Synthesis and bioactivity of N-benzoyl-N'-[5-(2'-substituted phenyl)-2-furoyl] semicarbazide derivatives

Article abstract of DOI:10.3390/molecules15064267

In order to find novel chitin synthesis inhibitors (CSIs) with good activity, benzoylphenylurea, a typical kind of CSIs, was chosen as the lead compound and 15 novel derivatives containing furan moieties were designed by converting the urea linkage of benzoylphenylureas into a semicarbazide and changing the aniline part into furoyl groups. The title compounds were synthesized by the reaction of substituted benzoyl isocyanates with 5-(substituted phenyl)-2-furoyl hydrazine, and the structures were confirmed by IR, ¹H-NMR, elemental analysis and single crystal X-ray diffraction analyses (compound E2). The bioassay results indicated that the title compounds exhibit good insecticidal activity, especially towards Plutella xylostella L., but had lower fungicidal activity. Inspiringly, the title compounds possessed obvious anticancer activity against human promyelocytic leukemic cell line (HL-60), and some of the title compounds also had activity against human hepatocellular carcinoma cell line (Bel-7402), human gastric carcinoma cell line (BGC-823), and human nasopharyngeal carcinoma cell line (KB). The results indicated that the linkage in the lead compounds was important to the bioactivity and spectra. The modification on the urea linkage is an effective strategy to discover new pesticide and drug candidates.

Full text of DOI:10.3390/molecules15064267

Molecules 2010, 15, 4267-4282; doi:10.3390/molecules15064267
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Bioactivity of N-Benzoyl-N'-[5-(2'-substituted
phenyl)-2-furoyl] Semicarbazide Derivatives
Zining Cui 1, Yun Ling 1, Baoju Li 2, Yongqiang Li 1, Changhui Rui 1, Jingrong Cui 3, Yanxia Shi 2
and Xinling Yang 1,*
1
Key Laboratory of Pesticide Chemistry and Application, Ministry of Agriculture, Department of
Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China;
E-Mails: ziningcui@gmail.com (Z.C.); lyun@cau.edu.cn (Y.L.); lyq@nankai.edu.cn (Y.L.);
chrui@ippcaas.cn (C.R.)
2
Institute of Vegetables and Flowers, Chinese Academy of Agricultural Science, Beijing 100081,
China; E-Mails: libaoju62197975@126.com (B.L.); shiyanxia813@163.com (Y.S.)
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Science, Peking
3
University, Beijing 100083, China; E-Mail: jrcui@bjmu.edu.cn (J.C.)
* Author to whom correspondence should be addressed; E-Mail: yangxl@cau.edu.cn;
Tel.: +86-10-6273-2223; Fax: +86-10-6273-2223.
Received: 5 May 2010; in revised form: 31 May 2010 / Accepted: 2 June 2010 /
Published: 11 June 2010
Abstract: In order to find novel chitin synthesis inhibitors (CSIs) with good activity,
benzoylphenylurea, a typical kind of CSIs, was chosen as the lead compound and 15 novel
derivatives containing furan moieties were designed by converting the urea linkage of
benzoylphenylureas into a semicarbazide and changing the aniline part into furoyl groups.
The title compounds were synthesized by the reaction of substituted benzoyl isocyanates
with 5-(substituted phenyl)-2-furoyl hydrazine, and the structures were confirmed by IR,
1H-NMR, elemental analysis and single crystal X-ray diffraction analyses (compound E2).
The bioassay results indicated that the title compounds exhibit good insecticidal activity,
especially towards Plutella xylostella L., but had lower fungicidal activity. Inspiringly, the
title compounds possessed obvious anticancer activity against human promyelocytic
leukemic cell line (HL-60), and some of the title compounds also had activity against
human hepatocellular carcinoma cell line (Bel-7402), human gastric carcinoma cell line
(BGC-823), and human nasopharyngeal carcinoma cell line (KB). The results indicated
that the linkage in the lead compounds was important to the bioactivity and spectra. The

Molecules 2010, 15
modification on the urea linkage is an effective strategy to discover new pesticide and drug
4268
candidates.
Keywords: chitin synthesis inhibitors; benzoylphenylurea; semicarbazide; synthesis;
bioactivity
1. Introduction
Chitin, the β-(1→4) glycoside polymer of N-acetyl-
D
-glucosamine, is a major structural component
of insect cuticles. In addition to the insect cuticles, chitin is also present in cell walls of fungi and
protozoa, but is absent in higher plants and vertebrates. This species-specificity provides the rationale
to select chitin as a safe target for pest control agents [1,2]. Chitin synthesis inhibitors (CSIs), which
can interfere with chitin formation, will affect the normal growth and development process of insects
and fungi but have no effect on plants and vertebrates. The unique mode of action coupled with
excellent activity on target and lower toxicity to non-target organisms (including many beneficial
arthropods) made these compounds a new tool for integrated pest management (IPM) [3–15].
Benzoylphenylureas (BPUs) have been developed as a typical kind of chitin synthesis inhibitors
since Dimilin (diflubenzuron) was introduced into market in the 1970s [3,4]. Their general structures A
(Scheme 1) consist of three parts including the benzoyl (X), the urea linkage (Y), and the aniline (Z) [7].
Scheme 1. Design strategy for title compounds E.
O
O
R2
X=benzoyl part
Y=urea linkage
Z=aniline part
N
H
N
H
R1
Z
X
Y
A: General structure of benzoylphenylureas
O
O
O
O
O
O
O
R3
R2
R3
R3
O
O
O
N
H
N
H
N
H
O
R1
R1
N
H
N
H
Y
Z
Z
X
B: X was modified with furoyl group [16]
C: Z was modified with furoyl group[17,18]
D: Y and Z were modified with carbamic
acid ester and furan methyl group [19]
Compounds in our previous work
O
O
Y
H
N
O
R2
N
H
N
H
R1
O
Z
E: Y and Z were modified with semicarbazide and furoyl group
Title compounds in present work

