Synthesis, crystal and molecular structure, vibrational spectroscopic, DFT and molecular docking of 4-(2-chlorobenzyl)-1-(4?hydroxy-3- ((4-hydroxypiperidin-1-yl) methyl-5-methoxyphenyl)-[1,2,4] triazolo [4,3-a] quinazolin-5(4H)-one

Article abstract of DOI:10.1016/j.molstruc.2021.131367

In current work, we have firstly synthesized 4-(2-chlorobenzyl)-1-(4?hydroxy-3- ((4-hydroxypiperidin-1-yl)methyl)-5-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1). The structural properties of 1 were explored using spectroscopy (¹

Full text of DOI:10.1016/j.molstruc.2021.131367

Journal of Molecular Structure 1247 (2022) 131367
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, crystal and molecular structure, vibrational spectroscopic,
DFT and molecular docking of 4-(2-chlorobenzyl)-1-(4–hydroxy-3-
((4-hydroxypiperidin-1-yl) methyl-5-methoxyphenyl)-[1,2,4] triazolo
[4,3-a] quinazolin-5(4H)-one
Qingmei Wua,b,1, Zhaopeng Zhengc,1, Wenjun Ye a,b, Qian Guoa,b, Tianhui Liaoa,b, Di Yang a,b
Chunshen Zhaoa,b, Weike Liaod, Huifang Chaie, Zhixu Zhoua,b,f,∗
,
a School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China
b Guizhou Engineering Laboratory for Synthetic Drugs, Guiyang 550025, China
c Department of Oncology, Guizhou Provincial Peoples Hospital, Guiyang 550005, China
d Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China
e College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, 550002, China
f Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang 550001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In current work, we have firstly synthesized 4-(2-chlorobenzyl)-1-(4–hydroxy-3- ((4-hydroxypiperidin-1-
yl)methyl)-5-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1). The structural properties of 1
were explored using spectroscopy (1H NMR, 13 C NMR, MS and FT-IR) and X-ray crystallography method.
The single-crystal structure confirmed by X-ray diffraction was consistent with the molecular structure
optimized by density functional theory (DFT) calculation at B3LYP/6–311 G (2d, p) level of theory. The ge-
ometrical parameters, molecular electrostatic potential (MEP) and frontier molecular orbital (FMO) anal-
ysis were performed by DFT using the B3LYP/6–311 G (2d, p) method. Molecular docking may suggest
a favorable interaction between 1 and SHP2 protein. The molecular dynamics (MD) simulation results
shown that there are hydrogen bonds, electrostatic interactions and Pi interactions between compound
1 and SHP2 proteins. The inhibitory activity of 1 on SHP2 protein at 10 μM is better than the reference
compound (SHP244).
Received 17 March 2021
Revised 17 August 2021
Accepted 22 August 2021
Available online 25 August 2021
Keywords:
Triazoloquinazolinone
Crystal structure
Spectroscopy
DFT
Molecular docking
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
in several intracellular signal transduction processes, such as RAS-
ERK, PI3K-AKT, JAK-STAT and mTOR pathways [15–17]. SHP2 is also
Azo heterocyclic compounds have been widely applied in phar-
maceutical, textile and printing industries [1]. It’s reported that
the biological activities of the azo compounds including antioxi-
dant, antibacterial, antiviral, anticancer and antitumor [2–5]. Tria-
zoloquinazolinone as a key pharmacophore in pharmaceutical syn-
thesis and has received considerable attention. A number of refer-
ences have reported that triazoloquinazolinones have a wide range
of biological activities, such as H1-antihistaminic [6–9], anticonvul-
sant [10], SHP2 inhibitory [11], antimicrobial [12], antitoxoplasmo-
sis [13], anticancer and potential antivascular [14] properties.
SHP2 (encoded by PTPN11), a widely expressed non-receptor
type protein tyrosine phosphatase (PTP), plays an essential role
participate in the programed cell death pathway (PD-1/PD-L1) and
contribute to immune evasion [18]. SHP2 is an oncoprotein and
a potential immunomodulator associated with a variety of tumor
diseases, and it is also a bona fide oncogene, gain-of-function SHP2
mutations leading to increased phosphatase activity cause Noonan
syndrome [19], as well as multiple forms of leukemia [20,21] and
solid tumors [22,23].
