Synthesis, cyrstal structure, fungicidal activity and molecular docking of nicotinic acyl urea derivatives

Article abstract of DOI:10.1016/j.molstruc.2019.127485

A series of nicotinic acyl urea derivatives were designed using boscalid as a lead compound. They were synthesized via four steps. Their structures were confirmed by ¹H NMR, HRMS and X-ray diffraction. Some of these new nicotinic acyl urea derivatives(4d, 4g, 4h and 4k) had moderate fungicidal activity against Gibberella zeae, Sclerotinia sclerotiorum, Rhizoctonia solani, Botrytis cinerea and Physalospora piricola at 50 mg/L, which is a little weaker than the commercial fungicide fluxapyroxad. The SAR was studied by using molecular docking.

Full text of DOI:10.1016/j.molstruc.2019.127485

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Synthesis, cyrstal structure, fungicidal activity and molecular docking of nicotinic acyl
urea derivatives
Pei-Pei Zhang, Qiao Wang, Li-Jing Min, Hong-Ke Wu, Jian-Quan Weng, Cheng-Xia
Tan, Yong-Gang Zhang, Xing-Hai Liu
PII:
S0022-2860(19)31594-7
DOI:
https://doi.org/10.1016/j.molstruc.2019.127485
MOLSTR 127485
Reference:
To appear in: Journal of Molecular Structure
Received Date: 18 July 2019
Revised Date: 6 November 2019
Accepted Date: 26 November 2019
Please cite this article as: P.-P. Zhang, Q. Wang, L.-J. Min, H.-K. Wu, J.-Q. Weng, C.-X. Tan,
Y.-G. Zhang, X.-H. Liu, Synthesis, cyrstal structure, fungicidal activity and molecular docking of
nicotinic acyl urea derivatives, Journal of Molecular Structure (2020), doi: https://doi.org/10.1016/
j.molstruc.2019.127485.
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Synthesis, Cyrstal Structure, Fungicidal Activity and Molecular
Docking of Nicotinic Acyl Urea Derivatives
1
1
2
1
1
1
Pei-Pei Zhang , Qiao Wang , Li-Jing Min , Hong-Ke Wu , Jian-Quan Weng , Cheng-Xia Tan ,
*
1*
Yong-Gang Zhang , Xing-Hai Liu
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014,
Zhejiang, China
. College of Life Science, Key Laboratory of Vector Biology and Pathogen Control of Zhejiang
Province, Huzhou University, Huzhou, 313000, Zhejiang, China
Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan,
1
2
3
Shandong, China
Abstract: A series of nicotinic acyl urea derivatives were designed using boscalid as a lead
1
compound. They were synthesized via four steps. Their structures were confirmed by H NMR,
HRMS and X-ray diffraction. Some of these new nicotinic acyl urea derivatives(4d, 4g, 4h and 4k)
had moderate fungicidal activity against Gibberella zeae, Sclerotinia sclerotiorum, Rhizoctonia
solani, Botrytis cinerea and Physalospora piricola at 50 mg/L, which is a little weaker than the
commercial fungicide fluxapyroxad. The SAR was studied by using molecular docking.
Keywords: nicotinic acyl urea derivatives; chemical synthesis; fungicidal activity; crystal
structure; molecular docking
Introduction
Heterocycles are important skeletons of natural and synthetic compounds due to their wide
[1-5]
biological activities . Compounds with the six-membered pyridine heterocycle have excellent
[
6,7]
[8,9]
[10]
biological activities, such as insecticidal
, fungicidal
, plant growth regulatory
,
,
[
11]
[12]
[13]
immunosuppressive
anti-inflammatory
, anticancer
, anti-human immunodeficiency virus (HIV)
[
14]
[15]
, and antioxidant
activities. Some of these derivatives had been
drugs or pesticides. Boscalid
developed
as
commercial