Molecules 2010, 15
4269
Numerous modifications on the benzoyl (X) and aniline (Z) parts have resulted in the discovery of
many commercial insecticides, such as chlorfluazuron, teflubenzuron, bistrifluoron, and noviflumuron
[7–11]. However, modification on the urea linkage (Y) has been considered less, although some efforts
on this part have been made. For example, Grosscurt found that the compounds had good insecticidal
properties when the urea linkages were converted into carbamoyl-2-pyrazolines [12]. Wang’s group
reported that the compounds resulting from substitution of the hydrogen on the nitrogen atom of the
urea linkage with carbamylosulfenyl or carbamate groups could retain the insecticidal activity [13–15].
In our previous work, the benzoyl (X) part was modified with a furoyl group to get benzoylureas B
[16], and the aniline (Z) part was replaced with a furoyl group to obtain dibenzoylureas C [17,18]. The
bioassay results indicated that some of the resulting compounds had certain insecticidal activity,
whereas when the Y and Z moieties were modified with carbamic acid ester and furan methyl groups,
the insecticidal activity disappeared and the compounds exhibited good fungicidal activity [19]. In the
present work, an effort of structure optimization was carried out, in which the urea linkage was
converted to a semicarbazide, while the aniline part was replaced with a 5-phenyl-2-furoyl group
(Scheme 1). Fifteen novel N-benzoyl-N'-[5-(2'-substituted phenyl)-2-furoyl] semicarbazides (E) were
designed and synthesized for the purpose of new pesticide and anticancer drug discovery. Their in vivo
insecticidal activity and in vitro fungicidal and antitumor activities were preliminarily evaluated.
2. Results and Discussion
2.1. Chemistry
The synthetic route of compounds E is shown in Scheme 2, where the starting materials were
substituted anilines and benzoic acids. All of the title compounds were prepared by the nucleophilic
addition reaction of 5-substituted aryl-2-furoyl hydrazine with benzoyl isocyanate under an anhydrous
atmosphere.
Scheme 2. General synthetic procedure for title compounds E.
COOH
COOH
NaNO2
HCl
O
O
NH2
N2Cl
R2
R2
cat. CuCl2
R2
2
acetone-H2O
R1
R1
(COCl)2
O
O
R1
O
SOCl2
NH3
NCO
NH2
OH
4
3
H
N
O
O
R2
H
N
O
N
H
N
H
4
NH2
SOCl2
NH2NH2 H2O
MeOH
O
2
O
O
R1
R2
E1~E15
E1: R1=H, R2=4-Cl; E2: R1=2,6-di-F, R2=4-F; E3: R1=3-CH3, R2=4-Cl; E4: R1=2,6-di-F, R2=4-Cl;
E5: R1=2-Cl, R2=4-Cl; E6: R1=2,6-di-Cl, R2=4-CH3; E7: R1=2,6-di-F, R2=4-CH3; E8: R1=2-Cl,
R2=4-CH3; E9: R1=2-OCH3, R2=2-NO2; E10: R1=3-CH3, R2=2-Cl; E11: R1=2,6-di-F, R2=2-Cl; E12:
R1=2-OCH3, R2=2-Cl; E13: R1=2,6-di-Cl, R2=2,4-di-F; E14: R1=2-Cl, R2=2,4-di-F; E15: R1=2-
OCH3, R2=4-Cl.

Molecules 2010, 15
4270
All of the structures of the title compounds were confirmed by 1H-NMR, IR, and elemental analyses.
In the IR spectra, the compounds showed absorption bands around 3,500 and 3,200 cm-1 originating
from the N-H stretching vibration. The strong bands around 1,750 cm-1 could be assigned to the C=O
stretching vibration. The bands between 1,690 and 1,650 cm-1 were carbonyl vibration of the
secondary amide. Absorption bands around 1,610, 1,520 and 1,480 cm-1 were attributed to the frame
vibrations of the phenyl and furan rings.
1
In the H-NMR spectrum, one sharp peak in the range from 9.70 to 11.50 ppm was due to the
presence of NH. The splits of most compounds were normal, except for the compounds with fluorine
substitution because of the coupling and splitting between fluorine and hydrogen. The fluorine atom
splits a hydrogen proton into a doublet, which complicated the proton signals. The protons on phenyl
rings were mostly split into multiple peaks in the range from 7.20 to 8.10 ppm and the protons on the
furan ring were split into a doublet in the range from 6.90 to 7.40 ppm.
The structures were further conformed by single crystal X-ray analysis of a typical example,
compound E2. Figure 1 gives a perspective view of the compound sad the crystal data are presented in
Table 1. Some important bond lengths, angels, and torsion angles of compound E2 are given in Table
2. It could be seen from the X-ray analysis of E2 that the single bonds distances of C11-N1, C12-N2,
C13-N3, and C12-N3 (1.363(3), 1.342(3), 1.369(3), and 1.398(3) Å) are equal to the van der Waals’
radii for a C–N double bond (1.35 Å), the single bonds C4-C7, C8-C11, and C13-C14 (1.461(4),
1.470(4), and 1.504(4) Å) are shorter than the standard C–C single bond (1.54 Å), but longer than C–C
double bond (1.34 Å), and the N1–N2 (1.387(3) Å) single bond is shorter than the standard N–N single
bond (1.45 Å), but longer than a N–N double bond (1.25 Å). All of these clearly indicated that the p
orbital of N atoms conjugated with the π molecular orbital and formed the delocalized π-bonds with
the conjoint furan and benzene ring. Unexpectedly, the p orbitals of N1, N2, and N3 seemed not to be
conjugated with the π molecular orbital of the C11–O2 ,C12–O3, and C13-O4 double bonds, which
was explained by the bond length of C11–O2, C12-O3, and C13–O4 (1.228(3), 1.224(3), and 1.219(3)
Å) that followed in the normal range of C–O double bonds (1.19-1.23 Å).
Figure 1. Molecular structure of compound E2, showing 30% probability ellipsoids, H
atoms were shown as small spheres of arbitrary radii.