In
this
paper,
4-(2-chlorobenzyl)−1-(4–hydroxy-3-((4-
hydroxypiperidin-1-yl)methyl)−5-methoxyphenyl)-[1,2,4]triazolo
[4,3-a]quinazolin-5(4H)-one (1) was designed based on the
SHP244 (SHP2 inhibitor) as the lead compound and synthesized
for the first time. The structure of 1 was confirmed using 1H
NMR, 13C NMR, ESI-MS and FT-IR spectra, and performed a single-
crystal X-ray diffraction analysis of the crystal structure. Density
functional theory (DFT) calculated optimized structure of 1 at
B3LYP/6–311 G (2d, p) level of theory [24]. The geometric data,
∗
Corresponding author.
E-mail address: zhixuzhou@126.com (Z. Zhou).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.molstruc.2021.131367
0022-2860/© 2021 Elsevier B.V. All rights reserved.

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
Fig. 1. Flow chart of the main points introduced in this study.
Scheme 1. Synthesis route of compound 1.
molecular electrostatic potential (MEP), frontier molecular orbital
(FMO) and vibrational property were calculated by DFT using
B3LYP/6–311 G (2d, p) basis set. Analyze the 13C NMR chemical
shift of 1 by calculated and experimental methods. Molecular
docking of molecular 1 with SHP2 protein was performed using
the Surflex-Dock program in the SYBYL-X 2.0 software, and the
docking study showed that molecular 1 bound to the binding
site on SHP2 protein.The SHP2 enzyme inhibitory activity was
evaluated at 10 μM.
2.2.1. Synthesis of 2-amino-N-(2-chlorobenzyl)benzamide (3)
Isatoic anhydride (20 g, 1 eq) and ethyl acetate (200 mL) were
added to a 500 mL flask, and 2-chlorobenzylamine (17.36 g, 1 eq)
was added with stirring. After stirring for 2 h at 40 °C, the reaction
solution was concentrated under reduced pressure, and the crude
product was slurried with water, methanol and hexane to give the
compound 3 (31.39 g, yield 98.2%). m.p. 108 ∼ 110 °C; 1H NMR
(400 MHz, CDCl3) δ: 7.47 – 7.44 (m, 1H), 7.41 – 7.37 (m, 1H), 7.34
(d, J = 7.9 Hz, 1H), 7.26 – 7.18 (m, 3H), 6.69 – 6.63 (m, 2H), 6.50
(s, 1H), 5.53 (s, 2H), 4.69 (d, J = 6.0 Hz, 2H); HRMS m/z Calcd for
C14 H13ClN2O [M + H]+ 261.0795, found 261.0786.
2. Experimental
2.1. General remarks
2.2.2. Synthesis of 3-(2-chlorobenzyl)−2-thioxo-2,3-
All reagents and solvents for synthesis and analysis were pur-
chased and used without further purification. 1H NMR and 13C
NMR spectra were recorded by Bruker ACF-400, 400 MHz spec-
trometer with the tetramethylsilane (TMS) as an internal standard.
Mass of 1 was taken in ESI mode on Agilent 1100 LC-MS. The FT-
IR spectrum was recorded in the region of 4000 – 400 cm−1 with
a resolution of 1.0 cm−1 by Bruker IFS-55 V IR spectrometer us-
ing KBr pellet technique. The melting point was determined using
a digital display microscopic melting point tester. For 1, the single-
crystal X-ray diffraction data were recorded with a Bruker APEX II
X-diffractometer, and collected using graphite monochromated Mo-
dihydroquinazolin-4(1H)-one (4)
Compound 3 (30 g, 1 eq) and ethanol (150 mL) were added to a
500 mL flask, then KOH (14.20 g, 2.2 eq) aqueous solution and CS2
(87.61 g, 10 eq) were added with stirring. After stirring for 6 h at
55 °C, the reaction solution was cooled to room temperature. Pre-
cipitated a large amount of white solid, filtered. The filter cake was
slurried with water and acetone to give the compound 4 (31.61 g,
yield 90.73%). m.p. 263 ∼ 265 °C; 1H NMR (400 MHz, DMSO–d6)
δ: 13.16 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H),
7.48 (dd, J = 10.8, 8.5 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.28 (t,
J = 7.1 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H),
5.67 (s, 2H); HRMS m/z Calcd for C15H11 ClN2OS [M + H]+ 303.0359,
found 303.0349.
