Design, Synthesis, Biological Activities, and 3D-QSAR of New N,N'-Diacylhydrazines Containing 2-(2,4-dichlorophenoxy)propane Moiety

Article abstract of DOI:10.1111/j.1747-0285.2011.01205.x

A series of new N,N'-diacylhydrazine derivatives were synthesized efficiently under microwave irradiation. Their structures were characterized by ¹H NMR, MS, and elemental analysis. Various biological activities of these compounds were tested. Most of them exhibited higher herbicidal activities against dicotyledonous weeds than monocotyledonous weeds. In addition, favorable in vivo fungicidal activities were also found of these compounds against Cladosporium cucumerinum, Corynespora cassiicola, Sclerotinia sclerotiorum(Lib.)de Bary, Erysiphe cichoracearum, and Colletotrichum orbiculare (Berk aLMont) Arx. All compounds displayed excellent plant growth regulatory activities: 100% inhibition was achieved against the radicle growth of cucumber. To further investigate the structure-activity relationship, comparative molecular field analysis was performed on the basis of herbicidal activity data, resulting in a statistically reliable model with good predictive power (r²=0.913, q²=0.556). Based on the calculation, five additional novel compounds were designed and synthesized. Satisfyingly, compound 4u displayed excellent herbicidal activity (94.7%) at 1500g/ha, although it is less active than 2,4-D. Meanwhile, this compound also exhibited good fungicidal activity against C. orbiculare (Berk aLMont) Arx (82.16%). A series of new N,N'-diacylhydrazine derivatives were synthesized under microwave irraiation. Various biological (herbicidal, plant growth regulatory, fungicidal) activities of these compounds were tested. The structure-activity relationship (CoMFA) was performed.

Full text of DOI:10.1111/j.1747-0285.2011.01205.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01205.x
Chem Biol Drug Des 2011; 78: 689–694
Research Article
Design, Synthesis, Biological Activities, and
3D-QSAR of New N,N¢-Diacylhydrazines
Containing 2-(2,4-dichlorophenoxy)propane
Moiety
Xing-Hai Liu1,*, Li Pan2, Yi Ma2, Jian-Quan
Weng1, Cheng-Xia Tan1, Yong-Hong Li2,
Yan-Xia Shi3, Bao-Ju Li3, Zheng-Ming Li2,*
and Yong-Gang Zhang4
Key words: N,N¢-diacylhydrazines, 2-(2,4-dichlorophenoxy)propane,
microwave synthesis, herbicidal activity, fungicidal activity, plant growth
regulatory activity, 3D-QSAR
Received 22 January 2011, revised 17 July 2011 and accepted for publi-
cation 23 July 2011
1Institute of Pesticide, Zhejiang University of Technology, Hangzhou
310014, China
2State-Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China
More recently, diacylhydrazine derivatives have become one of the
focuses in the development of agrochemicals because of their high
biological activities (1–6), especially herbicidal activities as well as
fungicidal activities. Some examples of diacylhydrazines are pre-
sented in Scheme 1.
3Institute of Vegetables and Flowers, Chinese Academy of
Agricultural Sciences, Beijing 100014, China
4Biology Institute of Shandong Academy of Science, Jinan 250014,
China
Aryloxyphenoxy-propionates, as an intriguing class of herbicides in
the international market (7), have drawn much attention in the past
decades. In particular, agrochemists were lured their studies to
develop novel modified 2,4-D structures for their remarkable herbi-
cidal activity. A variety of bioactive moieties involving phosphonates
(compound 4) (8), heterocycles (compound 5) (9) and other types of
substituents (compound 6) (10) were introduced to the aryloxyphen-
oxy-propionates structural core, which led to higher herbicidal activ-
ity where 1-(substituted phenoxyacetoxy) alkylphosphonates was
one class of the successful examples (11). Furthermore, some
substituted aryloxyacetic acid derivatives also exhibit good plant
growth-regulating activity(12). However, unfavorable responses
occurred in a few cases; for instance, suppression of leaf growth
was observed (13) when the substituted aryloxyacetic acids were
used to improve fruit set. Therefore, seeking highly active and
effective agents remains a sufficient room.
*Corresponding authors: Xing-Hai Liu, xhliu@zjut.edu.cn; Zheng-
Ming Li, nkzml@vip.163.com
Xing-Hai Liu and Li Pan contributed equally to this work.
