Novel α,β-unsaturated amide derivatives bearing α-amino phosphonate moiety as potential antiviral agents

Article abstract of DOI:10.1016/j.bmcl.2017.08.048

Based on flexible construction and broad bioactivity of ferulic acid, a series of novel α,β-unsaturated amide derivatives bearing α-aminophosphonate moiety were designed, synthesized and systematically evaluated for their antiviral activity. Bioassay results indicated that some compounds exhibited good antiviral activities against cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV) in vivo. Especially, compound g18 showed excellent curative and protective activities against CMV, with half-maximal effective concentration (EC₅₀) values of 284.67 μg/mL and 216.30 μg/mL, which were obviously superior to that of Ningnanmycin (352.08 μg/mL and 262.53 μg/mL). Preliminary structure-activity relationships (SARs) analysis revealed that the introduction of electron-withdrawing group at the 2-position or 4-position of the aromatic ring is favorable for antiviral activity. Present work provides a promising template for development of potential inhibitor of plant virus.

Full text of DOI:10.1016/j.bmcl.2017.08.048

Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel
a,b-unsaturated amide derivatives bearing a-amino phosphonate
moiety as potential antiviral agents
⇑
Xianmin Lan, Dandan Xie, Limin Yin, Zhenzhen Wang, Jin Chen, Awei Zhang, Baoan Song, Deyu Hu
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on flexible construction and broad bioactivity of ferulic acid, a series of novel
amide derivatives bearing a-aminophosphonate moiety were designed, synthesized and systematically
evaluated for their antiviral activity. Bioassay results indicated that some compounds exhibited good
antiviral activities against cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV) in vivo.
Especially, compound g18 showed excellent curative and protective activities against CMV, with half-
a
,b-unsaturated
Received 11 June 2017
Revised 16 August 2017
Accepted 21 August 2017
Available online xxxx
maximal effective concentration (EC50) values of 284.67
l
g/mL and 216.30
lg/mL, which were obviously
Keywords:
Ferulic acid
superior to that of Ningnanmycin (352.08 g/mL and 262.53
l
lg/mL). Preliminary structure-activity rela-
tionships (SARs) analysis revealed that the introduction of electron-withdrawing group at the 2-position
or 4-position of the aromatic ring is favorable for antiviral activity. Present work provides a promising
template for development of potential inhibitor of plant virus.
a
a
,b-Unsaturated amide
-Aminophosphonate
SARs
Ó 2017 Elsevier Ltd. All rights reserved.
Antiviral activity
Plant virus caused dramatic loss in agriculture and horticulture
all over the world.1 As the most common plant viruses, cucumber
mosaic virus (CMV) and tobacco mosaic virus (TMV) which were
widely distributed in the plant kingdom could infect many plants,
including cucumbers, tomatoes, tobacco, pepper, and ornamental
plants.2 Ningnanmycin is the most effective commercially avail-
able anti-plant virus agent and is widely used to prevent plant
virus disease. However, the use of this agent for field trial is largely
limited by its poor efficacy and high control cost.3–5 Accordingly,
many efforts have been made to develop novel and more potent
antiviral agents, some natural and synthesized products6–11 have
been investigated about their antiviral activity. However, few of
them have been successfully developed and applied in agriculture.
Thus, the development of novel and more practical antiviral agents
is increasingly required.
Natural product-based antiviral agents possess many advan-
tages, such as low mammalian toxicity, easy decomposition,
friendly to environment, unique mode of action, and so on.12,13
Therefore, using natural products as lead compounds to develop
new pesticides is a potential alternative. As a natural compound,
ferulic acid (Fig. 1) widely distributed in plant14 and exhibited
diverse physiological activities such as reduction of serum
cholesterol levels15 antioxidant properties16 antibacterial17 and
anticancer18,19 activities. Intriguingly, ferulic acid possess a unique
skeleton with A ring and ,b-unsaturated carboxylic acid (Fig. 1).