˚
Kα radiation (λ = 0.71073 A) at 100 K. The procedures used in this
study are as follows: collect data: APEX2; refine cell: SAINT; solve
structure: ShelXT; refine the structure and draw molecular figure:
ShelXL; calculate data: DFT; calculate bond distance and bond an-
gle: Gauss View 6.0; draw synthesis route: ChemDraw; interpret
output file: Gauss View 6.0; molecular docking: SYBYL-X 2.0 soft-
ware. molecular dynamics simulation: AMBERTOOL 12 software.
The enzyme inhibition rate of 1 was detected with SHP2 as the
target protein and SHP244 as the positive control. Flow chart of
the main points introduced in this study, as shown in Fig. 1.
2.2.3. Synthesis of (E)−3-(2-chlorobenzyl)−2-hydrazono-2,3-
dihydroquinazolin-4(1H)-one (5)
Compound 4 (30 g, 1 eq) and isopropanol (150 mL) were added
to a 500 mL flask, then 80% hydrazine hydrate (93 g, 15 eq)
was added with stirring. After stirring for 16 h at 83 °C, the re-
action solution was cooled to room temperature. Precipitated a
large amount of white solid, filtered. The filter cake was slur-
ried with water and tert–butyl methyl ether to give the com-
pound 5 (25.62 g, yield 85.97%). m.p. 207 ∼ 209 °C; 1H NMR
(400 MHz, DMSO–d6) δ: 7.89 (d, J = 7.2 Hz, 1H), 7.62 (s, 1H), 7.49
(d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 7.2 Hz,
1H), 7.22 (t, J = 7.4 Hz, 1H), 7.10 (s, 1H), 6.79 (s, 1H), 5.22 (s, 2H),
4.43 (s, 1H); HRMS m/z Calcd for C15H13ClN4O [M + H]+ 301.0856,
found 301.0847.
2.2. Synthetic details
Compound 1 was synthesized using isatoic anhydride as a raw
material by ring-opening, cyclization, substitution, aldimine con-
densation and Mannich reactions, as shown in Scheme 1. The
molecular structure of 1 was confirmed using 1H NMR, 13C NMR,
ESI-MS and FT-IR spectra, and the specific details were provided in
Supplementary Materials Fig.S1-S4.
2

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
2.2.4. Synthesis of 4-(2-chlorobenzyl)−1-(4–hydroxy-3-
The single crystal X-ray diffraction data of 1 can be obtained
free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, CCDC
2,050,842).
methoxyphenyl)-[1,2,4]triazolo[4,3-a] quinazolin-5(4H)-one (6)
Compound 5 (10 g, 1 eq) and isopropanol (200 mL) were added
to a 500 mL flask, then acetic acid (0.5 mL) and 4–hydroxy-3-
methoxybenzaldehyde (5.06 g, 1 eq) were added with stirring. Af-
ter stirring for 0.5 h at 83 °C, the reaction solution was cooled
to room temperature, and followed by FeCl3··6H2O (44.94 g, 5.5
eq) was added with stirring. After stirring for 1 h at 83 °C, the
reaction solution was cooled to room temperature. Precipitated
a small amount of brown-green solid, filtered. The filtrate was
poured into water (800 mL) and after stirring for 0.5 h at room
temperature, and precipitated a large amount of brown-gray solid,
filtered, and the filter cake was slurried with water, acetone and
tert–butyl methyl ether to give the compound 6 (14.20 g, yield
98.68%). m.p. 245 ∼ 247 °C; 1H NMR (400 MHz, DMSO–d6) δ: 9.76
(s, 1H), 8.26 (d, J = 7.1 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.58 –
7.53 (m, 2H), 7.34 (t, J = 6.0 Hz, 1H), 7.28 – 7.21 (m, 4H), 7.11
(d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 5.47 (s, 2H), 3.77 (s,
3H); HRMS m/z Calcd for C23H17 ClN4O3 [M + H]+ 433.1067, found
433.1056.
