Crystal structure and molecular docking studies of new pyrazole-4-carboxamides

Article abstract of DOI:10.1515/hc-2019-0012

Two pyrazol-4-carboxamides, 3-(difluoromethyl)-N-(mesitylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxa-mide (7a) and 3-(difluoromethyl)-N-((3,5-dimethylphenyl) carbamoyl)-1-methyl-1H-pyrazole-4-carboxamide (7b) were synthesized and their structures were confirmed by the aid of ¹H NMR and HRMS analyses. The structure of the pyrazole-4-carboxamide, 7a was also determined by X-ray diffraction. The preliminary activity results demonstrate that these two compounds exhibit good inhibitory activity against Botrytis cinerea. Further docking results indicated that the key active group is difluoromethyl pyrazole moiety.

Full text of DOI:10.1515/hc-2019-0012

Heterocycl. Commun. 2019; 25: 66–72
Preliminary Communications
Open Access
Li Qiao1, Peng-Peng Cai1, Zhong-Hua Shen1, Hong-Ke Wu1, Cheng-Xia Tan1, Jian-Quan Weng1 and
Xing-Hai Liu1,2*
Crystal structure and molecular docking studies of
new pyrazole-4-carboxamides
https://doi.org/10.1515/hc-2019-0012
and cholinesterases inhibitory activity [20]. On the other
hand, urea group is always important key building block
in many drugs or pesticides. The compounds with urea
group exhibited diversity bioactivities, such as mosquito
[21], antimicrobial [22], antiviral [23], antifungal [24-26]
and antinociceptive activity [27].
Received September 5, 2018; accepted January 31, 2019.
Abstract: Twoꢀpyrazol-4-carboxamides, 3-(difluoromethyl)-
N-(mesitylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxa-
mide (7a) and 3-(difluoromethyl)-N-((3,5-dimethylphenyl)
carbamoyl)-1-methyl-1H-pyrazole-4-carboxamide (7b) were
synthesized and their structures were confirmed by the
In view of these facts mentioned above, and
also as a part of our work on the synthesis of bioac-
tive lead compounds for drug discovery [28-46], two
1
aid of H NMR and HRMS analyses. The structure of the
pyrazole-4-carboxamide, 7a was also determined by X-ray
diffraction. The preliminary activity results demonstrate
that these two compounds exhibit good inhibitory activity
against Botrytis cinerea. Further docking results indica-
ted that the key active group is difluoromethyl pyrazole
moiety.
new pyrazole-4-carboxamides,
3-(difluoromethyl)-N-
(mesitylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxamide
(7a) and 3-(difluoromethyl)-N-((3,5-dimethylphenyl)
carbamoyl)-1-methyl-1H-pyrazole-4-carboxamide(7b)were
designed and synthesized. The structures were characte-
rized by the aid of 1H NMR and HRMS analysis. The single
crystal structure of compound 7a was determined by X-ray
diffraction. The fungicidal activity of these compounds
was tested and the docking studies were also carried out
to study the mode of action.