Molecules 2010, 15
4271
Table 1. Crystal and experimental data of compound E2.
Empirical formula
Formula weight
C19H12F3N3O4
403.32
T
173(2) K
Wavelength
Crystal system
Space group
1.54178 Å
Triclinic
P1
a = 6.8462(12) Å, α = 107.173(13)°
b = 11.552(2) Å, β = 104.549(12)°
c = 11.667(2) Å, γ = 93.363(13)°
844.4(3) Å3
Unit cell dimensions
Volume
Z
2
Dx
1.586 Mg/m3
Absorption coefficient
F (0 0 0)
1.171 mm-1
412
Crystal dimensions
θ range for data collection
Completeness to θ = 68.19
Limiting indices
Reflection collected/unique
Absorption correction
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
0.20 x 0.13 x 0.10 mm
4.05 to 68.19
96.7 %
-8≤h≤8, -13≤k≤13,-13≤l≤14
8794/2990 [R(int) = 0.0529]
Numerical
0.8919 and 0.7995
2990 / 0 / 263
1.088
＞
Final R indices [I 2σ (I)]
2θmax
(∆ρ)max
(∆ρ)min
R1 = 0.0555, wR2 = 0.1218
136.38° with Cu Kα
0.301 eÅ-3
-0.318 eÅ-3
Program system
Structure determination
Refinement
CCDC No.
SHELXS-97, SHELXL-97
Direct method
Full-matrix least-squares on F2
769209
Table 2. Selected bond lengths, angels, and torsion angles of compound E2.
(Å) Angles (°) Torsion angles
Lengths
(°)
-113.9(3)
2.0(5)
-177.7(3)
176.3(2)
0.0(3)
4.9(4)
4.1(4)
-176.2(2)
6.4(4)
122.7(3)
179.9(3)
C(4)-C(7)
C(8)-C(11)
1.461(4) O(2)-C(11)-N(1) 123.0(3) C(11)-N(1)-N(2)-C(12)
1.470(4) O(2)-C(11)-C(8) 123.4(3) C(6)-C(1)-C(2)-C(3)
C(13)-C(14) 1.504(4) O(3)-C(12)-N(3) 119.9(3) F(1)-C(1)-C(2)-C(3)
O(2)-C(11)
O(3)-C(12)
O(4)-C(13)
N(1)-C(11)
N(2)-C(12)
N(3)-C(13)
N(3)-C(12)
N(1)-N(2)
1.228(3) O(3)-C(12)-N(2) 124.9(3) C(5)-C(4)-C(7)-O(1)
1.224(3) O(4)-C(13)-C(14) 120.6(3) C(7)-O(1)-C(8)-C(9)
1.219(3) O(4)-C(13)-N(3) 124.2(3) N(2)-N(1)-C(11)-O(2)
1.363(3) N(2)-C(12)-N(3) 115.2(2) N(1)-N(2)-C(12)-O(3)
1.342(3) N(3)-C(13)-C(14) 115.2(3) N(1)-N(2)-C(12)-N(3)
1.369(3) C(13)-N(3)-C(12) 127.7(2) C(12)-N(3)-C(13)-O(4)
1.398(3) C(12)-N(2)-N(1) 119.9(2) O(4)-C(13)-C(14)-C(19)
1.387(3) C(11)-N(1)-N(2) 118.4(2) C(17)-C(18)-C(19)-F(3)

Molecules 2010, 15
4272
In the crystal of the structure, C(1), C(2), C(3), C(4), C(5), and C(6) formed a plane with a mean
deviation of 0.0099 Å, defined as plane I; C(7), C(8), C(9), C(10), and O(1) formed a plane with the a
mean deviation of 0.0009 Å, defined as plane II; O(2), C(11), N(1), and N(2) were nearly coplanar
with a mean deviation of 0.0144 Å, defined as plane III; O(3), C(12), N(3), C(31) and O(4) were
nearly coplanar with a mean deviation of 0.0163 Å, defined as plane IV; C(14), C(15), C(16), C(17),
C(18), and C(9) formed a plane with a mean deviation of 0.0075 Å, defined as plane V (Figure 1).
Plane II, plane III, plane IV and plane V form a dihedral angle with plane I of 4.2, 3.3, 73.3, and 17.5°.
Plane III, plane IV and plane V form a dihedral angle with plane II of 7.2, 75.8, and 19.9°. Plane IV
and plane V form a dihedral angle with plane III of 70.1 and 14.5. And the dihedral angle between
plane IV and plane V is 55.9°. The related data are summarized in Table 3.
Table 3. The dihedral angles and the mean deviation of the planes in compound E2.
Dihedral angles (°)
Plane I and plane II
Plane I and plane III
Plane I and plane IV
Plane I and plane V
Plane II and plane III
Plane II and plane IV
Plane II and plane V
Plane III and plane IV
Plane III and plane V
plane IV and plane V
4.2
3.3
73.3
17.5
7.2
75.8
19.9
70.1
14.5
55.9
The mean deviation of the plane (Å)
Plane I
0.0099
0.0009
0.0144
0.0163
0.0075
Plane II
Plane III
Plane IV
Plane V
2.2. Biological activity
Considering that the lead compounds B and C had good insecticidal activity against dipterous and
lepidopterous insects, and D had good fungicidal activity, we chose five strains of fungi and three
kinds of insects to evaluate whether the designed compounds retained the insecticidal and fungicidal
activity.
The bioassay showed that the title compounds exhibited lower fungicidal activity in vivo against the
five strains of fungi at the concentration of 50 µg mL-1 (Table 4). In the insecticidal activity shown in
Table 5, some title compounds possessed good activity to the Plutella xylostella L. at the concentration
of 500 µg mL-1, such as E10 and E15 were 95.0% and 85.0%, respectively.