(2-chloro-N-(4'-chloro-[1,1'-biphenyl]-2-yl)nicotinamide) is an excellent fungicide, targeting
succinate dehydrogenase (SDH), which can protect crops, vegetables and fruits (Figure 1). In this
fungicide, the pyridine and amide moieties essential. The urea group is also found in many
[16-19]
bioactive molecules
. For example, it is found in dimilin, an insect growth regulatory
compound targeting chitin synthetase (Figure 1). The sulfonyl urea herbicides targeting
acetolactate synthetase, such as nicosufuron (Figure 1), contain both pyridime and urea moieties,
such as nicosu.
Furthermore, the radius of the fluorine atom is close to that of hydrogen atom, and the space
structure of fluorine atom has little change after replacing hydrogen atom with fluorine atom. Due
to unique property of fluorine atom, lots of fluorinated compounds have frequently been shown to
have excellent biological activity, such as flubendiamide, dimilin, fluopyram.
Figure 1 Some representative pesticides containing pyridine and urea moieties
In our previous work, many bioactive heterocyclic compounds were designed and
[20-35]
[36,37]
[38-42]
synthesized
, especially herbicidal
and fungicidal
compounds with a pyridine ring.
In order to discover highly active fungicidal lead compounds (Figure 2), boscalid was selected as
template molecule. A urea group was introduced into the amide group and a fluorinated aromatic
ring replaced the 4'-chloro-[1,1'-biphenyl]-2-yl group. Some of these pyridine acyl urea
derivatives exhibited good fungicidal activity. The structure-activity relationships were also
studied with using docking methods.

Figure 2 The design method of nicotinic acyl urea derivatives
Results and Discussion
Synthesis
The synthetic process of nicotinic acyl urea derivatives is shown in Scheme 1. In the process of
synthesizing acid chloride, thionyl chloride (SOCl ) is both a reactant and a solvent. In order to
2
avoid polluting the environment, an exhaust gas absorption device was used in the reaction.
During the synthesis of 2-chloronicotinamide, the diluted acyl chloride should be slowly added
dropwise to the ammonia water ice bath. The nicotinamide isocyanate was used without
purification because the nicotinyl isocyanate is extremely unstable.
Scheme 1 Synthesis route of 2-chloro-N-(phenylcarbamoyl)nicotinamide compounds
Spectra

The synthesized compounds contain two NH groups, two CO groups and two aromatic rings.
1
Taking compound 4d as example: from the H NMR data, the two NH protons can be found as
two single peaks at 9.35 ppm and 10.81 ppm respectively, which is in accordance with the infrared
-1
-1
spectrum(3274.54 cm and 3108.58 cm ). For the pyridine ring and benzene ring, these protons
1
3
are in aromatic 6~8 ppm. From the C NMR data, the two CO peaks can be found at 167.59 ppm
and 146.49 ppm respectively, meanwhile it is also can be found two CO stretching band at
-1
-1
1
690.08 cm and 1582.69 cm in the FTIR spectrocopy. For the HRMS, the measured value is
within 0.003 from the theoretical value.
Crystal structure description
The structure of compound 4d was further confirmed by single crystal X-ray diffraction analysis
and is shown in Figure 3. The torsion angle of C(2)-N(1)-C(8)-N(2), N(1)-C(8)-N(2)-C(9) and
C(8)-N(2)-C(9)-C(10) was -178.55(17)°, -2.1(3)° and -179.37(18)° respectively, which indicated
the two carbonyl groups are opposite and the acyl urea bridge is nearly in the same plane. The
compound 4d has intramolecular and intermolecular hydrogen bonding. The parameters of two
type hydrongen bonds are given in Table 1. They are linked together by N-HꢀO. From Figure 1,
the N(1)-H(1)ꢀO(2) hydrogen bond formed a six member ring in the molecule. In the bc plane,
they are linked together by N(2)-H(2)...O(1) hydrogen bonds (Figure 4). These hydrogen-bonding
sequences are repeated to form a ring. The ring is shaped like a decagon and has two N(2) and two
O(1) atoms at the vertices, leading to a hydrogen-bond network defining cyclic motifs denoted
2
R2
(8). The hydrogen bond interactions strengthen the integration of the 3D networks. These
interactions are estimated to play a role in stabilizing the crystal structure.