Moreover, previous structure-activity relationship study implied
that the ,b-unsaturated carboxylic acid fragment of ferulic acid
is important for the antiviral activity.20 Additionally, as naturally
occurring amino acid analogues, -aminophosphonate and their
a
a
a
derivatives possess broad spectrum of biological activities.21–28 In
our previous work, some substituted amino aryl phosphonate
derivatives exhibited remarkable inhibitory effect against plant
virus.29–34 It is noteworthy that phosphonates possess more lipo-
philic nature and cell permeability along with physiological stabil-
ity as the phosphorus-carbon bond which is not susceptible to
enzymatic degradation by phosphatases.35,36
Considering the above, we proposed to replace the
rated carboxylic acid fragment of ferulic acid with ,b-unsaturated
amide bearing -aminophosphonate based on the bioisosterism,
a,b-unsatu-
a
a
which is an effective approach for developing and optimizing
bioactive lead compounds. Moreover, many studies have revealed
that the introduction of substituted benzyl groups into the pheno-
lic hydroxyl group (ring B) might favour bioactivity of the whole
molecule (Fig. 1).37–40 Inspired by it, we continued to place various
substituted benzyl groups at the hydroxy group on ring A (Fig. 1),
and synthesized a series of novel
a,b-unsaturated amide deriva-
tives bearing -aminophosphonate moiety. Their antiviral activity
a
against CMV and TMV in vivo were evaluated and their struc-
ture-activity relationships were preliminarily analyzed. To the best
⇑
Corresponding author.
E-mail address: dyhu@gzu.edu.cn (D. Hu).
http://dx.doi.org/10.1016/j.bmcl.2017.08.048
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lan X., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.08.048

2
X. Lan et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Fig. 1. Design of the target compounds.
of our knowledge, it’s the first report on the antiviral activity of
a
,b-
(m, 11H, Ar-H, Ar-CH@CH), 7.16 (s, 1H, Ar-H), 7.06 (dd, J = 15.7,
unsaturated amide derivatives bearing
moiety.
a-aminophosphonate
7.7 Hz, 2H, Ar-H), 6.77 (d, J = 15.8 Hz, 1H, CH@CH-CO), 5.54 (dd,
J = 21.3, 9.8 Hz, 1H, Ar-CH), 5.09 (s, 2H, Ar-OCH2), 4.01–3.79 (m,
The synthetic route for the target compounds g1–g26 was
summarized in Scheme 1. Intermediates c1–c2 were synthesized
according to literature method as described.41 Intermediate d
was prepared by literature method.42 Intermediates f1–f13 were
prepared by literature method.40 Target compounds g1–g26 were
synthesized via dehydration condensation reaction between
intermediates c1–c2 and f1–f13. All the target compounds were
characterized by 1H NMR, 13C NMR, 31P NMR, IR and HRMS, the
experimental details and data were provided in the Supplemen-
tary data and the representative data for g1 were shown as
below.
7H, OCH2CH3, Ar-OCH3), 1.15 (t, J = 7.0 Hz, 3H, OCH2CH3), 1.06 (t,
J = 7.0 Hz, 3H, OCH2CH3); 13C NMR (125 MHz, CDCl3, ppm) d:
165.55, 150.04, 149.78, 142.19, 136.70, 134.20, 134.04, 129.58,
128.92, 128.72, 128.09, 128.02, 127.29, 122.02, 117.78, 113.56,
110.47, 70.95, 63.53 (d, JC-P = 20.0 Hz), 56.10, 50.35, 49.12, 16.57,
16.27; 31P NMR (202 MHz, DMSO-d6, ppm) d: 21.84; HRMS (ESI):
Calculated for C28H33O6NP [M+H]+: 510.2040, found: 510.2037.
The anti-CMV activities of compounds g1–g26 were tested
using the half-leaf method.4 The inhibitory effects against CMV of
the target compounds were summarized in Table 1. As shown in
Table 1, most of the target compounds exhibited good to excellent
Data for diethyl (E)-((3-(4-(benzyloxy)-3-methoxyphenyl)acry-
lamido)(phenyl) methyl) phosphonate (g1). White solid; m.p. 118–
curative activities against CMV at 500 lg/mL. Compounds g3, g5,
120 °C; yield, 56.2%; IR (KBr, cmÀ1
) m: 3275.5, 2987.3, 1672.3,
g8, g16, g18, g21, and g23 showed higher curative activities
(54.2%, 54.7%, 54.9%, 55.6%, 58.2%, 57.1%, and 55.0%, respectively)
against CMV than Ningnanmycin (53.8%). Meanwhile, compounds
1626.7, 1514.6, 1264.3, 1139.2, 1026.3, 978.5; 1H NMR (500 MHz,
DMSO-d6, ppm) d: 9.01 (d, J = 8.9 Hz, 1H, CO-NH), 7.48–7.30
Scheme 1. Synthetic route of the target compounds.