A series of new N,N¢-diacylhydrazine derivatives
were synthesized efficiently under microwave
irradiation. Their structures were characterized
by 1H NMR, MS, and elemental analysis. Various
biological activities of these compounds were
tested. Most of them exhibited higher herbicidal
activities against dicotyledonous weeds than
monocotyledonous weeds. In addition, favorable
in vivo fungicidal activities were also found of
these compounds against Cladosporium cucumer-
inum, Corynespora cassiicola, Sclerotinia sclero-
tiorum(Lib.)de Bary, Erysiphe cichoracearum, and
Colletotrichum orbiculare (Berk aLMont) Arx. All
compounds displayed excellent plant growth reg-
ulatory activities: 100% inhibition was achieved
against the radicle growth of cucumber. To fur-
ther investigate the structure–activity relation-
ship, comparative molecular field analysis was
performed on the basis of herbicidal activity
In line with our continuous efforts to synthesize bioactive lead com-
pounds for crop protection, the title compounds 4a–4u were
designed by introducing 2-(2,4-dichlorophenoxy)propane acid phar-
macophore into the diacylhydrazine scaffold. Our original strategy is
depicted in Scheme 2.
data, resulting in
with good predictive
a
statistically reliable model
power
(r2 = 0.913,
q2 = 0.556). Based on the calculation, five addi-
tional novel compounds were designed and syn-
thesized. Satisfyingly, compound 4u displayed
excellent herbicidal activity (94.7%) at 1500 g ⁄ ha,
although it is less active than 2,4-D. Meanwhile,
this compound also exhibited good fungicidal
activity against C. orbiculare (Berk aLMont) Arx
(82.16%).
Materials and Methods
Instruments
Melting points were determined by an X-4 apparatus (Beijing Tech
Instruments Co., Beijing, China) and uncorrected. 1H NMR spectra
were measured on a Bruker AC-P500 instrument (300 MHz; Bruker,
689

Liu et al.
O
H
O
R
O
R
O
H
N
H
N
N
Ar
H
N
H
O
N
N
N
Ar
N
N
O
H
H
O
F3C
O
X
Cl
2
1
3
N
F3C
S
N
O
O
P
Cl
O
O
N
Cl
O
O
N
N
R
O
O
O
Ar
O
O
O
O
Cl
O
O
Scheme 1: Some representa-
tive structures of diacylhydrazine
and phenoxy moiety.
R
4
5
6
Cl
OH
O
O
O
O
Cl
OH
Cl
O
NH2NH2 H2O
MW
O
Cl
O
O
MW
Cl
Cl
2
R
Cl
O
HN NH
O
H
1
N
R
O
R
N
Cl
O
H
O
O
HN NH
O
NH2
RCOCl
MW
Cl
N
Lead compound
4a~4u
H
Cl
O
O
Cl
Cl
Cl
Scheme 2: Design strategy of title compounds.
3
4a~4u
R1
= alkyl, aryl, heterocyclic
Fallanden, Switzerland) using tetramethylsilane (TMS) as an internal
standard and DMSO-d6 as the solvent. Mass spectra were recorded
on a Thermo Finnigan LCQ Advantage LC ⁄ mass detector instrument.
Elemental analyses were performed on a Vario EL elemental ana-
lyzer. LWMC-250 domestic microwave oven was used to do micro-
wave reaction. All the reagents are of analytical grade or freshly
prepared before use.
Scheme 3: Synthetic route of title compounds.
Herbicidal activities assay
The herbicidal activities of 4a–4u were evaluated using a previ-
ously reported procedure (14).
Plant growth regulatory activity assay
The regulatory activity of compounds against the growth of cucum-
ber roots at the same department was evaluated as above. All
compounds were tested at a same concentration of 10 mg ⁄ L. The
detailed procedure was described as follows (3).
General method for preparing title compounds
2,4-dichlorophenol (5 mmol), KI (1 mmol), N,N-Dimethylformamide
(DMF) (1 mL), ethyl 2-chloropropanoate (5 mmol) and tetrabutyl
ammonium bromide (TBAB) (0.5 mmol) were placed in a dried
round-bottomed flask, and the mixture was irradiated by micro-
waves (200 W) for 4 min. On completion of the reaction, the mix-
ture was cooled to room temperature and then added to ethanol
(10 mL) with constant stirring. After filtering off the inorganic salts,
the reaction mixture was added to 85% hydrazine hydrate (5 mmol)
and subjected to microwave irradiation (500 W) for an additional
1 min. Then, it was cooled to room temperature and allowed to
settle for 1 h, and the precipitates were filtered off and recrystal-
lized from ethanol to afford the pure product 3. Then, 3 (1 mmol)
and substituted acyl chloride (1 mmol) were mixed in tetrahydro-
furan (THF). The mixture was put into the microwave oven (495 W)
and irradiated for 10 min to produce the crude solid, which on
recrystallization with ethanol gave the pure product as shown in
Scheme 3. The analysis data of title compounds were found in Sup-
porting Information.
