Synthesis and antiviral activities of amide derivatives containing the &α-aminophosphonate moiety

Article abstract of DOI:10.1021/jf072394k

Starting from (substituted-)benzaldehydes, the title compounds 6 were synthesized through five step reactions. Benzaldehydes were treated with ammonium hydroxide, followed by dialkyl phosphite, to give dialkyl N-(arylmethylene)-1-amino-1-aryl methylphosphonates (3). Phosphonates 3 were then easily hydrolyzed to give dialkyl 1-amino-1-aryl-methylphosphonates 5. Target compounds 6 were then obtained by the reaction of 5 and substituted benzoic or cinnamic acid. Their structures were clearly verified by spectroscopic data (IR, 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 6g, 6l, and 6n had the same inactivation effect of TMV (EC₅₀ = 54.8, 60.0, and 65.2 μg/mL, respectively) as commercial product Ningnanmycin (EC₅₀ = 55.6 μg/mL). To the best of our knowledge, this is the first report on the synthesis and antiviral activity of amide derivatives containing an α-aminophosphonate moiety.

Full text of DOI:10.1021/jf072394k

998 J. Agric. Food Chem. 2008, 56, 998–1001
Synthesis and Antiviral Activities of Amide
Derivatives Containing the r-Aminophosphonate
Moiety
DE-YU HU, QIONG-QIONG WAN, SONG YANG, BAO-AN SONG,*
PINAKI S. BHADURY, LIN-HONG JIN, KAI YAN, FANG LIU, ZHUO CHEN, 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, P. R. China
Starting from (substituted-)benzaldehydes, the title compounds 6 were synthesized through five step
reactions. Benzaldehydes were treated with ammonium hydroxide, followed by dialkyl phosphite, to
give dialkyl N-(arylmethylene)-1-amino-1-aryl methylphosphonates (3). Phosphonates 3 were then
easily hydrolyzed to give dialkyl 1-amino-1-aryl-methylphosphonates 5. Target compounds 6 were
then obtained by the reaction of 5 and substituted benzoic or cinnamic acid. Their structures were
clearly verified by spectroscopic data (IR, 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 6g,
6l, and 6n had the same inactivation effect of TMV (EC50 ) 54.8, 60.0, and 65.2 µg/mL, respectively)
as commercial product Ningnanmycin (EC50 ) 55.6 µg/mL). To the best of our knowledge, this is the
first report on the synthesis and antiviral activity of amide derivatives containing an R-aminophos-
phonate moiety.
KEYWORDS: Amide; r-aminophosphonate moiety; antiviral activity; synthesis
INTRODUCTION
is shown in Scheme 2. The bioassay test showed that the new
compounds 6 possessed weak-to-good antiviral activities. To
the best of our knowledge, this is the first report on the synthesis
and antifungal and antiviral activity of amide derivatives
containing an R-aminophosphonate moiety.
Recently, a variety of the reports regarding synthetic studies
of the amide derivatives have been presented because they were
documented to exhibit a wide range of biological activities.
Some derivatives of amide can serve not only as agrochemicals
such as fungicide, insecticide, and plant virucide, but also as
medicines such as antitumor agents (1–6). A large volume of
research on their synthesis and biological activities has been
reported during the last ten years (7, 8). On the other hand,
R-aminophosphonates have broad bioactivities and are widely
used as fungicide, plant virucide, and herbicide. Among these
compounds, studies are mainly concentrated on those con-
taining heterocycle moieties such as thiophene, furan, pyrole,
1,3,4-thiadiazole, and benzothiazole moieties, and many com-
pounds were reported with excellent bioactivities (9–15).
In our previous work, many substituted aryl aminophospho-
nate derivatives were synthesized and wer found to have good
antiviral activities (16–20). Hence, it is naturally interesting
whether or not the amide derivatives of R-aminophosphonates
will improve their antiviral activies. Also, few literatures have
yet reported this kind of amidylphosphonate compounds (21–23).