Figure 3 The molecular structure of compound 4d
Table 1. Hydrogen-bond Parameters (Ǻ) of Title Compound 4d
DꢁH…A
d(DꢁH)
0.86
d(H…A)
2.08
d(D…A)
2.717 (2)
∠ (DHA)
130.6
N(2)-H(2)...O(1) #
N(1)-H(1)...O(2)
0.86
1.95
2.7981 (19)
168.2
Symmetry transformations used to generate equivalent atoms: # 1-X,-Y,1-Z
Fungicidal Activity
Fungicidal activities of compound 4a~4k against Gibberella zeae (GZ), Phytophthora infestans
PI), Phytophthora capsici (PC), Sclerotinia sclerotiorum (SS), Rhizoctonia solani (RS),
(
Alternaria solani (AS), Botrytis cinerea (BC), Fusarium oxysporum (FO), Cercospora
arachidicola (CA), Physalospora piricola(PP) were evaluated at 50 ꢀg/mL according to our
[50]
previous work (Table 2).
Fluxapyroxad was used as a positive control. The primary bioassay
showed that several of the synthesized compounds exhibited good inhibiting activity against
Gibberella zeae, Sclerotinia sclerotiorum, Botrytis cinerea and Physalospora piricola. For the
Gibberella zeae, had compounds 4b (57.1%), 4d (64.3%), 4e (57.1%), 4g (71.4%), 4h (57.1%)
and 4k (57.1%) had good activity. But the positive control exhibited weak activity (28.6%) against
Gibberella zeae. Compounds 4d, 4h and 4j also exhibited good activity (>70%) against

Sclerotinia sclerotiorum. Compounds 4a, 4b and 4h also displayed moderate activity against
Botrytis cinerea, which is the same as the postitive control. Among all the ten fungi, most of these
compounds (e.g., 4b, 4d, 4g, 4h, 4i, 4k) had good activity against Physalospora piricola. There
was less fungicidal activity against Phytophthora infestans, Alternaria solani, Fusarium
oxysporum and Cercospora arachidicola. For Fusarium oxysporum and Phytophthora capsici,
only compound 4c (40% for Fusarium oxysporum) and 4d (40% for Phytophthora capsici)
exhibited moderate activity, which is a little better than the postivie control (29.4% and 16.7%).
Only 4c and 4h had moderate activity (40%) against Cercospora arachidicola, but they were
weaker than the positive control (100%).
Table 2. Fungicidal activity of title compound 4a~4k at 50 ꢀg/mL
NO
FO
CA
PP
AS
GZ
SS
BC
RS
PI
PC
4
4
a
6.7
13.3
40.0
33.3
6.7
20.0
6.0
22.2
55.6
38.9
66.7
38.9
38.9
66.7
55.6
54.5
13.6
55.6
63.6
0.0
11.1
33.3
44.4
33.3
22.2
11.1
44.4
22.2
33.3
44.4
22.2
88.9
0.0
35.7
57.1
21.4
64.3
57.1
21.4
71.4
57.1
41.7
16.7
57.1
28.6
0.0
44.4
50.0
33.3
77.8
38.9
11.1
22.2
72.2
24.4
70.7
27.8
96.4
0.0
63.6
63.6
36.4
27.3
45.5
9.1
30.9
24.7
37.0
58.0
12.3
30.9
12.3
43.2
11.1
22.2
24.7
88.4
0.0
5.9
11.8
29.4
23.5
5.9
20.0
10.0
10.0
40.0
20.0
20.0
20.0
6.0
b
4
c
40.0
20.0
20.0
20.0
6.0
4d
4
e
4
f
13.3
6.7
11.8
11.8
17.6
21.4
7.1
4
4
g
27.3
63.6
8.3
h
26.7
9.1
40.0
33.3
33.3
20.0
100
0.0
4
i
33.3
28.6
6.0
4
j
13.6
13.3
29.4
0.0
33.3
45.5
63.6
0.0
4k
5.9
FP
27.3
0.0
16.7
0.0
CK
Docking Study
Because of its higher fungicidal activity, compound 4d was selected to study the action mode of
the synthesized compounds. Its binding mode with SDH (PDB:2FBW) using software of
Discovery studio 2.5 was studies. Compound 4d tightly occupies the fungicide boscalid binding
site of SDH. The docking results are shown in Figure 4. From the docking results, the compound
4
d had a π-cation interaction. The π-cation bond was formed between the pyridine ring and Arg 43
amino acid residue with the distance of 3.8 Å. The other two hydrogen bonds were formed
between the C=O and Trp 173 and Tyr 58 amino acid residue with the distance of 2.0 Å and 2.2 Å,
respectively. Another H-F interaction was formed between the CF and Tyr 58 amino acid residue
3

