Synthesis and biological evaluation of arylhydrazinocyanoacrylates and N-aryl pyrazolecarboxylates

Article abstract of DOI:10.1016/j.bmcl.2009.04.048

A series of arylhydrazino-substituted cyanoacrylates 3 and N-aryl pyrazolecarboxylates 6 were synthesized and their bioactivities were evaluated. Though compounds 3 were designed as herbicide, some of them showed fungicidal activity and anti-tumor activit

Full text of DOI:10.1016/j.bmcl.2009.04.048

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2953–2956
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of arylhydrazinocyanoacrylates
and N-aryl pyrazolecarboxylates
*
Yuxiu Liu, Shaohua Liu, Yonghong Li, Haibin Song, Qingmin Wang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of arylhydrazino-substituted cyanoacrylates 3 and N-aryl pyrazolecarboxylates 6 were synthe-
sized and their bioactivities were evaluated. Though compounds 3 were designed as herbicide, some of
them showed fungicidal activity and anti-tumor activity. Some of the compounds 6 exhibited plant
growth regulatory activity.
Received 13 January 2009
Revised 23 March 2009
Accepted 15 April 2009
Available online 18 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyanoacrylates
Pyrazoles
Fungicidal
Anti-tumor activity
Herbicidal activity
Ar
Ar
NH
Compounds containing 2-cyanoacrylate skeleton (structure 1)
are of increasing interest because of their herbicidal1–3, fungi-
cidal4,5 or antiviral4–8 activities. In recent years, our group focused
on ethoxyethyl 2-cyanoacrylates bearing heteroaryl methylenea-
mino group (structure 2), which exhibited excellent herbicidal
activities.1–3 They are photosystem II (PSII) electron transport
inhibitors, which displace the native plastoquinone QB from its
binding site at the PSII reaction center therefore inhibit the growth
of weeds by disrupting photosynthetic electron transport. Detailed
QSAR study9,10 revealed that the type of aryl and substituents on it
played significant roles on the activity; however, no obvious result
was got about methylene moiety between aryl group and atom N.
In this Letter we designed structure 3 by replacing arylmethyle-
neamino moiety with arylhydrazino group in order to study struc-
ture-activity relationship. Herein, we report the synthesis of
compounds 3 and related compounds with varieties of biological
activities.
Compounds 3 were first to be prepared by refluxing aryl-
hydrazines 4 with 3-methylthio or 3-methoxy-2-cyanoacrylate
5 in ethanol, the same procedure as we prepared compounds
2. The reaction did give products in 40–96% yields. However,
the products we got were not expected compounds. Their
structures were later determined by crystal X-ray diffraction to
be 1-aryl-5-amino-4-pyrazolecarboxylate 6. (Scheme 1, Table 1
and Fig. 1).
R2
NC
R1
NH
R2
NC
R2
NC
NH
O
O
O
OR3
O
O
O
O
2
3
1
The formation of 6 suggested that compounds 3 were reac-
tion intermediates and could not stay at such harsh condi-
tion,11,12 then a series of reaction conditions were screened to
get compounds 3. It turned out that stirring a mixture of 4
and 5 in ethanol at À10 °C for 30 min gave best reaction conver-
sion and yield of 3. The product could be filtrated from the reac-
tion mixture, and then purified by silica gel chromatography.
However, only phenylhydrazines with one or two substituents
at ortho-position afforded acceptable yield of 3. (Table 2) Crystal
of 3i was got and X-ray structure was drawn in Figure 2. As seen
from the figure, the arylhydrazino group and carbonyl group are
at the same side of double bond because of the formation of
hydrogen bond.
Compounds 3 were tested herbicidal activity with compound 7
as control, a potential herbicide developed by our group previ-
ously.1 The data were listed in Table 3.
* Corresponding author. Tel./fax: +86 (0)22 23499842.
E-mail address: wang98h@263.net (Q. Wang).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.048