To extend our research work of developing R-aminophospho-
nates as antiviral agent, we designed and synthesized some novel
amidyl phosphonate derivatives, (Scheme 1). The synthetic route
MATERIAL AND METHODS
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
1
spectrometer in KBr disks. H, 13C, and 31P NMR (solvent dimethyl
sulfoxide (DMSO)) spectra were performed on a JEOL-ECX 500 NMR
spectrometer at room temperature using TMS as 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 analytical reagent grade or were chemically pure. All
solvents were dried, deoxygenated, and redistilled before use. Diethyl
Scheme 1. Structure comparison of amino-phosphonates and carbony-
lamino-phosphonates
* Corresponding author. E-mail: songbaoan22@yahoo.com.
10.1021/jf072394k CCC: $40.75
2008 American Chemical Society
Published on Web 01/10/2008

Synthesis and Antiviral Activities of Amide Derivatives
J. Agric. Food Chem., Vol. 56, No. 3, 2008 999
inoculated with the mixture of solvent and the virus for control. The
local lesion numbers were recorded 3–4 d after inoculation (27). Three
repetitions were conducted for each compound.
Scheme 2. Synthetic route of amide analogues containing R-aminophos-
phonate 6
Curative Effect of Compounds on TMV In Vivo. Growing leaves
of Nicotiana tabacum. L of the same ages were selected. The tobacco
mosaic virus (with a concentration of 6 × 10-3mg/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 d after inoculation
(27). For each compound, three repetitions were measured. The
inhibition rate of the compound was then calculated according to the
following formula (“av”, average).
Inhibition rate (%) )
av local lesion numbers of control
(
)
not treated with compound -
av local lesion numbers smeared with drugs
av local lesion numbers of control
× 100%
(
)
(
)
not treated with compound
RESULTS AND DISCUSSION
Synthesis. Amide compounds can be synthesized by treating
amine with acyl chloride. However, the side products HCl
generated in this method are harmful to the current reaction
because the ester group of the phosphonate is easily removed
by acidolysis. Thus, amide compounds containing phosphonate
were synthesized by the coupling reaction of dialkyl amino-
(substituted)phenyl-methylphosphonate and substituted benzoic
of cinnamic acid in the presence of DCC. The reaction
temperature during drop addition of DCC is crucial in this
exthothermal reaction. When DCC was dropped into the
reactants, the reaction temperature rises quickly and side
reactions become significant. Thus, the reaction temperature
during drop addition of DCC was controlled at 0 °C. This
method is easy, rapid, and moderate-yielding for the synthesis
of title compounds 6. Under this condition, target compounds
6 were synthesized in the yields from 40.5 to 90.6%, and their
structures were established by well defined IR, NMR, and
elemental analysis (see Supporting Information).
phosphite and di-n-propyl phosphite were prepared according to
literature methods as described (24). Intermediates 5a-c were prepared
according to the reported methods (25), and the detailed procedure can
be found in the Supporting Information.
General Procedure for the Preparation of Compounds 6a-s. A
solution of aromatic acid (1 mmol) in toluene (10 mL) was stirred,
followed by the addition of intermediate 5 (1 mmol), and then the
reaction system was cooled down to 0 °C. Then, 1,3-dicyclohexyl-
carbodiimide (DCC) (1 mmol) in toluene (10 mL) was added. The
mixture was reacted for 10∼24
h at 25 °C, and then the
1,3-dicyclohexylurea (DCU) was filtered off. The toluene solvent was
evaporated to the crude product, which was purified by chromatography
on silica using a mixture of petroleum ether and ethyl acetate (4:1) as
an eluant to give the target compounds in yields of 40.5-90.6%. The
example data of 6a was shown as follows, and data for 6b-s can be
found in the Supporting Information.