Fungicidal activities assay
Fungicidal activity of 4a–4u against Cladosporium cucumerinum
(CCu), Corynespora cassiicola (CCa), Sclerotinia sclerotiorum(Lib.)de
Bary (SS), Erysiphe cichoracearum (EC), and Colletotrichum orbicu-
lare (Berk aLMont) Arx. (CO) was evaluated according to reference
(15).
3D-QSAR analysis
Molecular modeling was performed using SYBYL 6.91 software (Tri-
pos, Inc., San Francisco, CA, USA), and the comparative molecular
field analysis (CoMFA) method was carried out according to our
previous work (16).
690
Chem Biol Drug Des 2011; 78: 689–694

Bioactive and QSAR of N,N¢-diacylhydrazines
and Brassica napus except 4a, 4p, and 4q. And also, most of
these compounds show better herbicidal activities in postemergence
treatment than in preemergence treatment against A. retroflexus
and B. napus. Notably, some aryl-substituted compounds show
surprisingly higher herbicidal activity against monocotyledon (Echino-
chloa crus-galli) for preemergence than the corresponding
alkyl-substituted compounds except 4p. For the compound 4p,
further bioassay was conducted against E. crus-galli, Digitaria san-
guinalis, B. napus, and Amaranthus retroflerus. It is indicated from
Table 2 that compound 4p has good (96.9%) herbicidal activity
against dicotyledonous weeds A. retroflerus at a dose of 375 g ⁄ ha,
which is comparable with that of the commercial herbicide 2,4-D.
However, compound 4p has weak herbicidal activity against other
three plants at the same dosage.
Results and Discussion
Synthesis
The synthetic route of the title compounds was outlined in
Scheme 3. At first, 2,4-dichlorophenol (5 mmol), K2CO3 (6 mmol),
DMF (10 mL), and ethyl 2-chloropropanoate (5 mmol) were placed in
a dried round-bottomed flask, and the mixture was stirred at room
temperature for overnight. When the reaction reached completion,
reaction mixture was poured into water, and compound 2 was
afforded by filtration. Next, to a solution of compound 2 (2 mmol)
in ethanol (10 mL) was added 85% hydrazine hydrate (3 mmol).
After refluxing for 6 h, the reaction mixture was cooled to room
temperature, and the precipitates were filtered off and recrystal-
lized from ethanol to afford the pure product 3. For the last step,
3(1 mmol), Et3N (1.1 mmol), and substituted acyl chloride (1 mmol)
were mixed in THF and refluxed for 4 h to prepare the crude solid.
To optimize the reaction condition and reaction times, microwave
irradiation was employed. All these microwave steps are according
to the references (17). The key intermediate 2, 3 can be obtained
with excellent yield (>95%) in short reaction time. The processes
are shown in the experiment section and Scheme 3.
Plant growth regulatory activity
To elucidate why these compounds had excellent herbicidal activity,
the cotyledon root of cucumber activity of title compounds was
determined. Surprisingly, as listed in Table 1, all the testing com-
pounds showed 100% inhibition on the root cotyledon of cucumber.
Such strong inhibition of plant root growth can possibly the reason
attributing to the aforementioned excellent herbicidal activity.
Herbicidal activity
The herbicidal activities of these compounds were determined in
vivo. The results for these compounds 4a–u are summarized in
Table 1. As shown in Table 1, all the compounds exhibit excellent
herbicidal activity in postemergence against Amaranthus retroflexus
Fungicidal activities
The in vivo fungicidal results of title compounds are listed in
Table 3. Most of the compounds showed promising results in inhib-
Table 1: The herbicidala and plant growth regulatorya activity of title compounds
Ech.
Bra.
Dig.
Ama.
No.