with the distance of 2.2 Å. The results indicated that the main key active group is pyridine ring
and the amide moiety.
Figure 4 The docking mode of compound 4d and SDH
Experimental
Instruments and reagents
1
Melting points were determined by an X-4 apparatus. H NMR spectra were measured on a Bruker
1
3
AV-500 instrument using TMS as an internal standard and CDCl as the solvent. C NMR spectra
3
were measured on a Bruker AV-600 instrument using TMS as an internal standard and DMSO-d6
as the solvent. FTIR was tested on a Nocolet 670 FTIR spectrocopy instrument. HRMS was
determined on a JOEL AccuTOF (JMS-T 100LC) instrument equipped with electrospray
ionization (ESI) ion source. All the reagents used were of analytical grade or freshly prepared
before use. The course of the reactions was monitored by TLC; analytical TLC was performed on
silica gel GF .
2
54
Synthesis
[42]
Intermediate 1, 2, and 3 were synthesized according to our previous work
Synthesis of compounds 4a-4k
.
Synthesis of compound 4a: To a solution of 2-chloronicotinoyl isocyanate 3 (0.18 g, 1 mmol) in
CH Cl (10 mL), 4-fluoroaniline (0.12g, 1.1 mmol) was added dropwise. Then the mixture was
2
2
stirred at room temperature for 10 h. After the reaction was completed, the solvent was evaporated
to give a crude product. The final compound 4a was purified by using colum
chromatograph(V /V =2/1). The other compounds 4b-4k were prepared according to this
EA
PE