Data for Diethylphenyl(3,4,5-trimethoxybenzamido)methylphos-
phonate (6a). White crystal; mp, 149∼151 °C; yield, 40.5%; IR (KBr):
νmax 3246.2, 2995.5, 1649.1, 1246.0, 1031.9; 1H NMR (500 MHz,
DMSO) δ: 1.10 (t, J ) 7.45 Hz, 3H, CH3), 1.32 (t, J ) 7.15 Hz, 3H,
CH3), 3.72∼4.19 (m, 13H, 3OCH3 + 2OCH2), 5.69∼5.73 (m, 1H, CH),
7.04∼7.53 (m, 7H, Ar-H + NH); 13C NMR (125 MHz, DMSO) δ:
166.53, 153.19, 141.30, 135.17, 129.13, 128.24, 28.19, 104.74, 63.57,
63.51, 60.90, 56.36, 51.33, 50.12, 16.45, 16.15; 31P NMR (200 MHz,
DMSO) δ: 22.18; Anal. Calcd for C21H28NO7P: C, 57.66; H, 6.45; N,
3.20. Found: C, 57.84; H, 6.62; N, 3.17.
Antiviral Biological Assay. Purification of Tobacco Mosaic Virus.
Using Gooding’s method (26), the upper leaves of Nicotiana tabacum
L inoculated with TMV were selected and were ground in phosphate
buffer and then filtered through double layer pledget. The filtrate was
centrifuged at 10 000g, treated twice with PEG, and then centrifuged
again. The whole experiment was carried out at 4 °C. Absorbance values
Antiviral Activity. The antiviral activity of compounds 6a-s
against TMV is assayed by the reported method (26, 27). The
results of in vivo bioassay against TMV are given in Table 1.
Commercially available plant virucide Ningnanmycin (28), also
probably the most successful registered plant antiviral agent by
now in China, was used as a reference antiviral agent. The data
provided in Table 1 indicate that the introduction of dialkyl-
phosphonyl in amide might improve their protective activities.
The title compounds 6a-s showed protection activity of
39.1–58.8%. Compound 6h (R1 is H, R2 is 3-FC6H4, and R3 is
Et), 6l (R1 is H, R2 is 2-ClC6H4, and R3 is Et), 6n (R1 is H, R2
is C6H5CH)CH, and R3 is Et), and 6r (R1 is H, R2 is 3,4,5-
tri-MeOC6H2, and R3 is n-Pr) have the same protection activity
(56.0, 58.0, 58.7, and 58.8%, respectively) as that of the standard
reference (60.2%). The highest protective activity was achieved
when R1 is H, R2 is 4-FC6H4, and R3 is Et (6g), with a protection
activity of 65.7% against TMV at 500 µg/mL recorded in this
case, which is equivalent to that of Ningnanmycin. From the
data presented in Table 1, it can be observed that the title
compounds 6a-s possess potential inactivation bioactivities,
with values of 45.6, 33.7, 42.4, 70.0, 80.0, 78.0, 99.1, 82.1,
45.3, 70.7, 62.2, 90.6, 39.0, 88.2, 51.5, 80.0, 86.6, 83.4, and
78.9% at 500 µg/mL, respectively. Among these compounds,
6g is much more active against TMV than the other ones, with
the inactivation rate of 99.1%, which is equivalent to Ningnan-
mycin (100%) against TMV at 500 µg/mL. The data also
were estimated to be at 260 nm using an ultraviolet spectrophotometer.
0.1%,260nm
Virus concentration ) (A260 × dilution ratio)/E
.
1cm
Protective Effects of Compounds on TMV In Vivo. The compound
solution was smeared on the left side while solvent was served as control
on the right side of growing Nicotiana tabacum. Lleaves 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 d
after inoculation were counted (27). Three repetitions were conducted
for each compound.
Inactivation Effect of Compounds on 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 Nicotiana tabacum. L., while the right side of the leaves was

1000 J. Agric. Food Chem., Vol. 56, No. 3, 2008
Hu et al.