2.4. SHP2 kinase assay
The SHP2 kinase activities were evaluated using previously re-
ported protocol [28]. Briefly, the phosphatase reactions were per-
formed at room temperature in 384-well plate (Corning) and a fi-
nal reaction volume of 25 μL, the following assay buffer condi-
tions: 60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA,
0.05% P-20, 5 mM DTT. 0.5 nM of SHP2 was co-incubated with of
0.5 μM of bisphosphorylated IRS1 peptide and 10 μM of SHP244
or 1. After 30 min incubation at 25 °C, the surrogate substrate
DiFMUP (Invitrogen) was added to the reaction and incubated at
25 °C for 30 min. The reaction was then quenched by the addi-
tion of 5μL of a 160 μM solution of bpV. The plate was read using
Envision (Perkin Elmer) at 340 nm and 450 nm, respectively.
3. Computational methods
2.2.5. Synthesis of 4-(2-chlorobenzyl)−1-(4–hydroxy-3-((4-
3.1. DFT calculations
hydroxypiperidin-1-yl)methyl)−5- methoxyphenyl)-
[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (1)
The DFT calculations were performed by the Gaussian 09 soft-
ware package using B3LYP/6–311 G (2d, p) method, and the the-
oretical errors were corrected using a scaling factor of 0.961 [29].
Gauss View 6.0 program was used to calculate bond distance and
bond angle. The output file was interpretated using Gauss View 6.0
program. The geometrical parameters, MEP and FMO analysis were
conducted by DFT using the B3LYP/6–311 G (2d, p) method. The
13C chemical shift was calculated by Gauge-Independent Atomic
Orbital (GIAO) method [30].
Compound 6 (1 g, 1 eq) and acetic acid (20 mL) were added
to a 500 mL flask, then 4-hydroxypiperidine (0.93 g, 4 eq) and
37% formaldehyde (0.75 g, 4 eq) were added with stirring. After
stirring for 6 h at 80 °C, the reaction solution was concentrated
under reduced pressure. The concentrate was poured into water
and the pH was adjusted to 8 - 9 with NaOH saturated solution,
and the mixed solution was extracted with dichloromethane. The
combined organic layer was dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. The crude product was slurried
with tert–butyl methyl ether to give the compound 1 (0.88 g, yield
69.84%). m.p. 134 ∼ 139 °C; 1H NMR (400 MHz, DMSO–d6) δ: 8.27
(d, J = 9.3 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.59–7.53 (m, 2H), 7.37
– 7.32 (m, 1H), 7.25 (q, J = 7.9 Hz, 3H), 7.17 (s, 1H), 7.04 (s, 1H),
5.48 (s, 2H), 3.78 (s, 3H), 3.72 (s, 2H), 3.58 – 3.51 (m, 1H), 2.85–
2.74 (m, 2H), 2.25 (t, J = 9.6 Hz, 2H), 1.81 – 1.72 (m, 2H), 1.43
(q, J = 10.5, 8.9 Hz, 2H); 13C NMR (100 MHz, DMSO–d6) δ:158.88,
149.17, 148.89, 148.69, 148.20, 135.04, 134.65, 133.43, 132.20,
129.80, 129.73, 129.39, 127.86, 127.79, 127.10, 123.98, 123.13,
118.40, 117.69, 116.29, 112.86, 65.91, 59.03, 56.41, 50.68, 44.25,
34.64; HRMS m/z Calcd for C29H28ClN5O4 [M + H]+ 546.1908,
found 546.1896.