method.
-chloro-N-((4-fluorophenyl)carbamoyl)nicotinamide 4a
White solid,yield 59.3 %,melting point 197~200 °C, FT-IR (KBr, νmax, cm ): 3473.11(NH),
2
−
1
3
1
7
231.86(NH), 3102.52, 2969.74, 1690.96(C=O), 1611.61(C=O), 1556.68, 1398.93, 1284.99,
1
256.76, 1159.03, 1071.03; H NMR (CDCl , 500 MHz), δ, ppm: 7.06 (t, J= 7.2 Hz, 2H, Ph),
3
.43-7.46 (m, 1H, Py), 7.48-7.50 (m, 2H, Ph), 8.11-8.13 (m, 1H, Py),8.61-8.62 (m, 1H, Py), 9.21
1
3
(
s, 1H, NH),10.42 (s, 1H, NH); C NMR (DMSO-d , 150 MHz), δ, ppm: 116.08(d, J=21.7Hz),
6
1
1
2
2
22.39(d, J=4.5Hz), 123.48, 131.80, 134.19(d, J=2.1Hz), 138.76, 146.52, 150.82, 151.60, 158.17,
59.77, 167.63; HRMS (ESI) for C H ClFN O m/z Calculated, 294.0440, Found,
1
3
9
3
2
+
94.0439[M+H]
-chloro-N-((3,4-difluorophenyl)carbamoyl)nicotinamide4b
−
1
White solid,yield 57.6 %,melting point 218~221 °C, FT-IR (KBr, νmax, cm ): 3220.63(NH),
3
1
2
127.51(NH), 2968.59, 1708.49(C=O), 1626.62(C=O), 1561.68, 1496.89, 1403.00, 1323.51,
1
284.69, 1230.68, 1206.14, 1146.21, 1072.55; H NMR (CDCl , 500 MHz), δ, ppm: 7.09-7.18 ( m,
3
H, Ph), 7.45-7.48 (m,1H, Py), 7.55-7.59 (m, 1H, Ph), 8.10-8.22 (m, 1H, Py), 8.62-8.64 (m, 1H,
1
3
Py), 9.47 (s, 1H, NH), 10.52 (s, 1H, NH); C NMR (DMSO-d , 150 MHz), δ, ppm: 167.61,
6
1
51.69, 150.84, 148.64(d, J = 13.1 Hz), 147.06(d, J = 12.7 Hz), 146.49, 138.82, 134.93(d, J = 8.5
Hz), 131.66, 123.51, 118.08(d, J = 17.9 Hz), 117.04, 109.91(d, J = 21.7 Hz); HRMS (ESI) for
+
C H ClF N O m/z Calculated, 312.0346, Found, 312.0364[M+H]
1
3
8
2
3
2
2
-chloro-N-((4-(trifluoromethyl)phenyl)carbamoyl)nicotinamide 4c
−
1
White solid,yield57.9 %, melting point 213~215 °C, FT-IR (KBr, νmax, cm ): 3457.27(NH),
3
1
228.08(NH), 3136.92, 2972.40, 1712.70(C=O), 1686.07(C=O), 1504.51, 1402.61, 1334.83,
1
293.66, 1229.05, 1191.19, 1155.40, 1112.13, 1072.42, 1018.35; H NMR (CDCl , 500 MHz), δ,
3
ppm: 7.56-7.59 (m, 1H, Py), 7.71 (d, J= 6.8 Hz, 2H, Ph), 7.81 (d, J= 6.8 Hz, 2H, Ph), 8.11-8.13 (m,
1
3
1
H, Py), 8.55-8.57 (m, 1H, Py), 10.54 (s, 1H, NH), 11.44 (s, 1H, NH); C NMR (DMSO-d , 150
6
MHz), δ, ppm: 167.70, 151.69, 150.76, 146.49, 141.62, 138.82, 131.68, 126.67, 125.65 (q, J =
70.9 Hz, CF ), 124.41(q, J=31.9Hz), 123.50, 120.37; HRMS (ESI) for C H ClF N O m/z
2
3
14
9
3
3
2
+
Calculated, 344.0408, Found, 344.0444[M+H]
-chloro-N-((2-(trifluoromethyl)phenyl)carbamoyl)nicotinamide4d
White solid,yield 57.2 %, melting point 186~189 °C, FT-IR (KBr, νmax, cm ): 3274.54(NH),
2
−
1