Molecules 2010, 15
Table 4. Fungicidal activity of compounds E against five fungus species at 50 µg mL-1.
4273
Inhibitory rate (%)
Fusarium
Oxysporum
7.50
Compd.
Phytophthora
Capsici
1.94
Botrytis
Cinerea
13.61
9.17
Rhizoctonia Corynespora
Solanii
Cassiicola
E1
0.00
2.22
E2
9.72
37.50
29.17
10.28
32.22
14.17
5.83
14.44
28.89
20.83
9.72
4.72
8.61
8.61
30.28
22.78
68.33 c
3.61
1.39
14.44
8.33
E3
22.50
37.50
23.61
49.17
8.89
31.94
10.28
12.50
19.44
20.83
13.06
21.67
4.17
6.11
E4
23.33
54.72
49.17
29.17
48.89
28.61
0.00
0.00
45.28
4.17
41.39
0.00
6.39
8.06
E5
E6
E7
0.00
0.00
11.39
5.83
E8
8.33
8.33
E9
0.56
0.00
10.28
8.33
E10
E11
50.00
0.00
0.00
0.00
0.00
6.94
E12
12.22
19.72
18.06
5.00
E13
E14
7.78
10.56
5.56
E15
DMF(control)
fungicidesa
4.17
86.39 a
13.06
76.67 d
14.72
68.61 e
69.72 b
aControl fungicides: a, 50% dimethomoph WP; b, 40% dimetachlone WP; c, 70% thiophanate-
methyl WP; d, 3% jinggangmycin AS; e, 75%chlorothalonil WP
Table 5. Insecticidal activity of compounds E at 500 µg mL-1.
Inhibitory rate (%)
Compd.
Plutella xylostella L.
Aphis gossypii
20.0
Tetranchus urticae
E1
E2
15.0
32.0
33.0
30.0
25.0
20.0
14.0
24.0
0
0
0
0
0
0
0
0
0
0
20.0
E3
29.4
E4
17.1
E5
23.1
E6
12.9
E7
27.3
E8
32.7
E9
18.5
E10
95.0
45.0
16.0
10.0
0
15.4
23.2
19.2
38.1
0
0
0
0
E11
E12
E13
E14
24.5
0
E15
85.0
0
14.8
2.4
0
0
CK
Hexaflumuron
RH-5849
100
100
22.6
22.1
100
100
NT: not detected.

Molecules 2010, 15
4274
All the title compounds exhibited lower in vitro insecticidal activity towards Aphis gossypii at the
concentration of 500 µg mL-1. The highest mortality was 38.0% of E13. The commercial pesticides
RH-5849 and hexaflumuron, which display similar structures as the title compounds also showed
lower activity to Aphis gossypii (the results were 22.1% and 22.6%), which indicated that these kinds
of structures were not suitable for the control of Aphis gossypii. None of the title compounds had
activity towards Tetranchus urticae at the concentration of 500 µg mL-1.
Ren [20] and Nishat [21] reported that compounds containing semicarbazides showed excellent
anticancer activity. Enlightened by the results from Ren and Nishat, we also studied the anticancer
activity of the title compounds, in which the urea linkage was converted into a semicarbazide.
Four kinds of cancer cells lines, human promyelocytic leukemic cell line (HL-60), human
hepatocellular carcinoma cell line (Bel-7402), human gastric carcinoma cell line (BGC-823), and
human nasopharyngeal carcinoma cell line (KB) were chosen for the bioassay. As shown in Table 6,
most of the compounds E showed good activity against HL-60. Moreover, some of them exhibited
good activity to the solid tumor cells BGC-823 and Bel-7402. Among them E15 exhibited higher
activity and broader spectra than others. It had excellent activity of 0.14, 0.36 and 0.09 mM against
HL-60, Bel-7402, and BGC-823, respectively.
Table 6. The IC50 values of antitumor activity of compounds E.
IC50 (mM)
Compd.
HL-60
1.56
1.26
-
Bel-7402
-
-
-
BGC-823
-
-
-
KB
-
-
-
E1
E2
E3
E4
-
-
-
-
E5
0.13
-
-
-
-
-
-
-
E6
E7
11.99
-
5.39
-
-
-
-
-
E8
E9
5.39
-
-
-
-
-
-
-
-
-
-
-
E10
E11
E12
E13
E14
E15
0.44
2.93
0.18
2.63
0.14
11.02
-
-
-
1.42
-
59.46
-
-
0.36
0.09
- means IC50 > 100 mM.
Comparing the title compounds E with lead compounds B, C, and D, it can be seen that the linkage
(Y) is important for the bioactivity and spectra. When the linkage was urea and semicarbazide, the
compounds exhibited insecticidal activity, especially towards lepidopterous insects, but had lower
effects on fungi. When the linkage was converted to a carbamic acid ester, the compounds had no
insecticidal activity, but possessed good fungicidal activity. Moreover, the title compounds E exhibited
anticancer activity.