Please cite this article in press as: Lan X., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.08.048

X. Lan et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
3
Table 1
Antiviral activity of the target compounds against CMV in vivo.
Compd.
Curative activitya (%)
Protection activitya(%)
Inactivation activitya (%)
Curative activity EC50
(lg/mL)
Protection activity EC50 (lg/mL)
g1
g2
g3
g4
g5
g6
g7
g8
39.4 2.5
50.2 1.7
54.2 2.4
34.8 3.2
54.7 2.5
38.6 3.6
51.1 2.2
54.9 3.1
28.5 2.6
50.1 2.9
48.2 3.3
43.1 3.4
33.4 2.4
43.4 2.6
51.2 3.4
55.6 2.8
33.8 5.3
58.2 3.3
36.2 3.9
52.2 3.2
57.1 2.3
30.2 4.7
55.0 2.6
51.1 3.6
46.4 3.4
40.3 3.4
53.8 2.1
41.2 2.7
52.5 3.2
56.3 2.9
35.6 4.2
57.5 2.7
31.2 4.2
49.2 3.3
54.2 3.4
28.2 3.8
48.7 2.6
40.4 3.9
46.2 2.8
35.2 2.6
46.4 2.0
55.2 5.3
57.4 4.3
36.6 5.6
59.7 2.2
30.6 3.4
53.6 3.1
58.6 3.2
27.3 3.2
56.2 2.8
55.4 3.2
54.2 2.8
36.5 2.6
57.2 1.9
55.8 2.4
69.2 3.1
68.2 4.8
56.2 2.7
75.5 5.4
49.2 2.2
65.5 4.5
85.4 2.4
46.2 3.2
65.5 3.1
73.6 2.8
66.5 2.6
43.2 2.4
66.8 2.2
65.6 4.1
78.6 3.6
55.4 2.6
80.5 3.6
65.2 2.6
77.3 4.2
83.2 2.7
45.3 2.5
78.6 3.2
79.6 4.4
76.5 2.6
50.2 2.5
92.7 2.8
996.14 7.05
456.73 7.83
332.06 5.46
1505.81 11.23
342.36 4.55
851.67 10.6
428.12 6.33
347.77 4.15
1504.95 17.61
436.73 6.92
534.02 7.32
398.27 8.37
1411.34 12.64
777.43 8.69
408.37 6.47
323.27 6.18
1544.82 7.37
284.67 4.35
900.72 9.92
400.78 7.22
296.99 4.35
1511.53 12.7
347.89 5.57
396.61 5.66
505.25 4.45
874.09 4.63
352.08 5.11
826.71 6.19
306.32 4.44
292.82 5.16
/
254.53 5.11
1613.66 12.39
558.39 8.78
287.64 4.82
/
/
/
/
/
/
273.43 5.59
236.90 4.15
/
216.30 4.09
/
314.77 5.62
227.04 3.43
1128.75 13.34
278.15 5.33
308.70 6.11
302.46 7.03
/
g9
g10
g11
g12
g13
g14
g15
g16
g17
g18
g19
g20
g21
g22
g23
g24
g25
g26
Controlb
262.53 4.19
a
Average of three replicate at 500
The commercial anti-plant virus agent Ningnanmycin was used as control.
l
g/mL.
b
g5, g16, g18, and g21 also displayed comparative or even higher
protective effects (57.5%, 57.4%, 59.7%, and 58.6%, respectively)
against CMV compared to Ningnanmycin (57.2%).