3
108.58(NH), 2973.10, 1690.08(C=O), 1582.69(C=O), 1528.89, 1402.81, 1316.36, 1212.62,
1
1
177.01, 1130.51, 1058.95; H NMR (CDCl , 500 MHz), δ, ppm: 7.30 (t, J= 4.2 Hz, 1H, Ph),
3
7
.42-7.45 (m,1H, Py), 7.58 (t, J= 6.4 Hz, 1H, Ph), 7.68 (d, J= 6.4 Hz, 1H, Ph), 8.13 (d, J= 6.8 Hz,
1
3
1
H, Ph), 8.19-8.21 (m, 1H, Py ), 8.59-8.61 (m, 1H, Py ), 9.35 (s, 1H, NH), 10.81 (s, 1H, NH); C
NMR (DMSO-d , 150 MHz), δ, ppm: 167.59, 151.64, 150.92, 146.49, 138.82, 138.78, 131.74,
6
1
1
3
2
30.59, 130.01(q, J = 32.0 Hz), 124.23(d, J = 8.7Hz), 123.51(q, J = 271.9 Hz, CF ), 123.50,
3
20.72, 116.57; HRMS (ESI) for C H ClF N O m/z Calculated, 344.0408, Found,
1
4
9
3
3
2
+
44.0427[M+H]
-chloro-N-((2,6-difluorophenyl)carbamoyl)nicotinamide4e
1
White solid, yield 56.9 %, melting point 196~198 °C, H NMR (CDCl , 500 MHz), δ, ppm: 7.00 (t,
3
J= 6.4 Hz, 2H, Ph), 7.25-7.30 (m, 1H, Ph), 7.35-7.38 (m, 1H, Py), 8.02-8.04 (m, 1H, Py),
8
.55-8.56 (m, 1H, Py), 9.72 (s, 1H, NH), 9.92 (s, 1H, NH); HRMS (ESI) for C H ClF N O m/z
1
3
8
2
3
2
+
Calculated, 312.0346, Found, 312.0365[M+H]
2
-chloro-N-((2-(trifluoromethoxy)phenyl)carbamoyl)nicotinamide 4f
−
1
Yellow solid, yield 68.0 %, melting point 118~120 °C, FT-IR (KBr, νmax, cm ): 3225.93(NH),
3
142.34(NH), 1711.98(C=O), 1614.30(C=O), 1560.65, 1494.37, 1402.81, 1288.33, 1266.56,
1
1
155.19, 1072.04; H NMR (CDCl , 500 MHz), δ, ppm: 7.14-7.17 (m, 1H, Ph), 7.29-7.33 (m, 2H,
3
Ph), 7.42-7.45 (m, 1H, Py), 8.18-8.20 (m, 1H, Py), 8.26-8.29 (m, 1H, Ph), 8.59-8.61 (m, 1H, Py),
1
3
9
1
2
.19 (s, 1H, NH), 10.99 (s, 1H, NH); C NMR (DMSO-d , 150 MHz), δ, ppm: 168.37, 167.37,
6
51.13(q, J = 105.7Hz), 150.47, 146.76, 146.56, 134.95, 133.85, 131.30, 126.65, 125.35(d, J =
2.1 Hz), 124.27(q, J = 271 Hz, OCF ), 123.47, 120.57(q, J = 29.2 Hz); HRMS (ESI) for
3
+
C H ClF N O m/z Calculated, 360.0357, Found, 360.0377[M+H]
1
4
9
3
3
3
2
-chloro-N-((3-fluorophenyl)carbamoyl)nicotinamide4g
White solid, yield62.7 %, melting point 189~192 °C, FT-IR (KBr, νmax
321.73(NH),3123.60(NH), 2966.57, 1710.78(C=O), 1611.10(C=O), 1494.93, 1292.,49, 1228.52,
−
1
,
cm ):
3
1
1
137.95, 1073.57; H NMR (CDCl , 500 MHz), δ, ppm: 6.85-6.89 (m, 1H, Ph), 7.10-7.12 (m, 1H,
3
Py), 7.29-7.32 (m, 1H, Py), 7.40-7.47 (m, 2H, Ph), 8.09-8.11 (m, 1H, Py), 8.66 (s, 1H, Ph), 9.83 (s,
1
3
1
1
1
H, NH), 10.58 (s, 1H, NH); C NMR (DMSO-d , 150 MHz ), δ, ppm: 172.44, 168.24, 166.64,
6
56.43, 155.48, 151.24, 144.37(d, J=11.1Hz), 143.63(d, J=19.1Hz), 136.44, 135.83, 128.27,
20.96, 115.69(q, J=11.8Hz), 112.11(q, J=26.1Hz); HRMS (ESI) for C H ClFN O m/z
1
3
9
3
2