2954
Y. Liu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2953–2956
O
O
ArNHNH
O
O
R1
R2
OC2H4OC2H5
R2
i
CN
3
+
CN
ArNHNH2
O
R2
N
O
O
5a R1= R2 = SMe
ii
5b R1= OMe, R2 = Et
5c R1= OMe, R2 = i-Pr
4
NH2
N
Ar
6
Scheme 1. Reagents and conditions: (i) EtOH, reflux, 1–2 h; (ii) EtOH, À10 °C, 30 min.
Table 1
Table 2
Compounds 6 synthesized from 4 and 5a
Compounds 3 synthesized from 4 and 5a
Compound
Ar
R2
Yieldb
Compound
Ar
R2
Yieldb
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
Phenyl
Phenyl
Phenyl
SMe
Et
i-Pr
SMe
Et
i-Pr
SMe
Et
i-Pr
SMe
i-Pr
SMe
i-Pr
SMe
96
62
53
80
63
68
75
75
40
50
74
86
62
63
3a
3b
3c
3d
3e
3f
3g
3h
3i
2,4-Cl2-phenyl
2,4-Cl2-phenyl
2,3-Cl2-phenyl
2,3-Cl2-phenyl
2,4,5-Cl3-phenyl
2,4,5-Cl3-phenyl
2,6-Cl2-phenyl
2,6-Cl2-phenyl
2,4,6-Cl3-phenyl
2,4,6-Cl3-phenyl
Et
i-Pr
Et
i-Pr
Et
i-Pr
Et
i-Pr
Et
i-Pr
29
31
35
20
32
30
30
31
31
29
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-NO2-phenyl
4-NO2-phenyl
4-NO2-phenyl
4-Me-phenyl
4-Me-phenyl
2,4-Cl2-phenyl
2,4-Cl2-phenyl
2,4-Me2-phenyl
3j
a
Characterization of compounds 6 can be found in Supplementary data.
b
Separated yields.
a
Characterization of compounds 6 can be found in Supplementary data.
Separated yields.
b
O
O
Cl
O
NH
N
S
CN
7
As shown in Table 3, all the compounds 3 had no obvious her-
bicidal reactivity compared to arylmethyleneamino-substituted
cyanoacrylate 7. We had mentioned that compounds 2 (including
Figure 2. X-ray diagram of compound 3i. Crystallographic data for 3i has been
deposited in the Cambridge Crystallographic Data Center (CCDC 715100).
7) are a kind of PSII electron transport inhibitors and they can bind
with D1 protein at the PSII reaction center. The methylene moiety
between aryl and atom N in structure 2 allows aryl group to rotate
to a proper position, therefore making the molecular binding more
tightly with the protein. However, when methylene moiety is
changed to NH, aryl group in structure 3 cannot rotate freely be-
Figure 1. X-ray diagram of compound 6n. Crystallographic data for 6n has been
deposited in the Cambridge Crystallographic Data Center (CCDC 725099).

Y. Liu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2953–2956
2955
Table 3
Herbicidal activities of compounds 3, 6 and 7 (1.5 kg/ha, percent inhibition, %)a
Compound
Postemergence treatment
Preemergence treatment
Rape
Amaranth pigweed
Alfalfa
Hairy crabgrass
Rape
Amaranth pigweed
Alfalfa
Hairy crabgrass
3a
3b
3c
3d
3e
3f
3g
3h
3i
0
1.6
4.3
0.2
0
5.0
11.1
2.3
0
18.0
3.9
15.6
22.7
15.6
20.3
22.7
15.6
13.3
13.3
32.0
0
0
0
0
0
0
0
0
38.0
0
0
7.5
3.3
5.1
4.7
3.7
2.3
1.4
5.6
21.0
38.3
0
0
0
0
0
38.3
0
0
0
20.0
0
0
17.9
5.4
16.1
0
0
0
0
1.8
17.9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
54.1
0
0
0
0
0
0
0
5.9
0
5.9
5.9
8.8
0
8.8
0
10.0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3.6
0
3.8
0
0
3.8
0
0
0
00
0
0
0
0
0
0
0
0
0
0
0
5.3
9.9
0
0
0
0
15.0
0
0
40.0
0
0
0
10.0
15.0
30.0
0
3j
0
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
7
53.6
61.5
58.8
0
0
26.4
0
15.0
0
52.7
40.70
0
0
0
0
0
0
18.8
0
0
0
100
0
16.6
0
55.3
24.1
100
0
47.6
0
32.4
a
Assay method and procedure were described in Supplementary data.
cause p-
p
conjugation exists between N1 and the aromatic ring
Compounds 3 and 6 were also evaluated if they have fungicidal
activities, plant growth regulatory activity or anti-tumor activity
because similar structures were found to have varieties of bioactiv-
ity.13–19 As shown in Table 4, compounds 3a, 3b, 3c and 3d exhib-
ited good antifungal activity against Physalospora piricola.
Compounds 3a and 3b also showed moderate activity against Cer-
cospora arachidicola. Most of the compounds 6 gave moderate fun-
(Fig. 1, the bond length of C6–N1 in compound 3i is 1.40 Å, shorter
than normal C–N single bond, which is 1.47 Å), therefore com-
pounds 3 cannot bind with the protein as tightly as compound 7.
Thus, compounds 3 could not effectively inhibit electron transport
thereby did not show any herbicidal effect. Compounds 6 were also
tested but did not exhibit any herbicidal activity.
Table 4
Fungicidal activities (50 mg/L) and plant growth regulatory activities (10 mg/L) of compounds 3 and 6. (percent inhibition, %)a
Compound
Fungicidal activities
Regulatory activities
G. zeae
A. solani
C. arachidicola
P. piricola
C. cucumerinum
3a
3b
3c
3d
3e
3f
3g
3h
3i
28.6
4.8
14.4
14.4
9.6
14.4
0
4.8
40.0
40.0
20.0
35.0
10.0
10.0
10.0
10.0
25.0
10.0
8.0
20.0
32.0
20.0
0
0
8.0
51.5
51.5
24.2
36.4
21.3
18.2
24.4
0
15.5
18.2
41.2
35.3
20.6
26.5
41.2
23.5
11.8
39.2
44.1
35.3
20.6
47.1
76.0
73.3
65.3
66.7
36.0
26.7
24.0
10.7
46.7
6.7
38.9
22.2
13.9
25.0
13.9
16.7
0
0
22.2
8.3
12.7
18.2
1.8
23.6
14.5
23.6
12.7
36.4
40
À5.2
À27.8
À12.7
72.9
À39.0
À1.5
À6.0
À6.0
À16.5
À2.2
50.4
46.3
46.3
66.6
111.3
38.2
54.4
5.6
19.2
4.8
3j
6a
6b
6c
6d
6e
6f
6g
6h
6i
42.2
46.7
46.7
37.8
53.3
44.4
51.1
11.1
46.7
46.7
51.1
42.2
0
1.3
32.0
36.0
38.7
33.3
13.3
40.0
46.7
22.7
13.3
46.7
8.0
16.0
28.0
12.0
16.0
21.9
66.6
21.9
17.8
6j
6k
6l
20
40
32.7
6m
26.7
28.0
44.1
9.3
30.9
À2.4
6n
46.7
100
8.0
100
35.3
100
9.3
100
10.9
100
42.2
—
Difenoconazoleb
IAAc
—
—
—
—
—
>150
a
Assay method and procedure were described in Supplementary data.
Commercial fungicidal agent.
Indole-3-acetic acid, commercial plant growth regulatory agent.
b
c