Molecules 2010, 15
4275
3. Experimental
3.1. Materials and methods
All the melting points were determined with a Cole-Parmer melting point apparatus and are
uncorrected. IR spectra were recorded on a Thermo Nicolet Nexus 470 FT-IR spectrometer as KBr
pellets. 1H-NMR spectra were recorded on a Bruker DPX300 instrument (Switzerland), with DMSO-d6
as solvent and tetramethylsilane as the internal standard. Elemental analysis was performed by the
Analytical Center in the Institute of Chemistry, Chinese Academy of Sciences, using a Flash EA 1112
elemental analyzer. The solvents and reagents were mainly purchased from the Beijing Chemical
Reagents Co., P. R. China.
3.2. General procedure for the preparation of key intermediates 2 and 4
The different substituted benzoyl isocyanates 4 were obtained by the reaction of the corresponding
benzamides and oxalyl dichloride according to the literature [22]. The 5-substituted phenyl-2-
furancarboxylic acids 2 were prepared according to the method given in reference [23].
3.3. General synthetic procedure for compounds E
According to the literature [23], different 5-(substituted phenyl)-2-furoyl hydrazines 5 were
prepared. Then 4 (5 mmol) was added to a solution of compound 5 (5 mmol) in purified toluene (25
mL). The reaction mixture was kept at room temperature for 2 h. The solvent were evaporated off
under reduced pressure, and the resulting solid was purified by vacuum column chromatography on
silica gel using petroleum ether (60–90 °C) and ethyl acetate as the eluent to yield E.
N-benzoyl-N'-[5-(4'-chlorophenyl)-2-furoyl] semicarbazide (E1): White powdery crystals: yield 78.9%,
1
m.p. 238–239 °C. H-NMR δ: 7.22 (d, J = 3.57 Hz, 1H, FuH), 7.34 (d, J = 3.63 Hz, 1H, FuH),
7.52–7.72 (m, 5H, 2ArH-Fu + 3ArH), 7.92–8.04 (m, 4H, 2ArH-Fu + 2ArH), 10.13 (s, 1H, NHCO),
10.71 (s, 1H, CONH), 11.11 (s, 1H, CONHCO); IR ν: 3405.9, 3255.7, 1686.8, 1653.8, 1604.8, 1534.9,
1474.4, 1441.7, 1271.5, 1093.0, 1025.6 cm-1; Anal. calcd.(%) for C19H14ClN3O4: C 59.46, H 3.68, N
10.95; found C 59.73, H 3.58, N 10.89.
N-2,6-difluorobenzoyl-N'-[5-(4'-fluorophenyl)-2-furoyl] semicarbazide (E2): Light yellow powdery
crystals: yield 75.8%, m.p. 207–208 °C. 1H-NMR δ: 7.15 (d, J = 3.60 Hz, 1H, FuH), 7.23–7.40 (m, 5H,
FuH + 2ArH-Fu + 2ArH), 7.57–7.67 (m, 1H, ArH), 7.99–8.06 (m, 2H, ArH-Fu), 9.72 (s, 1H, NHCO),
10.63 (s, 1H, CONH), 11.48 (s, 1H, CONHCO); IR ν: 3425.0, 3262.8, 3131.9, 2951.2, 1738.0, 1698.2,
1648.5, 1626.0, 1592.9, 1512.0, 1482.2, 1315.9, 1284.2, 1265.3, 1234.1, 1161.2, 1109.4, 1030.2,
1014.6 cm-1; Anal. calcd.(%) for C19H12F3N3O4: C 56.58, H 3.00, N 10.42; found C 56.53, H 3.08, N
10.37.
N-3-methylbenzoyl-N'-[5-(4'-chlorophenyl)-2-furoyl] semicarbazide (E3): Light yellow powdery
crystals: yield 83.6%, m.p. 221–222 °C. 1H-NMR δ: 2.39 (s, 3H, CH3), 7.23 (d, J = 3.57 Hz, 1H, FuH),
7.34 (d, J = 3.66 Hz, 1H, FuH), 7.43–7.47 (m, 2H, ArH), 7.58 (dd, J = 6.71, 1.94 Hz, 2H, ArH-Fu),