To gain insight into the potential inhibitory capacity of these
compounds against CMV, the EC50 values of curative and protective
activities of some target compounds were evaluated and listed in
Table 1. Compounds g3, g5, g8, g16, and g23 exerted comparative
curative activities (with EC50 values of 332.06, 342.36, 347.77,
190.74, 191.04, 180.37, and 183.16
were comparable to that of Ningnanmycin (165.95
Bioassays results showed that the ,b-unsaturated amide
derivatives bearing -aminophosphonate moiety exhibited excel-
l
g/mL, respectively, which
lg/mL).
a
a
lent curative activities against CMV. Accordingly, the structure-
activity relationships (SARs) analysis was deduced on the basis of
the EC50 values of the anti-CMV activities. The results indicated
that the compounds bearing electron-withdrawing group at the
4-position of the substituted aromatic rings (R2) are favorable for
antiviral activity, for examples g2 (4-F-Ph), g3 (4-Cl-Ph), g5 (4-
CF3-Ph) > g1 (Ph) > g6 (4-CH3-Ph), and g15 (4-F-Ph), g16 (4-Cl-
Ph), g18 (4-CF3-Ph) > g14 (Ph) > g19 (4-CH3-Ph). Meanwhile, we
found the similar trend of 2-position on R2 relative to 4-position,
such as, g7 (2-Cl-Ph), g8 (2-CF3-Ph) > g9 (2-CH3-Ph) and g20 (2-
Cl-Ph), g21 (2-CF3-Ph) > g22 (2-CH3-Ph). Unfortunately, the com-
pounds containing two electron-withdrawing groups on R2 and
R1 bearing H are unfavorable for antiviral activity compared to
one electron-withdrawing group on R2, this trend was confirmed
with the orders g11 (2,4-diF-Ph), g12 (2-Cl-4-F-Ph) < g2 (4-F-Ph)
and g10 (2,4-diCl-Ph), g12 (2-Cl-4-F-Ph) < g3 (4-Cl-Ph). The intro-
duction of pyridine heterocyclic instead of benzene led to signifi-
cantly decreased inhibitory activities against CMV. Additionally,
most of compounds whose R1 are Cl atoms showed higher anti-
CMV activities than corresponding compounds whose R1 are H
atoms except for compounds g17, g19, g22, and g25. These inter-
esting results generally demonstrated that the introduction of Cl
323.27, and 347.89
to that of Ningnanmycin (352.08
g18 and g21 possessed obviously higher curative activities (with
EC50 values of 284.67 and 296.99 g/mL, respectively) against
CMV than that of Ningnanmycin (352.08 g/mL). Moreover, com-
lg/mL, respectively) against CMV compared
l
g/mL). Especially, compounds
l
l
pounds g5, g16, g18, and g21 exerted more potent protective
effects (with EC50 values of 254.53, 236.90, 216.30, and
227.04
mycin (262.53
l
g/mL, respectively) against CMV than that of Ningnan-
g/mL).
l
The anti-TMV activities of compounds g1–g26 were also tested
using the half-leaf method and the results of the preliminary bioas-
says were listed in Table 2. As shown in Table 2, compounds g5,
g16, g18, and g23 showed similar curative activities against TMV
to that of Ningnanmycin (56.2%) at 500 lg/mL, with the values of
51.7%, 52.6%, 53.7%, and 52.2%, respectively. Compounds g5, g9,
g16, g18, g21, and g24 exhibited 68.3%, 67.6%, 70.4%, 72.5%,
68.7%, and 71.4% protective effects at 500 lg/mL, respectively,
which were comparable to that of Ningnanmycin (73.3%). In addi-
tion, compounds g16 and g24 displayed comparable inactivating
efficacies (89.6% and 90.5%, respectively) to that of Ningnanmycin
(92.5%).
atom at the 4-position of the benzene ring belong to the
a-
aminophosphonate moiety did somewhat contribute to antiviral
activity.
Based on the preliminary biological evaluation, The EC50 values
of curative and protective activities against TMV of some target
compounds were evaluated. As shown in Table 2, compound g18
possessed excellent curative activity against TMV, with EC50 value
In summary, on the basis of the structure of naturally occurring
ferulic acid, a series of novel
a,b-unsaturated amide derivatives
bearing -aminophosphonate moiety were designed, synthesized,
a
and systematically evaluated for their antiviral activity against
CMV and TMV in vivo. The bioassay results indicated that some
compounds exhibited good antiviral activities, of which compound
g18 possessed excellent curative and protective activities against
of 285.42
(254.91 g/mL). Compounds g5, g16, g18, and g24 exhibited
remarkable protective activities against TMV, with EC50 values of
lg/mL, which was similar to that of Ningnanmycin
l
Please cite this article in press as: Lan X., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.08.048

4
X. Lan et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Table 2
Antiviral activity of the target compounds against TMV in vivo.