2956
Y. Liu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2953–2956
Table 5
Anti-tumor activities of compounds 3 and 6a
Compound
Leukemia HL-60 cell
10À5 10À6
Liver cancer BEL-7402 cell
10À4
10À7
10À4
10À5
10À6
10À7
3a
3b
3c
3d
3e
3f
3g
3h
3i
57.2
73.2
69.4
48.8
80.4
81.1
80.4
73.4
84.3
80.3
10.6
28.5
41.5
10.0
56.1
56.8
43.5
0
0
0
0
0
0
6.5
24.9
19.0
0
0
4.3
12.1
15.1
0
0
5.3
11.6
14.7
0
17.6
50.0
36.2
7.3
6.0
26.8
28.7
11.8
23.4
35.9
7.7
23.1
0
45.9
55.3
49.1
94.5
96.9
79.8
45.1
95.9
84.3
49.0
48.4
45.2
48.6
46.7
45.6
32.9
21.2
24.3
8.3
7.1
4.3
0
2.5
0
4.3
2.4
0.8
0
1.5
0
0
0
72.4
21.4
36.6
20.8
0.6
22.3
13.1
27.8
16.9
11.8
49.9
54.6
17.3
3.6
9.0
0
4.2
0
10.7
0
17.1
9.5
3.9
12.7
0
0
0
6.2
0
0
11.5
7.6
0
5.2
0
5.5
0
0
3j
6a
6g
6h
6i
6l
6m
6n
6.8
0
1.3
9.0
8.4
4.4
21.0
4.3
4.4
9.4
0
5.5
0
4.2
0
0
Percent inhibition (%) in different concentration of compounds.
a
Assay method and procedure were described in Supplementary data.
gicidal activity against Gibberella Zeae. For plant growth regulatory
activity, most of the compounds 3 exhibited inhibited-growth
activity whereas compound 3d showed accelerated-growth regula-
tory activity as high as 72.9%. Compounds 6 showed much different
activities depending on the structure, of which 6e gave the highest
activity (111%). To our pleasure, most of the compounds 3 and two
of compounds 6 also showed good anti-tumor activity at concen-
tration of 10À4 mol/L. Compound 3g still remained moderate
anti-tumor activity for both leukemia HL-60 cell and liver cancer
BEL-7402 cell at the concentration 10À5 mol/L (Table 5).
References and notes
1. Wang, Q.; Sun, H.; Cao, H.; Cheng, M.; Huang, R. J. Agric. Food Chem. 2003, 51, 5030.
2. Wang, Q.; Li, H.; Li, Y.; Huang, R. J. Agric. Food Chem. 2004, 52, 1918.
3. Liu, Y.; Cai, B.; Li, Y.; Song, H.; Huang, R.; Wang, Q. J. Agric. Food Chem. 2007, 55,
3011.
4. Li, H.; Diao, Y.; Wang, J.; Chen, C.; Ni, J.; Zhou, M. Crop Prot. 2008, 27, 90.
5. Lv, Y.; Wang, X.; Song, B.; Yang, S.; Yan, K.; Xu, G.; Bhadury, P. S.; Liu, F.; Jin, L.;
Hu, D. Molecules 2007, 12, 965.
6. Song, B.; Zhang, H.; Wang, H.; Yang, S.; Jin, L.; Hu, D.; Pang, L.; Xue, W. J. Agric.
Food Chem. 2005, 53, 7886.
7. Long, N.; Cai, X.; Song, B.; Yang, S.; Chen, Z.; Bhadury, P. S.; Hu, D.; Jin, L.; Xue,
W. J. Agric. Food Chem. 2008, 56, 5242.
8. Chen, Z.; Wang, X.; Song, B.; Wang, H.; Bhadury, P. S.; Yan, K.; Zhang, H.; Yang,
S.; Jin, L.; Hu, D.; Xue, W.; Zeng, S.; Wang, J. Bioorg. Med. Chem. 2008, 16, 3076.