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7.80–7.86 (m, 2H, ArH), 7.99–8.02 (m, 2H, ArH-Fu), 10.13 (s, 1H, NHCO), 10.72 (d, J = 1.08 Hz, 1H,
CONH), 11.05 (s, 1H, CONHCO); IR ν: 33401.9, 3245.5, 3131.9, 1712.5, 1669.7, 1586.1, 1538.4,
1510.3, 1473.8, 1410.8, 1318.8, 1278.0, 1234.9, 1095.5, 1034.1 cm-1; Anal. calcd.(%) for
C19H14ClN3O4: C 60.38, H 4.05, N 10.56; found C 60.35, H 4.20, N 10.47.
N-2,6-difluorobenzoyl-N'-[5-(4'-chlororophenyl)-2-furoyl] semicarbazide (E4): Light brown powdery
1
crystals: yield 82.6%, m.p. 220–221 °C. H-NMR δ: 7.22–7.28 (m, 3H, FuH + 2ArH), 7.34 (d,
J = 3.66 Hz, 1H, FuH), 7.56–7.72 (m, 3H, 2ArH-Fu + ArH), 7.98–8.02 (m, 2H, ArH-Fu), 9.74 (s, 1H,
NHCO), 10.67 (s, 1H, CONH), 11.48 (s, 1H, CONHCO); IR ν: 3425.0, 3266.2, 3143.5, 1738.7, 1699.1,
1649.4, 1625.3, 1592.1, 1527.1, 1470.1, 1314.6, 1282.4, 1265.2, 1236.8, 1111.4, 1094.7, 1012.7 cm-1;
Anal. calcd.(%) for C19H12ClF2N3O4: C 54.36, H 2.88, N 10.01; found C 54.57, H 3.10, N 10.00.
N-2-chlorobenzoyl-N'-[5-(4'-chlorophenyl)-2-furoyl] semicarbazide (E5): White powdery crystals:
yield 85.1%, m.p. 196–197 °C. 1H-NMR δ: 7.22 (d, J = 3.60 Hz, 1H, FuH), 7.34 (d, J = 3.63 Hz, 1H,
FuH), 7.43–7.62 (m, 6H, 2ArH-Fu + 4ArH), 7.99–8.02 (m, 2H, ArH-Fu), 9.84 (s, 1H, NHCO), 10.68
(s, 1H, CONH), 11.26 (s, 1H, CONHCO); IR ν: 3733.6, 3419.6, 3239.0, 1727.9, 1689.1, 1650.9,
1523.6, 1488.8, 1471.0, 1433.8, 1313.9, 1281.7, 1246.6, 1112.3, 1093.7, 1056.4, 1028.9 cm-1; Anal.
calcd.(%) for C19H13Cl2N3O4: C 54.56, H 3.13, N 10.05; found C 54.23, H 3.30, N 9.86.
N-2,6-dichlorobenzoyl-N'-[5-(4'-methylphenyl)-2-furoyl] semicarbazide (E6): White powdery crystals:
1
yield 78.6%, m.p. 210–211 °C. H-NMR δ: 2.35 (s, 3H, CH3), 7.10 (d, J = 3.30 Hz, 1H, FuH),
7.29–7.32 (m, 3H, 2ArH-Fu + FuH), 7.46–7.60 (m, 3H, ArH), 7.86 (d, J = 7.83 Hz, 2H, ArH-Fu), 9.83
(s, 1H, NHCO), 10.63 (s, 1H, CONH), 11.54 (s, 1H, CONHCO); IR ν: 3247.1, 3135.7, 2973.3, 1716.4,
1700.4, 1677.6, 1596.8, 1535.3, 1486.2, 1433.1, 1307.0, 1260.4, 1211.8, 1144.4, 1019.7 cm-1; Anal.
calcd.(%) for C20H15Cl2N3O4: C 55.57, H 3.50, N 9.72; found C 55.61, H 3.76, N 9.67.
N-2,6-difluorobenzoyl-N'-[5-(4'-methylphenyl)-2-furoyl] semicarbazide (E7): Light yellow powdery
crystals: yield 78.2%, m.p. 211–212 °C. 1H-NMR δ: 2.35 (s, 3H, CH3), 7.09 (d, J = 3.60 Hz, 1H, FuH),
7.23–7.32 (m, 5H, FuH + 2ArH-Fu + 2ArH), 7.57–7.65 (m, 1H, ArH), 7.86 (d, J = 8.16 Hz, 2H, ArH-
Fu), 9.72 (s, 1H, NHCO), 10.59 (s, 1H, CONH), 11.47 (s, 1H, CONHCO); IR ν: 3276.1, 3124.8,
3023.9, 2950.5, 1739.5, 1697.2, 1650.4, 1625.5, 1593.2, 1535.1, 1468.1, 1368.1, 1316.2, 1282.0,
1233.4, 1112.2, 1058.7, 1029.8, 1012.4 cm-1; Anal. calcd.(%) for C20H15F2N3O4: C 60.15, H 3.79, N
10.52; found C 60.20, H 4.00, N 10.31.
N-2-chlorobenzoyl-N'-[5-(4'-methylphenyl)-2-furoyl] semicarbazide (E8): Light yellow powdery
crystals: yield 79.5%, m.p. 206–207 °C. 1H-NMR δ: 2.35 (s, 3H, CH3), 7.09 (d, J = 3.60 Hz, 1H, FuH),
7.29–7.32 (m, 3H, 2ArH-Fu + FuH), 7.43–7.61 (m, 4H, ArH), 7.86 (d, J = 8.16 Hz, 2H, ArH-Fu), 9.81
(s, 1H, NHCO), 10.59 (s, 1H, CONH), 11.23 (s, 1H, CONHCO); IR ν: 3262.8, 3128.0, 1725.3, 1685.5,
1657.5, 1544.0, 1484.7, 1318.4, 1286.8, 1246.9, 1224.8, 1101.2, 1055.8, 1031.2 cm-1; Anal. calcd.(%)
for C19H14ClN3O4: C 60.38, H 4.05, N 10.56; found C 60.17, H 4.09, N 10.44.
N-2-methoxybenzoyl-N'-[5-(2'-nitrophenyl)-2-furoyl] semicarbazide (E9): Brown powdery crystals:
1
yield 73.4%, m.p. 191–192 °C. H-NMR δ: 3.93 (s, 3H, OCH3), 6.95 (d, J = 3.66 Hz, 1H, FuH), 7.10