Keywords: pyrazole; urea; synthesis; crystal structure;
docking
Introduction
Heterocyclic compounds received important attention Results and discussion
due to their wide range of biological activities [1-5]. Many
pyrazole carboxamide compounds had been developed Synthesis
as commercial fungicides targeting succinate dehydroge-
nase inhibitors (SDHIs), including penthiopyrad, seda- The synthetic route of 3-(difluoromethyl)-N-(mesitylcarb-
xane, pydiflumetofen, bixafen, fluxapyroxad, isopyrazam amoyl)-1-methyl-1H-pyrazole-4-carboxamide is outlined
and benzovindiflupyr. In addition, pyrazole derivatives in Scheme 1. In this paper, ethyl-2-(ethoxymethylene)-
displayed diversity activities, such as antimicrobial [6], 4,4-difluoro-3-oxobutanoate and triethyl orthoformate
DPPH radical scavenging [7], anticancer activity [8], anti- took place smoothly in the presence of acetic anhydride
fungal [9, 10], anti-inflammatory [11], nematicidal [12-19] resulted in the formation of intermediate 1[47]. Then the
pyrazole ring was prepared by reacting intermediate 1
with methylhydrazine[48]. The pyrazole ester hydrosis
under NaOH condition, then acid by HCl[49]. The pyrazole
acyl chloride was given using the SOCl2 as chlorinate
reagent[50]. Then the pyrazole acyl chloride reacted with
NH3•H2O to give pyrazole amide[50]. The key intermedi-
ate pyrazole isocyanate was prepared by pyrazole amide
and triphosgene[50]. Finally, the key intermediate pyra-
zole isocyanate reacted with 2,4,6-trimethylaniline and
* Corresponding author: Xing-Hai Liu, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou,
310014, Zhejiang, China; Key Laboratory of Green Pesticide and
Agricultural Bioengineering, Ministry of Education, Guizhou
University, Guiyang 550025, China
Li Qiao, Peng-Peng Cai, Zhong-Hua Shen, Hong-Ke Wu,
Cheng-Xia Tan and Jian-Quan Weng, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou, 310014,
Zhejiang, China
Open Access. © 2019 Li Qiao et al., published by De Gruyter.ꢀ
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Scheme 1ꢂThe synthetic route of title compounds
3,5-dimethylaniline at room temperature. The reaction longer than the general C=N double bond length of 1.27
condition is mild. Å, which indicated significant electron delocalization in
The structures of the pure compounds 7a and 7b were the fused ring system. The torsion angle of C7-N3-C6-C3
confirmed by 1H NMR, and HR MS. From the 1H NMR data of and C8-N4-C7-N3 was -175.7(2)° and -179.4(2)° respectively,
compound 7a, the signals at 2.28 and 2.31 ppm were reco- which indicated the two carbonyl groups are opposite.
gnized as three methyl group of benzene ring. The appea- The angle between the pyrazole ring and benzene ring is
rance of signal at 3.92 ppm belongs to the methyl protons 68.2 º.
of pyrazole ring. The two NH protons of urea bridge are
In the intermolecular edge-to-face π-π stacking
found at 10.04 and 10.86 ppm as single peak. The CHF2 pattern of the title compound, it is worth mention that
proton signals were triple peak with the coupling constant the two molecules of each stacking unit are cetrosym-
54 Hz due to the influence of F atom. The high resolution metric, which can be proved by the relative position of
mass spectroscopies of the two compounds are in agree- the phenyl rings (C8, C9, C10, C11, C12, C13) and methyl
ment with their molecular formula C16H18F2N4O2 (7a) and of pyrazole: the centroid separation of them is 3.131 Å.
C15H16F2N4O2 (7b).
These interactions are estimated to play a role in stabi-
lizing the crystal structure. The title compound 7a has
an extensive network of hydrogen bonding. The para-
meters of intramolecular and intermolecular bonds
are given in Table 2. From Fig. 1, the N(4)-H(4)…O(1)
Crystal structure
The crystal belongs to triclinic system with space group hydrogen bond formed a six member ring in the mole-
P-1. The molecular structure of compound 7a is shown cule. In the ac plane, they are linked together by N(3)-
in Fig. 1, and the packing diagram in Fig. 2. The selected H(3)...O(2) hydrogen bonds. This hydrogen-bonding
bond lengths and torsion angles are listed in Table 1.
sequence is repeated to form a ring. The ring is shaped
Fig.1 View of the title compound 7a, with displace- like a decagon and has two N(4) and two O(1) atoms at
ment ellipsoids drawn at the 30% probability level.
the vertices, leading to a hydrogen-bond network defi-
Generally, the average bond lengths and bond angles ning cyclic motifs denoted R22 (8). The hydrogen bonds
of pyrazole ring and phenyl ring were normal ranges. and weak π-π interactions strengthen the integration of
The N2-C4 [1.346(3) Å], N1-C2 [1.336(3) Å] bond were the 3D networks.
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L. Qiao et al.: Crystal structure and molecular docking studies
Figure 1ꢂView of the title compound 7a, with displacement ellipsoids drawn at the 30% probability level.
Figure 2ꢂA view of pack molecule 7a.