9. Han, X.; Liu, Y.; Liu, Y.; Lai, L.; Huang, R.; Wang, Q. Chin. J. Chem. 2007, 25, 1135.
10. Liu, Y.; Wei, D.; Zhu, Y.; Liu, S.; Zhang, Y.; Zhao, Q.; Cai, B.; Li, Y.; Song, H.; Liu,
Y.; Wang, Y.; Huang, R.; Wang, Q. J. Agric. Food Chem. 2008, 56, 204.
11. Cernuchova, P.; Vo-Thanh, G.; Milata, V.; Loupy, A.; Jantova, S.; Theiszova, M.
Tetrahedron 2005, 61, 5379.
12. Guerrini, G.; Ciciani, G.; Cambi, G.; Bruni, F.; Selleri, S.; Melani, F.; Montali, M.; Martini,
C.; Ghelardini, C.; Norcini, M.; Costanzo, A. Bioorg. Med. Chem. 2008, 16, 4471.
13. Ouyang, G.; Chen, Z.; Cai, X.; Song, B.; Bhadury, P. S.; Yang, S.; Jin, L.; Xue, W.;
Hu, D.; Zeng, S. Bioorg. Med. Chem. 2008, 16, 9699.
In summary, arylhydrazino-substituted cyanoacrylates 3 and
N-aryl pyrazolecarboxylates 6 were synthesized from arylhydr-
azine and 3-methylthio (or 3-methoxy)-2-cyanoacrylate
5 in
different reaction conditions. Though there is structural similarity
between compounds 3 and 2, 3 did not exhibit any herbicidal
activity. But at the optional screening of bioactivities, some of
the compounds 3 showed fungicidal activity and anti-tumor activ-
ity, and some of the compounds 6 exhibited good plant growth reg-
ulatory activity. These result deserved further investigation.
14. Farag, A. M.; Mayhoub, A. S.; Barakat, S. E.; Bayomi, A. H. Bioorg. Med. Chem.
2008, 16, 881.
15. Bouabdallah, I.; M’Barek, L. A.; Zyad, A.; Ramdani, A.; Zidane, I.; Melhaoui, A.
Nat. Prod. Res. 2006, 20, 1024.
Acknowledgement
16. Bernardino, A. M. R.; Gomes, A. O.;Charret, K. S.; Freitas, A. C. C.; Machado, G. M. C.;
Canto-Cavalheiro, M. M.; Leon, L. L.; Amaral, V. F. Eur. J. Med. Chem. 2006, 41, 80.
17. Park, H.; Lee, K.; Park, S.; Ahn, B.; Lee, J.; Cho, H.; Lee, K. Bioorg. Med. Chem. Lett.
2005, 15, 3307.
This work was supported by the National Natural Science Foun-
dation of China (20872072).
18. Goldstein, D. M.; Alfredson, T.; Bertrand, J.; Browner, M. F.; Clifford, K.;
Dalrymple, S. A.; Dunn, J.; Freire-Moar, J.; Harris, S.; Labadie, S. S.; La Fargue, J.;
Lapierre, J. M.; Larrabee, S.; Li, F.; Papp, E.; McWeeney, D.; Ramesha, C.; Roberts,
R.; Rotstein, D.; San Pablo, B.; Sjogren, E. B.; So, O.-Y.; Talamas, F. X.; Tao, W.;
Trejo, A.; Villasenor, A.; Welch, M.; Welch, T.; Weller, P.; Whiteley, P. E.; Young,
K.; Zipfel, S. J. Med. Chem. 2006, 49, 1562.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.04.048.
19. Abadi, A. H.; Eissa, A. A. H.; Hassan, G. S. Chem. Pharm. Bull. 2003, 51, 838.