+
Calculated, 294.0440, Found, 294.0466[M+H]
2
-chloro-N-((2,3,4-trifluorophenyl)carbamoyl)nicotinamide4h
1
White solid, yield66.2 %, melting point 203~206 °C, H NMR (CDCl , 500 MHz), δ, ppm:
3
6
.97-7.03 (m, 1H, Ph), 7.46-7.48 (m, 1H, Py), 7.85-7.90 (m, 1H, Ph), 8.19-8.21 (m, 1H, Py),
.62-8.63 (m, 1H, Py), 9.06 (s, 1H, NH), 10.70 (s, 1H, NH); HRMS (ESI) for C H ClF N O m/z
8
1
3
7
3
3
2
+
Calculated, 330.0252, Found, 330.0277[M+H]
2
-chloro-N-((3-(trifluoromethyl)phenyl)carbamoyl)nicotinamide4i
−
1
White solid, yield53.6 %, melting point 185~188 °C, FT-IR (KBr, νmax, cm ): 3453.20(NH),
3
1
268.61(NH), 3150.97, 1707.83(C=O), 1610.97(C=O), 1558.41, 1491.99, 1405.72, 1405.72,
1
384.26, 1332.43, 1171.56, 1070.62; H NMR (CDCl , 500 MHz), δ, ppm: 7.43 (d, J= 6.8 Hz, 1H,
3
Ph), 7.45-7.47 (m, 1H, Py), 7.50 (d, J= 6.8 Hz, 1H, Ph), 7.68 (d, J= 6.8 Hz, 1H, Ph), 7.86 (s, 1H,
1
3
Ph), 8.12-8.14 (m, 1H, Py), 8.61-8.63 (m, 1H, Py), 9.36 (s, 1H, NH), 10.68 (s, 1H, NH); C NMR
(
DMSO-d , 150 MHz), δ, ppm: 167.59, 151.64, 150.92, 146.49, 138.82, 138.78, 131.74, 130.59,
6
1
30.16(q, J=32Hz), 125.38(q, J=272Hz, CF ), 124.23, 123.50, 120.71, 116.57; HRMS (ESI) for
3
+
C H ClF N O m/z Calculated, 344.0408, Found, 344.0423[M+H]
1
4
9
3
3
2
2
-chloro-N-((2,6-dimethyl-4-(perfluoropropan-2-yl)phenyl)carbamoyl)nicotinamide 4j
−
1
White solid, yield 66.7 %, melting point 198~201 °C, FT-IR (KBr, νmax, cm ): 3462.60(NH),
3
275.73(NH), 3098.72, 2957.60, 1695.97(C=O), 1582.30(C=O), 1527.45, 1403.80, 1296.49,
1
1
241.81, 1165.20, 1118.44, 981.66; H NMR (CDCl , 500 MHz), δ, ppm: 3.97 (s, 6H, CH ), 7.37
3
3
(s, 2H, Ph), 7.42-7.44 (m, 1H, Py), 8.19-8.21 (m, 1H, Py), 8.59-8.60 (m, 1H, Py), 8.99 (s, 1H, NH),
1
3
9
1
.89 (s, 1H, NH); C NMR (DMSO-d , 150 MHz), δ, ppm: 170.80, 167.58, 159.26(d, J =4.6 Hz),
6
57.60(d, J =4.6 Hz), 151.67, 151.19, 146.56, 138.86, 131.60, 128.91(t, J=9.8 Hz), 123.46,
114.14(t, J=16.5Hz), 112.34(d, J=3.8Hz), 112.19(t, J=3.4Hz), 60.23, 21.13, 14.46; HRMS (ESI)
+
for C H ClF N O m/z Calculated, 472.0657, Found, 472.0693[M+H]
18
13
7
3
2
2
-chloro-N-((2-methyl-4-(perfluoropropan-2-yl)phenyl)carbamoyl)nicotinamide 4k
−
1
White solid, yield62.6 %, melting point 142~145 °C, FT-IR (KBr, νmax, cm ): 3441.97(NH),
3
234.69(NH), 3139.04, 2973.58, 1709.43(C=O), 1603.15(C=O), 1559.13, 1503.11, 1408.80,
1
1
283.54, 1231.98, 1180.23, 1071.14, 981.27; H NMR (CDCl , 500 MHz), δ, ppm: 2.47 (s, 3H,
3
CH ), 7.44-7.46 (m, 1H, Py), 7.47-7.49 (m, 2H, Ph), 8.16-8.18 (m, 1H, Py), 8.20 (d, J= 6.8 Hz, 1H,
3
1
3
Ph), 8.61-8.62 (m, 1H, Py), 9.31 (s, 1H, NH), 10.64 (s, 1H, NH); C NMR (DMSO-d , 150 MHz),
6