R
CRC
Pre-
Post-
Pre-
Post-
Pre-
Post-
Pre-
Post-
4a
4b
4c
4d
4e
4f
Phenyl
)100
)100
)100
)100
)100
)100
)100
)100
)100
)100
)100
)100
)100
)100
)100
)100
)100
)63.5
)100
)100
)100
65.7
100
100
100
39.4
100
24.5
20.0
20.7
17.8
8.7
22.8
21.1
22.8
11.5
17.2
16.6
29.4
26.6
23.9
13.1
6.5
28.5
14.5
11.2
23.9
6.1
58.0
58.6
100
100
100
100
100
63.6
91.9
90.5
100
100
100
100
100
100
100
70.8
83.0
91.9
100
100
100
37.0
25.0
14.3
10.7
28.6
10.7
7.1
3.6
19.6
0
14.3
0
14.3
0
45.3
74.7
85.3
74.7
78.9
100
93.7
100
85.3
100
100
73.5
100
100
64.7
100
56.1
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
6.3
p-nitro phenyl
p-chloro phenyl
p-fluoro phenyl
m-methyl phenyl
m-chloro phenyl
o-chloro phenyl
2,4-dichloro phenyl
o-methoxyl phenyl
4-pyridyl
Isoxazoyl
1-cycan cyclopropyl
Ethyl
Iso-propyl
Butyl
65.7
63.3
84.0
94.7
100
64.6
100
92.1
91.7
100
100
100
98.7
60.5
91.7
21.1
94.7
96.7
88.2
94.7
31.5
59.5
50.0
29.6
72.2
33.3
46.2
55.8
55.6
28.8
67.3
71.2
59.6
25.0
55.6
5.8
4g
4h
4i
4j
100
4k
4l
28.2
18.4
36.8
4.6
16.1
100
4m
4n
4o
4p
4q
4r
0
0
14.3
0
0
Cyclopropyl
2,4-dichlorophenoxymethyl
(2-(2,4-dichlorophenoxy)acetyl)propyl
p-iodo phenyl
3-pyridyl
p-methoxyl phenyl
2,4-D
0
17.6
52.9
100
100
91.2
81.1
19.0
14.9
24.1
0.6
6.1
42.4
75.0
71.2
69.2
39.5
100
100
100
100
4s
4t
12.6
15.4
13.6
85.4
0
1.8
7.1
100
4u
100
100
100
Ech, Echinochloa crus-galli; Dig, Digitaria sanguinalis; Bra, Brassica napus; Ama, Amaranthus retroflerus; Pre, preemergence; Post, postemergence.
aThe test concentration of herbicidal activity is at 1500 g ⁄ ha, and the cotyledon root of cucumber (CRC) is at 10 mg ⁄ mL.
Chem Biol Drug Des 2011; 78: 689–694
691

Liu et al.
Table 2: Herbicidal activities of compounds 4p and 2,4-D (per-
cent inhibition, %)
Table 4: Summary of comparative molecular field analysis (CoM-
FA)
Ech.
Bra.
Dig.
Ama.
Contributor (%)
No.
Rate g ⁄ ha Pre- Post- Pre- Post- Pre- Post- Pre- Post-
q2
r2
S
F
No. Steric Electrostatic
82.3 17.7
4p
375
750
37.6
0
14.8 58.8 24.1
0
45.1 96.9
92.7 100
52.4 100
78.6 100
CoMFA 0.566 0.913 0.325 97.186 4f
44.5 2.5 43.2 60.0 50.4 9.0
2,4-D 375
0
0
0
0
100
100
0
50.0
0
0
750
32.6 32.4
cylhydrazine had moderate control effect against C. cassiicola, such
as compounds 4l, 4m, and 4q.
Table 3: Fungicidal activity of title compounds (percent relative
control efficacy) at 500 ppm
Comparative molecular field analysis
Comparative molecular field analysis method is widely used in drug
design, because it allows for rapid prediction of QSAR of newly
designed molecules (16). The results of these computations are
summarized in Table 4. The compound 4f was used as a template
to build the other molecular structures. Because these compounds
share a common skeleton, 16 atoms marked with an asterisk were
used for rms-fitting onto the corresponding atoms of the template
structure (Figure 1).
No.