Evaluation of fungicidal activity
the other three fungals Fusarium oxysporum, Corynes-
pora mazei, Pseudomonas syringae, they exhibited weak
Fungicidal activity of compounds 7a and 7b against activity with inhibitory -49.20% and -55.59%, 19.13% and
Fusarium oxysporum, Corynespora mazei, Pseudomonas 0.43%, -14.77% and 6.09% at 50 μg/mL, respectively.
syringae and Botrytis cinerea was evaluated at 50 μg/mL
according to our previous work [9, 42], Fluxapyroxad was Docking study
used as controls and the results are listed in Table 3. The
primary bioassay showed the two compounds exhibits In order to study the action mode of high active com-
good inhibiting activity (60.00% and 77.27%) towards pound and the target, the binding modes between SDH
Botrytis cinere, which is the same as control (67.27%). For (PDB:2FBW) and the active compound 7a were selected
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as exemplified in the case of representative compound by resolution mass spectra were recorded on an Agilent LC-
using the Discovery studio. The compound 7a can tightly Q-TOF-MS 6520 instrument. Crystallographic data of the
occupy binding site of SDH, the docking results are shown compound were collected on a Bruker APEX-II CCD dif-
in Figure 3. From the docking results, the compound 7a fractometer. All the reagents are of analytical grade or
held two weak interactions: π-cation and π-sigma. The freshly prepared before use.
π-cation bond was formed between the pyrazole ring and
Arg 43 amino acid residue with the distance of 4.1821 Å.
The other π-sigma bond was formed between the pyrazole
General procedure
ring and Ile 218 amino acid residue with the distance of
The intermediates 1, 2, 3, 4, 5 and 6 were synthesized
2.82714 Å. The results indicated that the key active group
according to our previous work [42]. A 10 mL round bottom
is difluoromethyl pyrazole moiety.
flask was charged with 3-(difluoromethyl)-1-methyl-1H-py-
razole-4-carbonyl isocyanate 6 (201 mg, 1 mmol) and
2,4,6-trimethylaniline (135 mg, 1 mmol) in CH2Cl2 (4 mL).
Experimental
Instruments
The mixture was stirred at room temperature for overnight
and the correspondence product was given. The target
compounds were filtered and crude solids were recrystal-
lized from ethanol to give the compound 7a. White solid,
Melting points were determined by an X-4 apparatus and
1
yield 66.7%, 224.2 mg, m.p. 247~248 °C, H NMR ( 500
1
uncorrected. H NMR spectra were measured on a Bruker
MHz, CDCl3 ) δ: 2.28 (s, 6H, 2CH3), 2.31 (s, 3H, CH3), 3.62
AV-400 or 500 MHz instrument using TMS as an inter-
(s, 3H, CH3), 6.85 (t, J = 54 Hz, 1H, CHF2), 6.97 (m, 2H, Ar),
nal standard and CDCl3 or DMSO-d6 as the solvent. High
8.35 (s, 1H, CH), 10.04 (s, 1H, NH), 10.86 (s, 1H, NH); HRMS
(ESI) for C16H18F2N4O2 m/z: Calculated, 337.1471, Found,
Table 1ꢀSelected Bond lengths (Å), Selected Bond angles (°) for
Compound 7a.
Bond
Dist.
Angle
(°)
F(1)-C(1)
F(2)-C(1)
N(1)-N(2)
O(1)-C(6)
O(2)-C(7)
N(1)-C(2)
N(3)-C(7)
N(2)-C(4)
N(4)-C(7)
C(1)-C(2)
C(2)-C(3)
1.376(3)
1.363(3)
1.360(3)
1.232(3)
1.242(3)
1.336(3)
1.391(3)
1.346(3)
1.345(3)
1.494(4)
1.424(4)
C(2)-N(1)-N(2)
C(4)-N(2)-N(1)
C(4)-N(2)-C(5)
N(1)-N(2)-C(5)
C(6)-N(3)-C(7)
C(7)-N(4)-C(8)
F(2)-C(1)-F(1)
N(1)-C(2)-C(1)
C(3)-C(2)-C(1)
N(3)-C(6)-C(3)
N(4)-C(7)-N(3)
104.4(2)
112.6(2)
127.2(2)
120.2(2)
127.8(2)
121.7(2)
105.7(2)
120.0(2)
128.3(2)
115.2(2)
119.1(2)
Table 2ꢀHydrogen-bond Parameters (Ǻ) of Compound 7a
D—H…A
d(D—H) d(H…A) d(D…A)
≠(DHA)
N(3)-H(3)...O(2)#
N(4)-H(4)...O(1)
0.88
0.88
2.03
1.98
2.693(5)
2.830(6)
130.8
161.6