δ, ppm: 168.30, 151.82, 150.83, 146.55, 139.53, 138.97, 131.46, 129.06, 127.58(d, J=10.5Hz),
1
24.44(d, J=9.9Hz), 123.49, 121.83(d, J=28.3Hz), 121.24, 120.37, 120.24, 119.92(d, J=28.1Hz),
+
1
8.00; HRMS (ESI) for C H ClF N O m/z Calculated, 458.0501, Found, 458.0567[M+H]
17
11
7
3
2
X-ray crystal structure determination
The crystal of title compound with dimensions of 0.26mm × 0.22mm × 0.10mm was mounted on a
Rigaku saturn diffractometer with a graphite-monochromated MoKα radiation (λ = 0.71073Å) by
using a phi and scan modes at 296 (2) K in the range of 6.898°≤θ≤59.088°. The crystal belongs to
monoclinic system with space group P2 /n and crystal parameters of a= 9.9863(11) Å, b = 14.4202
1
3
(
13) Å, c = 10.6579 (12) Å, α = 90°, β = 104.945 (11)°, γ = 90°, V= 1482.9 (3) A ,Dc= 1.539
3
-1
g/cm . The absorption coefficient ꢀ=0.303mm and Z=4. The structure was solved by direct
[43]
2
methods with SHELXS-97 and refined by the full-matrix least squares method on F data using
SHELXL-97. The empirical absorption corrections were applied to all intensity data. The H atom
of N-H was initially located in a difference Fourier map and were refined with the restraint Uiso
(H) = 1.2Ueq (N). Other H atoms were positioned geometrically and refined using a riding model,
with d(C---H) = 0.93-0.97 Å and Uiso(H) = 1.2Ueq(C) or 1.5Ueq(Cmethyl). The detailed
parameters were listed in Table 3.
Table 3 Crystal data and structure refinement for SHELX
Name
Parameter
Empirical formula
Formula weight
Temperature/K
Crystal system
C H ClF N O
2
1
4
9
3
3
343.69
296(2)
monoclinic
3
Crystal size/mm
0.36 × 0.3 × 0.28
Space group
P2 /n
1
Radiation
MoK α (λ = 0.71073)
6.898 to 59.088
Θ
2
range for data collection/°
Index ranges
-13ꢂhꢂ13, -19ꢂkꢂ18, -14ꢂlꢂ14
13174
Reflections collected
Independent reflections
Data/restraints/parameters
3624 [R = 0.0353, R
= 0.0343]
sigma
int
3624/0/208

2
Goodness-of-fit on F
1.054
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Å
R = 0.0587, wR = 0.1455
1
2
R = 0.0810, wR = 0.1649
1
2
-3
0.40/-0.63
Docking studies
Molecular docking studies were done using Discovery Studio 2.5 software. The binding sites were
generated from the SDH structure (PDB code: 2FBW). The detailed method was done according
[44]
to our previous work
.
Supplementary material
Crystallographic data for the structure reported in this article have been deposited with the
Cambridge Crystallographic Data Center, CCDC 1943590. Copies of this information may be
obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge, CBZ IEZ, UK.
Facsimile
(44)
01223
336
033,
E-mail:
deposit@ccdc.cam.ac.uk
or
http//www.ccdc.com.ac.uk/deposit. The FTIR, NMR and HRMS can be found in the supporting
information.
Acknowledgements
This work was supported financially by Zhejiang Provincial Natural Science Foundation of China
(No. LY19C140002), the Opening Foundation of the Key Laboratory of Green Pesticide and
Agricultural Bioengineering, Ministry of Education, Guizhou University(No. 2018GDGP0104),
Research Fund of Department of Education of Zhejiang Province(No. Y201941832).
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[

Highlights
►
The new nicotinic acyl urea derivatives were designed and
synthesized.
►
The antifungal activity were examined with new nicotinic acyl
ureas.
►
The crystal of compound 4d was determined and used as
docking temple.
►
The structure-activity relationship was studied using molecular
docking method.

CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
All authors have seen the manuscript and approved to submit to your
journal.
Thank you very much for your attention and consideration.
Sincerely yours,
Xing-Hai Liu