CCa
CCu
EC
17.25
SS
24.29
31.23
53.37
22.65
4.96
37.94
)0.43
27.54
6.08
15.02
21.41
27.54
5.24
76.78
24.23
25.09
16.02
34.09
41.29
)6.50
)1.08
CO
63.76
4a
4b
4c
4d
4e
4f
4g
4h
4i
39.00
7.00
55.00
60.00
39.00
57.00
0.50
14.00
13.00
21.00
40.00
18.00
13.00
22.00
11.00
10.00
30.00
4.00
50.86
44.20
33.77
51.30
21.52
76.62
60.26
)5.20
22.85
14.99
64.94
38.21
71.90
10.00
24.03
)5.19
53.25
45.67
66.74
)5.19
54.50
59.81
32.71
78.72
60.84
31.14
62.75
14.93
56.02
50.88
79.34
67.58
29.89
45.11
71.98
80.28
69.95
32.82
69.36
82.16
38.00
)4.00
14.00
50.00
34.00
68.00
45.00
36.00
46.00
52.00
46.00
40.00
15.00
15.00
55.00
22.00
62.00
48.00
62.00
87.00
Experimental and predicted activities by CoMFA for all compounds
are listed in Table S1. The plots of the predicted versus the actual
activity values for all the compounds are shown in Figure S1. As
shown in Table 4, a predictive CoMFA model was established with
the conventional correlation coefficient r2 = 0.913 and the cross-val-
idated coefficient q2 = 0.566. It is shown in Figure 2A,B that the
contributions of steric and electrostatic fields ('SD*coeff') are
82.3% and 17.7%, respectively. With the CoMFA, we obtained the
isocontour diagrams of the steric and electrostatic field contribu-
tions ('SD*coeff'), which is displayed in Figure 2. In Figure 2A, the
steric field contours are represented with different colors: the green
color at 2 position means that a bulky group here would be favor-
able for higher herbicidal activity, while the yellow color means
oppositely. As shown in Figure 2A, there is a yellow region located
around the 4 position of the benzene ring, indicating that the bulky
groups at this position will decrease the herbicidal activity. This is
in agreement with the actual experimental data: for example, com-
pounds 4b, 4c, and 4d all have lower herbicidal activity with a
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
a
50.00
18.00
16.00
19.00
50.00
b
c
d
e
99.00
100.00
100.00
100.00
Control pesticide:
a: Daconil 75% WP; b: 40% Fuxing EC; c: Myclobutanil 12.5% EC; d: Dimeth-
achlon 40% WP; e: 25% Prochloraz EC.
iting the mycelial growth of all test fungi at a concentration of
500 lg ⁄ mL. Meanwhile, all of these compounds were found safe
for the cucumber plants. As shown in Table 3, compound 4q and
4u exhibit good control effect against C. orbiculare (Berk aLMont)
Arx. No fungicidal activities were found of these compounds
against S. sclerotiorum (Lib.) de Bary, except that compound 4c
(53.37%) and 4n (76.78%) displayed moderate control effect.
Compounds 4h, 4l, 4n, and 4t showed fair fungicidal activity
(control effect 60–76%) against E. cichoracearum. Compounds 4a,
4b, 4d, 4q, and 4u held above 50% control effect against C. cu-
cumerinum. For the C. cassiicola, it was found that most of the hal-
ogen-substituted aryl derivatives have higher control effect than the
other substituted aryl derivatives. Furthermore, some of the alkyl a-
Figure 1: Superposition modes of compounds.
Chem Biol Drug Des 2011; 78: 689–694
692

Bioactive and QSAR of N,N¢-diacylhydrazines
A
B
Figure 2: Steric (A) and Electrostatic (B) contribution contour maps of comparative molecular field analysis.
bulky group in this position. In the same figure, the electrostatic
contours are displayed in distinguishable colors: blue means that an
increase in the positive charge will lead to an increase in the activ-
ity, while the red contour defines in the opposite. So, the target
compounds bearing an electron-withdrawing group at the 2 position
or 3 position of the benzene ring and an electron-donating group at
the other positions displayed higher activity. These results provide
useful information for further optimization of the compounds.
According to the aforementioned CoMFA, compound 4u
(R = p-OMe Ph) was designed, synthesized, and tested for its herbi-
cidal activity against B. napus. The results indicated that the inhibi-
tion of compound 4u is 94.7%, in which inhibition is as good as
control. Meanwhile, the compound 4u exhibited good fungicidal
activity against C. orbiculare (Berk aLMont) Arx(82.16%).
propylcarbonyl]-N¢-(aryloxyacetyl)hydrazines.
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In conclusion, a series of N,N¢-diacylhydrazines bearing 2,4-dichloro-
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and microwave irradiations. The herbicidal tests showed that these
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Based on the biological screening data, these novel N,N¢-diacylhydr-
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This work was supported financially by National Natural Science
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Figure S1. The plots of the predicted versus the actual activity
values for all the compounds.
Table S1. The structures, activities and total score of compounds.
Appendix S1. Analytical data for title compounds.
Appendix S2. The detailed biological methods.
Appendix S3. The detailed 3D-QSAR method.
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