Symmetry transformations used to generate equivalent atoms: #-1-
X,-Y,-Z
Figure 3ꢂThe docking mode of compound 7a and the SDH
Table 3ꢀThe fungicidal activity of compounds 7a and 7b against four fungus at 50 mg/L
No
R
Corynespora mazei
Pseudomonas syringae
Fusarium oxysporum
Botrytis cinerea
7a
2,4,6-3Me
3,5-2Me
Fluxapyroxad
water
-49.20
-55.59
74.09
0
19.13
0.43
52.55
0
-14.77
6.09
71.301
0
60.00
77.27
67.27
0
7b
Control
CK
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L. Qiao et al.: Crystal structure and molecular docking studies
337.1470 [M+H]+. The compound 7b was synthesized accor- CDOCKER protocol. CDOCKER is a grid-based molecular
ding to this method. 3-(difluoromethyl)-N-((3,5-dimethyl- docking method that employs CHARMM-based molecu-
phenyl)carbamoyl)-1-methyl-1H-pyrazole-4-carboxamide lar dynamics (MD) scheme to dock ligands into a recep-
7b :White solid, yield 53.5%, 172.3 mg, m.p. 207~208 °C, tor binding site. The receptor was held rigid while the
1H NMR ( 500 MHz, DMSO-d6) δ: 2.35 (s, 6H, 2CH3), 3.85 ligands were allowed to be flexible during the refine-
(s, 3H, CH3), 6.85 (s, 1H, Ar), 7.14 (t, J = 54 Hz, 1H, CHF2), ment. Each molecule was allowed to produce ten diffe-
7.19 (s, 2H, Ar), 8.39 (s, 1H, CH), 9.89 (s, 1H, NH), 10.69 rent interaction poses with the protein. Then, docking
(s, 1H, NH); HRMS (ESI) for C15H16F2N4O2 m/z: Calculated, scores (-CDOCKER interaction energy) of the best-fitted
323.1314, Found, 323.1314 [M+H]+.
poses with the active site at the SDH structure were
recorded.
Structure determination
Conclusion
The cube-shaped single crystal of compound 7a was
obtained by recrystallization from EtOH. The crystal with
dimensions of 0.20mm × 0.18mm ×0.08mm was mounted
on a Rigaku Saturn diffractometer with a graphite-mono-
chromated MoKα radiation (λ = 0.71073Å) by using a Phi
scan mode at 110(2) K in the range of 3.646≤θ≤55.758°.
A total of 9797 reflections were collected, of which 3892
were independent (Rint = 0.0813) and 2075 were obser-
ved with I > 2σ(I). The calculations were performed with
SHELXS-97 program [51] and the empirical absorption
corrections were applied to all intensity data. The non-
hydrogen atoms were refined anisotropically. The hydro-
gen atoms were determined with theoretical calculations
and refined isotropically. Crystal data for title compound:
triclinic system, P-1 space group with a = 8.426(9) Å, b =
9.149(9) Å, c = 12.406(16) Å, α = 68.374(11)°, β = 71.393(15)°,
γ = 74.816(11)°, V = 831.3(16) Å3, Z = 2, T = 110(2) K,
μ(MoKα) = 0.106 mm-1, Dcalc = 1.344 g/cm3, μ(MoKa) =
0.106 mm-1, GOOF = 0.973. The final full-matrix least-
squares refinement gave R = 0.0654 and wR = 0.1429.
In summary, two new pyrazole-4-carboxamides, had been
synthesized by multi-step reaction and characterized by
1H NMR, HRMS and single-crystal X-ray structure determi-
nation. The results show that the crystal structure exhi-
bits intermolecular and intramolecular hydrogen bonds.
The fungicidal activity results showed that it possessed
moderate activity against Botrytis cinerea. The docking
results indicated the key active group is difluoromethyl
pyrazole moiety.
Acknowledgement: This work was funded by Zhejiang
Provincial Natural Science Foundation of China (No.
LY19C140002), Research Fund of Department of Education
of Zhejiang Province(Y201840646) and the Opening Foun-
dation of the Key Laboratory of Green Pesticide and Agri-
cultural Bioengineering, Ministry of Education, Guizhou
University, grant No. 2018GDGP0104.
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