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(td, J = 7.50, 0.73 Hz, 1H, ArH),7.20–7.23 (m, 1H, ArH), 7.39 (d, J = 3.63 Hz, 1H, FuH), 7.55–7.58
(m, 1H, ArH), 7.68–7.73 (m, 2H, ArH + ArH-Fu), 7.81–7.86 (m, 1H, ArH-Fu), 8.00–8.03 (m, 2H,
ArH-Fu), 10.00 (s, 1H, NHCO), 10.50 (s, 1H, CONH), 10.63 (s, 1H, CONHCO); IR ν: 3358.1, 3227.9,
3124.2, 1715.7, 1672.0, 1598.8, 1528.0, 1478.3, 1364.7, 1292.9, 1248.9, 1225.1, 1175.6, 1107.8,
1038.0, 1015.9 cm-1; Anal. calcd.(%) for C20H16N4O7: C 56.61, H 3.80, N 13.20; found C 56.76, H
4.03, N 13.07.
N-3-methylbenzoyl-N'-[5-(2'-chlorophenyl)-2-furoyl] semicarbazide (E10): Light yellow powdery
crystals: yield 81.2%, m.p. 209–210 °C. 1H-NMR δ: 2.39 (s, 3H, CH3), 7.33 (d, J = 3.69 Hz, 1H, FuH),
7.39 (d, J = 3.69 Hz, 1H, FuH), 7.41–7.55 (m, 4H, 3ArH-Fu + ArH), 7.62 (dd, J = 7.91,0.83 Hz, 1H,
ArH),7.80–7.86 (m, 2H, ArH), 8.23 (dd, J = 7.88, 1.70 Hz, 1H, ArH-Fu), 10.14 (s, 1H, NHCO), 10.75
(d, J = 1.08 Hz, 1H, CONH), 11.05 (s, 1H, CONHCO); IR ν: 3413.4, 3243.4, 1711.8, 1667.3, 1516.9,
1469.5, 1316.6, 1281.4, 1231.0, 1085.0, 1029.4 cm-1; Anal. calcd.(%) for C19H14ClN3O4: C 60.38, H
4.05, N 10.56; found C 60.56, H 4.11, N 10.55.
N-2,6-difluorobenzoyl-N'-[5-(2'-chlorophenyl)-2-furoyl] semicarbazide (E11): Light yellow powdery
crystals: yield 84.3%, m.p. 192–193 °C. 1H-NMR δ: 7.22–7.28 (m, 2H, ArH), 7.33 (d, J = 3.69 Hz, 1H,
FuH), 7.38 (d, J = 3.69 Hz, 1H, FuH), 7.41–7.55 (m, 2H, 2ArH-Fu), 7.60–7.63 (m, 2H, ArH-Fu +
ArH), 8.23 (dd, J = 7.85, 1.70 Hz, 1H, ArH-Fu), 9.73 (s, 1H, NHCO), 10.69 (s, 1H, CONH), 11.47 (s,
1H, CONHCO); IR ν: 3406.3, 3271.5, 3163.4, 1728.0, 1700.1, 1673.5, 1627.1, 1593.0, 1549.9, 1490.9,
1468.0, 1317.4, 1283.9, 1236.7, 1029.5, 1011.8 cm-1; Anal. calcd.(%) for C19H12ClF2N3O4: C 54.36, H
2.88, N 10.01; found C 54.23, H 3.08, N 10.06.
N-2-methoxybenzoyl-N'-[5-(2'-chlorophenyl)-2-furoyl] semicarbazide (E12): White powdery crystals:
yield 84.3%, m.p. 190–191 °C. 1H-NMR δ: 3.88 (s, 3H, OCH3), 7.10 (td, J = 7.51, 0.81 Hz, 1H, ArH),
7.20–7.23 (m, 1H, ArH), 7.33–7.63 (m, 6H, 2FuH + 3ArH-Fu + ArH), 7.69–7.71 (m, 1H, ArH), 8.23
(dd, J = 7.82, 1.58 Hz, 1H, ArH-Fu), 10.02 (s, 1H, NHCO), 10.52 (d, J = 1.08 Hz, 1H, CONH), 10.72
(s, 1H, CONHCO); IR ν: 3362.4, 3226.6, 1715.6, 1669.5, 1649.9, 1598.6, 1521.2, 1479.2, 1317.9,
1292.0, 1248.7, 1225.8, 1175.3, 1016.6 cm-1; Anal. calcd.(%) for C20H16ClN3O5: C 58.05, H 3.90, N
10.15; found C 57.70, H 3.67, N 10.59.
N-2,6-dichlorobenzoyl-N'-[5-(2',4'-difluorophenyl)-2-furoyl] semicarbazide (E13): Light yellow
powdery crystals: yield 78.6%, m.p. 224–225 °C. 1H-NMR δ: 6.98 (brs, 1H, FuH), 7.30–7.35 (m, 2H,
FuH + ArH-Fu), 7.44–7.61 (m, 4H, ArH-Fu + 3ArH), 8.26–8.31 (m, 1H, ArH-Fu), 9.85 (s, 1H,
NHCO), 10.73 (s, 1H, CONH), 11.54(s, 1H, CONHCO); IR ν: 3421.2, 3265.8, 3158.9, 2962.2, 1739.3,
1691.4, 1665.6, 1597.3, 1535.3, 1513.6, 1483.3, 1432.0, 1314.6, 1272.2, 1225.5, 1147.4, 1103.9,
1033.7 cm-1; Anal. calcd.(%) for C19H11Cl2F2N3O4: C 54.36, H 2.88, N 10.01; found C 54.26, H 2.87,
N 10.18.
N-2-chlorobenzoyl-N'-[5-(2',4'-difluorophenyl)-2-furoyl] semicarbazide (E14): Light yellow powdery
crystals: yield 86.2%, m.p. 216–217 °C. 1H-NMR δ: 6.98 (t, J = 3.72 Hz, 1H, FuH), 7.30–7.37 (m, 2H,
FuH + ArH-Fu), 7.43–7.62 (m, 5H, ArH-Fu + 4ArH), 8.23–8.31 (m, 1H, ArH-Fu), 9.86 (s, 1H,
NHCO), 10.73 (s, 1H, CONH), 11.27 (s, 1H, CONHCO); IR ν: 3411.1, 3237.3, 1729.7, 1685.3, 1658.7,

