꢀ-
unsaturated center presumably leads to a transition state in which
the orientation of R-aminophosphonate and ester carbonyl is
cis due to the presence of an intramolecular hydrogen bonding.
The (E)-configuration of the title compounds was established
by X-ray single crystal structure analysis of typical 8v, as shown
in Figure 1. All compounds were confirmed by elemental
analyses and IR, H NMR, and 13C NMR spectral data.
1

Cyanoacrylates Containing R-Aminophosphonate Moiety
J. Agric. Food Chem., Vol. 56, No. 13, 2008 5245
Table 1. Protection Effect, Inactivation Effect, and Curative Effect of the New Compounds against TMV in Vivoa
agent
concentration (µg/mL)
protection effect (%)
inactivation effect (%)
curative effect (%)
8a
8b
8c
8d
8e
8f
8g
8 h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
29.6* ( 4.9
44.4* ( 4.0
40.8* ( 4.2
55.9 ( 3.8
44.0* ( 3.3
41.6 ( 5.0
37.6 ( 3.0
56.5 ( 3.8
48.3* ( 4.0
41.2* ( 3.2
43.1 ( 2.8
38.4 ( 2.8
44.4* ( 2.9
48.3 ( 4.5
55.6* ( 3.2
45.8* ( 5.2
54.4* ( 4.4
40.2* ( 2.6
42.8* ( 3.2
55.1* ( 5.9
42.4* ( 4.1
39.0* ( 3.5
45.0* ( 2.1
47.7* ( 3.7
59.9* ( 2.5
64.1* ( 1.6
47.1* ( 2.2
45.7* ( 3.0
92.8** ( 1.9
92.1* ( 1.9
71.0* ( 2.8
37.8* ( 4.1
84.0** ( 2.1
74.1* ( 2.8
46.8* ( 3.1
51.5* ( 3.5
55.9* ( 4.9
80.6 ( 1.4
70.0* ( 1.6
60.8* ( 3.7
63.0* ( 2.2
5.7 ( 2.1
56.7* ( 2.9
37.7* ( 4.6
43.3* ( 2.7
60.2* ( 2.6
58.4* ( 3.4
50.5 ( 4.3
42.8* ( 3.9
55.8* ( 4.2
50.7* ( 3.6
55.2* ( 3.1
43.2 ( 2.7
35.1* ( 4.2
51.8* ( 2.8
52.7* ( 3.9
54.4* ( 3.6
53.9 ( 5.4
28.8 ( 4.8
25.4* ( 3.9
25.4* ( 2.1
55.0* ( 2.9
53.8* ( 4.3
52.9 ( 5.9
28.4 ( 2.5
49.9* ( 2.2
55.8* ( 1.7
9.6 ( 2.4
8s
8t
8u
8v
8w
8x
70.7* ( 2.3
51.9* ( 3.0
50.0* ( 2.9
51.5* ( 2.3
11.0 ( 0.9
73.4** ( 2.8
99.5** ( 2.9
Ningnamycin
a All results are expressed as mean ( SD; n ) 3 for all groups; *P < 0.05, **P < 0.01.
Table 2. Antiviral Activities in Vivo (%) of Various Concentrations of Compounds 8d, 8e, 8f, 8h, 8i, 8m, 8n, 8s, and 8x against TMV
inactivation effect (%)
compd.
500 µg/mL
250 µg/mL
125 µg/mL
62.5 µg/mL
30.7 µg/mL
EC50(µg/mL)
8d
8e
8f
8 h
8i
8m
93.6
93.7
72.0
85.1
75.0
80.2
70.5
71.1
74.9
99.0
70.2
69.7
50.1
65.7
64.1
62.0
48.8
49.0
58.9
80.0
66.9
60.6
47.9
51.6
50.1
53.8
44.2
46.2
48.9
70.0
53.7
52.5
33.1
48.5
39.1
42.8
34.4
35.8
41.2
60.1
37.6
40.8
20.9
42.6
30.7
27.8
20.8
26.9
29.0
42.1
55.5
55.3
159.0
62.6
118.2
87.9
167.3
150.9
127.9
50.9
8n
8s
8x
Ningnamycin
In addition, as shown in Table 2, compounds 8d, 8e, 8f, 8h,
8i, 8m, 8n, 8s, and 8x were found to display good antiviral
activities. These compounds were bioassayed further to inves-
tigate their inactivation activities at different concentrations with
Ningnanmycin serving as the commercial control. As shown in
Table 2, the inactivation effect against TMV of compounds 8d,
8e, 8f, 8h, 8i, 8m, 8n, 8s, and 8x are significant. The EC50 values
were 55.5, 55.3, 159.0, 62.6, 118.2, 87.9, 167.3, 150.9, and 127.9
µg/mL, respectively. Among these compounds, 8d and 8e had
more potent antiviral activity than the others, being similar to
that of Ningnanmycin (EC50 ) 50.9 µg/mL) against TMV.
In summary, a series of new cyanoacrylate derivatives
containing R-aminophosphonate moieties 8a-8x were designed
and synthesized by refluxing a mixture of alkyl 2-cyano-3,3-
dimethylthioacrylate or cyarylamide and R-aminobenzylphos-
phonate in ethanol. The in vivo tests indicated that compounds
8d and 8 h exhibited excellent protection effects against TMV
and that the curative activity of compound 8d against TMV is
much higher than that of Ningnanmycin, while a very similar
inactivation bioactivity level of compounds 8d and 8e and
Ningnanmycin against TMV was observed. Therefore, the
present work demonstrates that the antiviral activity of cy-
anoacrylate derivatives was significantly improved via the
introduction of the R-aminophosphonates moiety. Effects of
steric, hydrophobic, electrostatic, and electrostatic parameters
on structure-activity relationships and structural modification
studies of compounds 8d, 8e, and 8h are currently underway.
Supporting Information Available: Detailed procedure for
the synthesis of 5a-f, 6a-e, and 7a-e and analytical data for
8b-8x. This information is available free of charge via the
Internet at http://pubs.acs.org.
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Received for review February 9, 2008. Revised manuscript received
March 22, 2008. Accepted April 10, 2008. We thank the National Key
Program for Basic Research (No. 2003CB114404), the Cultivation Fund
of the Key Scientific and Technical Innovation Project, the Ministry of
Education of China (No. 705039), the National Basic Research Priorities
Program (No. 2005CCA01500), and the National Natural Science
Foundation of China (No. 20672024) for financial support.
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