Compd.
Curative activitya (%)
Protection activitya(%)
Inactivation activitya (%)
Curative activity EC50
(
lg/mL)
Protection activity EC50 (lg/mL)
g1
g2
g3
g4
g5
g6
g7
g8
40.2 4.1
45.2 3.2
49.7 2.7
38.8 3.5
51.7 2.5
32.6 3.6
43.8 4.0
45.8 2.5
34.5 5.0
45.6 4.2
48.2 3.7
44.4 4.1
23.4 4.1
45.4 2.6
49.2 3.4
52.6 2.8
40.5 4.4
53.7 3.6
34.6 3.7
49.5 3.2
47.9 2.5
30.5 3.7
52.2 3.9
50.2 3.4
48.4 3.5
38.4 3.5
56.6 2.6
55.2 2.5
62.6 2.1
65.8 3.7
45.6 4.2
68.3 2.9
34.4 3.3
57.7 5.2
60.7 2.8
67.6 3.7
56.1 3.2
48.8 2.3
54.6 2.8
33.6 2.8
46.4 2.4
65.2 3.7
70.4 4.3
48.6 5.6
72.5 3.2
46.2 3.5
63.6 3.8
68.7 3.2
52.3 3.6
58.8 1.7
71.4 2.2
57.6 3.9
46.5 3.9
73.3 1.7
60.2 3.7
79.3 4.5
65.2 4.0
75.6 2.5
78.4 3.4
69.2 2.7
85.5 3.5
74.4 2.4
76.2 3.0
67.5 3.4
75.3 2.7
66.4 2.7
43.4 2.7
67.4 2.7
81.7 2.3
89.6 2.2
86.4 4.1
86.6 3.1
75.9 2.3
87.2 2.2
76.2 2.2
75.3 3.5
88.7 3.1
90.5 4.2
68.2 2.4
40.2 2.3
92.5 2.3
981.21 10.66
369.94 6.98
310.32 5.27
/
302.09 6.29
1511.97 11.64
/
319.39 6.22
771.25 8.99
/
410.31 7.01
/
/
/
448.67 6.15
242.49 6.51
215.21 4.52
/
190.74 3.67
/
/
267.59 4.19
210.34 6.14
/
528.81 8.10
/
/
/
227.98 5.52
191.04 4.25
/
180.37 5.57
/
247.92 6.21
202.38 4.55
735.74 9.18
320.72 6.77
183.16 5.10
/
g9
g10
g11
g12
g13
g14
g15
g16
g17
g18
g19
g20
g21
g22
g23
g24
g25
g26
Control
/
296.84 6.14
/
285.42 5.56
/
350.23 4.87
/
/
300.44 6.11
310.66 6.51
/
/
/
b
254.91 3.07
165.95 3.12
a
Average of three replicate at 500
The commercial anti-plant virus agent Ningnanmycin was used as control.
l
g/mL.
b
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CMV with EC50 values of 284.67 and 216.30
obviously superior to that of Ningnanmycin (352.08 and
lg/mL, which were
262.53 lg/mL). SARs analysis implied that the introduction of elec-
tron-withdrawing groups at the 2-position or 4-position of the R2
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Cl atom at the 4-position of the benzene ring belong to the
aminophosphonate moiety did somewhat contribute to antiviral
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (No. 21672044 and 21562013) and
Subsidy Project for Outstanding Key Laboratory of Guizhou Pro-
vince in China (20154004) and the Provincial University Coopera-
tion Plan of Guizhou Province in China (No. 20147001) and
Collaborative Innovation Center for Natural Products and Biological
Drugs of Yunnan for supporting the project.
A. Supplementary data
Supplementary data associated (containing information on the
synthesis, characterization, and bioactivity test methods of the title
compounds) with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2017.08.048.
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Please cite this article in press as: Lan X., et al. Bioorg. Med. Chem. Lett. (2017), http://dx.doi.org/10.1016/j.bmcl.2017.08.048