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1573.2, 1526.8, 1508.7, 1482.5, 1431.9, 1312.6, 1272.0, 1241.9, 1148.5, 1104.0, 1033.9 cm-1; Anal.
calcd.(%) for C19H12ClF2N3O4: C 50.24, H 2.44, N 9.25; found C 50.09, H 2.51, N 9.54.
N-2-methoxybenzoyl-N'-[5-(4'-chlorophenyl)-2-furoyl] semicarbazide (E15): White powdery crystals:
1
yield 84.6%, m.p. 192–193 °C. H-NMR δ: 3.93(s, 3H, OCH3), 7.10(td, J = 7.51,0.79 Hz,1H,
ArH),7 .20–7.24(m,2H, FuH+ ArH), 7.34(d, J = 3.57 Hz, 1H, FuH), 7.56–7.62 (m, 4H, 2ArH-
Fu+2ArH), 7.99–8.02(m, 2H, ArH-Fu), 10.01 (s, 1H, NHCO), 10.52 (s, 1H, CONH), 10.70 (s, 1H,
CONHCO); IR ν: 394.2, 3331.0, 2969.1, 1742.1, 1721.9, 1660.1, 1597.9, 1478.0, 1408.6, 1295.7,
1253.2, 1228.8, 1091.0, 1049.3, 1018.4 cm-1; Anal. calcd.(%) for C20H16ClN3O5: C 58.05, H 3.90, N
10.15; found C 57.76, H 3.66, N 10.42.
3.4. X-ray structure determination of E2
Compound E2 was recrystallized from methanol to obtain colorless crystal suitable for X-ray single
crystal diffraction. Cell constants at 173(2) K were determined by a least-square fit to the setting
parameters of E2 independent reflections measured on a Rigaku raxis Rapid IP Area Detector
diffractometer with a graphite-monochromated Cu Kα radiation (λ = 0.154178 nm) and operating in
the phi and scan modes. The structure was solved by direct method with SHELXS-97 [24,25] and
refined by the full-matrix least squares method on F2 data using SHELXL-97 [25,26]. The empirical
absorption corrections were applied to all intensity data. H atom of N—H was initially located in a
difference Fourier map and was refined with the restraint Uiso(H) = 1.2 Ueq(N). Other H atoms were
positioned geometrically and refined using a riding model, with d(C…H) = 0.093—0.097 nm and
Uiso(H) = 1.2 Ueq(C) or 1.5 Ueq(C-methyl). Crystallographic data for the structure have been
deposited with the Cambridge Crystallographic Data Center as supplementary publication No. CCDC
769209. These data can be obtained free of charge from the CCDC via
www.ccdc.cam.ac.uk/data_request/cif.
3.5. Biological assays
(a) The preliminary fungicidal activity in vitro was tested against five kinds of strains:
Phytophthora Capsici, Botrytis Cinerea, Fusarium Oxysporum, Rhizoctonia Solanii and Corynespora
Cassiicola. All the strains were conserved in the Institute of Vegetable and Flowers, Chinese Academy
of Agricultural Science. Commercialized fungicides: 50% dimethomoph WP, 40% dimetachlone WP,
70% thiophanate-methyl WP, 3% jinggangmycin AS and 75% chlorothalonil WP were used as
controls for the above five strains, respectively.
The fungicidal activity of the title compounds E against above five strains in vitro was evaluated
using the mycelium growth rate test [27]. Both control fungicides and the title compounds were
dissolved in DMF at the concentration of 50 µg mL-1. The culture media was obtained by mixing the
solution of compounds E in DMF with potato dextrose agar (PDA), on which fungus cakes were
placed. The blank test was made using DMF. The culture had been stored in an incubator at 24 0.5 °C
for 2 days. Three replicates were performed. After the mycelia grew completely, the diameters of the
mycelia were measured and the inhibitory rates were calculated according to the formula:
I (%) = (C-T)/C × 100%

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in which I stands for the inhibition (%), C for the diameter of mycelia in the blank control test (in mm),
and T for the diameter of mycelia in the presence of compounds E (in mm). The results are shown in
Table 4.
(b) Insecticidal activity against Plutella xylostella L., Aphis gossypii and Tetranchus urticae was
evaluated using the immersion method [28]. Test solutions were made by dissolving the title
compounds E in DMSO, adding a little 0.1% Tween-80 as the emulsifier, and then diluting to 500 µg
mL-1 with water. The insects were raised at 27 1 °C, with 12:12 h (light/dark) photoperiod and 80%
relative humidity. The results were observed after 72 h and expressed by percentage death. The solvent
of DMSO was set as blank control. Hexaflumuron and RH-5849 were used as insecticidal controls.
Three replicates were performed. The results are shown in Table 5.
(c) Anticancer activity was screened against four different cell lines: a human promyelocytic
leukemic cell line (HL-60), a human hepatocellular carcinoma cell line (Bel-7402), a human gastric
carcinoma cell line (BGC-823), and a human nasopharyngeal carcinoma cell line (KB). All the title
compounds were dissolved in DMSO. The four types of cell line were grown and maintained in RPMI-
1640 medium supplemented with 10% fetal bovine serum (FBS), penicillin (100 U mL-1), and
streptomycin (100 µg mL-1) at 37 °C in humidified incubators in an atmosphere of 5% CO2.
All the experiments were performed on exponentially growing cancer cells. Numbers of viable
cancer cells were determined by MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide]
[29] and SRB [30] assays. The cancer cells (1~2.5 × 104 cells mL-1) were inoculated in 96-well culture
plates (180 µL/well). After 24 h, 20 µL of culture medium containing compounds of various
concentrations were added to the wells and, the cells were incubated for 48 h. 20 µL of RPMI-1640
medium was added to the control cells. HL-60 cells were assayed by MTT, and the Bel-7402, BGC-
823 and KB cells were assayed by SRB. The absorbance of each well was measured using a
microculture plate reader at 570 nm (MTT) and 540 nm (SRB). The inhibition rate was calculated
according to the following formula:
Inhibition rate = (ODcontrol - ODtreated)/ODcontrol × 100%
Three replicates were performed. The IC50 values of some active target compounds were evaluated
using logit analysis [31]. The results are shown in Table 6.
4. Conclusions
In summary, a series of novel semicarbazide derivatives were synthesized by the nucleophilic
addition reaction of 5-substituted aryl-2-furoyl hydrazines with benzoyl isocyanates. Compared with
the lead compounds, the title compounds showed good insecticidal activity, especially towards
lepidopterous insects, but exhibited lower activity against the five kinds of common plant pathogens
tested. Inspiringly, the title compounds possessed obvious anticancer activity against human
promyelocytic leukemic cell line (HL-60), and some of the title compounds also had activity against
solid human tumor cells. The results indicated that the linkage (Y) of the lead compounds was
important for the bioactivity and spectra and that modification on the urea linkage was an effective
strategy to discover new pesticide and drug candidates.

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Acknowledgements
We are grateful to the National High Technology Research and Development Program of China
(2006AA10A201), the National Key Project for Basic Research (2010CB126104), the National
Natural Science Foundation of China (20972185) and the Scientific Research Foundation of the
Graduate School of China Agricultural University.
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Sample Availability: Samples of the compounds are available from the authors.
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