Table 1. The Protection Effect, Inactivation Effect, and Curative Effect of the New Compounds against TMV In Vivoa
agents
concentration (µg/mL)
protection effect (%)
inactivation effect (%)
curative effect(%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
42.0* ( 1.9
41.2* ( 4.4
39.1* ( 1.2
43.1* ( 0.9
50.0* ( 1.4
42.0* ( 2.1
65.7* ( 4.9
56.0* ( 2.9
41.1 ( 3.9
41.0* ( 5.9
39.2* ( 1.0
58.0* ( 3.3
40.9* ( 0.5
58.7 ( 6.6
39.0* ( 2.2
44.0* ( 1.9
50.9* ( 1.9
58.8* ( 4.5
49.9* ( 2.2
60.2* ( 1.6
45.6** ( 1.1
33.7* ( 0.8
42.4* ( 2.0
70.0** ( 3.1
80.0* ( 2.9
78.0** ( 1.1
99.1** ( 2.0
82.1* ( 1.7
45.3* ( 1.6
70.7* ( 0.8
62.2* ( 0.6
90.6* ( 1.3
39.0* ( 1.8
88.2** ( 2.2
51.5* ( 0.6
80.0* ( 2.0
86.6* ( 2.9
83.4* ( 1.6
78.9** ( 2.2
100** ( 1.2
35.6* ( 0.6
17.1* ( 1.2
8.7 ( 0.6
32.2* ( 2.0
20.8* ( 1.2
53.6* ( 0.4
19.2* ( 0.5
24.6* ( 1.0
2.4 ( 0.9
6.2 ( 0.8
2.1 ( 0.2
20.0* ( 1.9
19.7* ( 15
50.0* ( 0.5
22.4* ( 1.2
53.7 ( 0.9
44.1 ( 2.0
55.0* ( 0.7
45.3* ( 2.6
55.4* ( 1.9
6q
6r
6s
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 Compounds 6a-6s
TMV
curative effect
125
inactivation effect
concentration (µg mL-1
)
500
250
EC50 (µg mL-1
)
250
125
62.5
EC50 (µg mL-1
)
6f
6g
6l
6n
6p
6q
6r
56.0
22.0
19.0
51.0
54.0
43.0
56.7
42.0
60.0
49.0
34.0
255.6
70.9
100.0
82.2
79.9
60.0
65.0
61.0
51.0
100.0
47.2
76.1
60.9
61.2
39.2
46.0
30.3
23.0
78.4
36.7
70.0
59.0
49.1
31.2
40.1
28.8
10.0
69.0
119.1
54.8
60.0
39.9
38.0
21.0
50.6
23.9
51.0
32.3
31.6
12.9
40.9
14.0
40.9
438.8
421.9
545.5
250.1
559.8
245.9
65.2
198.9
149.9
210.0
278.9
55.6
6s
ningnamycin
indicate that a change in the substituent might also affect the
curative activity of title compounds 6a-s. Compound 6f (R1 is
H, R2 is 2-FC6H4, and R3 is Et), 6p (R1 is H, R2 is 2-CF3C6H4,
and R3 is n-Pr), and 6r (R1 is H, R2 is 3,4,5-tri-MeOC6H2, and
R3 is n-Pr) have curative activities against TMV of up to 53.6,
53.7, and 55.0% at 500 µg/mL. The other compounds have a
relatively lower curative activity than those of 6f, 6p, and 6r.
In addition, as shown in Table 1, compounds 6f, 6g, 6l, 6n,
6p, 6q, 6r, and 6s were found to display good antiviral activities.
Thus, these eight compounds were further bioassayed to
investigate their activities at different concentrations, with
Ningnanmycin also used as the control. As shown in Table 2,
the curative effect against TMV of compounds 6f and 6r are
significant. Their EC50 values on TMV were 255.6 and 250.1
µg/mL, respectively, which are similar to that of Ningnanmycin
(245.9 µg/mL). Compounds 6g, 6l, and 6n were highly effective
at inactivating TMV, and the EC50 values were 54.8, 60.0, and
65.2 µg/mL, respectively. Among these compounds, 6g had
more potent antiviral activities against TMV than the other ones,
with the same antiviral activity against TMV as Ningnanmycin.
To the best of our knowledge, this is the first report about the
syntheses and antiviral activity of amide-based R-aminophos-
phonate derivatives. Further structural optimization and mode
of action (MOA) investigation are well under way.
material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENT
The authors wish to thank the National Key Program for Basic
Research (No. 2003CB114404), the Cultivation Fund of the Key
Scientific and Technical Innovation Project, Ministry of Educa-
tion of China (Nos. 705039 and 706051), and the National Basic
Research Priorities Program (No. 2005CCA01500) for the
financial support.
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Received for review August 9, 2007. Revised manuscript received
November 28, 2007. Accepted November 30, 2007.
JF072394K