3.2. Molecular docking
Download the SHP2 protein crystal structure (PDB: 6BMR) in
the PDB protein database (https://www.rcsb.org/), then extract the
required ligands use the SYBYL-X 2.0 software [31] and gener-
ate docking bag use the Surflex-Dock (SFXC) Docking mode. The
structures of the compounds were created by the structure tool
in SYBYL-X 2.0 software, and a conformation library was gener-
ated through force field optimization. Molecular docking of ligand
molecules with SHP2 protein were performed using the Surflex-
Dock suite in the SYBYL-X 2.0 software. Finally, with the help of
the docking total score, the interaction between the protein and
compounds was studied.
2.3. Crystal structure determination
3.3. Molecular dynamics
Compound 1 was dissolved and grown in acetonitrile at room
temperature to obtain a single crystal. A colorless transparent crys-
tal of 1 with a size of 0.15 mm × 0.08 mm × 0.05 mm was
mounted on X-ray diffractometer. The single-crystal X-ray diffrac-
tion data were recorded using Bruker APEX II diffractometer, and
collected the data using graphite monochromated Mo-Kα radiation
The molecular dynamics simulation could be used to predict
the drug-receptor interactions during the design phase of novel
compounds development. Herein, the interaction between com-
pound 1 and SHP2 protein was further studied by MD simulation
using AMBERTOOL 12 software [32]. Topology and parameter files
were generated with the LEaP program on structure of the com-
plexes obtained by the afore mentioned docking procedures. Anal-
ysis of MD trajectories generated was performed by Ptraj module
in AMBERTOOL 12.
˚
(λ = 0.71073 A) at 170 K. A total of 15,637 reflections were col-
lected in the range of 2.003 – 26.066° (index ranges: –11 ≤ h ≤ 12,
–13 ≤ k ≤ 13, –18 ≤ l ≤ 17) using an ϕ-ω scan mode, and 5486
reflections were independent with Rint = 0.0826, of which 3113 ob-
served reflections with I > 2σ (I) were used to determinate and
refine the structure [25]. The structure was solved using SHELXT-
2018/3 [26], and refined using SHELXL-2018/3 [27]. The title com-
pound 1 of the final R = 0.0754 and wR = 0.2310 (w = 1/[σ2
4. Results and discussion
4.1. Synthesis and characterization
2
2
(Fo
)
+
(0.1145P)2
+
0.1650 P], where
P
=
(Fo +2Fc2)/3),
The target compound was synthesized using five steps: ring-
opening, cyclization, substitution, aldimine condensation and Man-
nich reactions. The structural properties of the title compound 1
3
˚
(ꢀρ)max = 0.631, (ꢀρ)min = −0.495 e/A , (ꢀ/σ)max = 0.000 and
S = 1.054.
3

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
Fig. 2. The crystal and DFT-optimized structure of 1.
Table 1
4.3. Conformational stability
The crystal data and parameters for the structure refinement of 1.
Compound
1
The Spartan 08 program [34] was used to search for the ini-
tial conformation of 1. The frequency calculations and geome-
try optimizations of all conformers of 1 were carried out using
DFT/B3LYP/6-311 G (2d, p) in Gauss View 6.0 package. The rela-
CCDC
2,050,842
Molecular formula
Molecular weight
Crystal system
Space group
C29H28ClN5O4
546.01
tive Gibbs free energies ꢀG = exp(−Gi/RT ) (R = 8.314 J·(mol·K)−1
,
Triclinic
P-1
T = 295.15ꢀK) and Boltzmann distribution (Boltzmann weighting
˚
a(A)
9.7787(12)
exp(−Gi/RT )
factor Pi =
× 100 %) [21] of 1 are shown in Table 3.
˚
b(A)
10.7815(16)
exp(−G j/RT )
j
˚
c(A)
14.6154(16)
The rotation of the C(6)-C(7) bond or the C(16)-C(17) bond
causes eight conformations of 1. The eight relatively stable con-
formers are 1–1 (69.10%), 1–2 (6.28%), 1–3 (5.76%), 1–4 (4.46%), 1–
5 (4.32%), 1–6 (4.00%), 1–7 (3.48%), 1–8 (2.60%). As shown in Fig. 4.
The DFT-optimized structures of 1 were compared with the
crystal structure obtained using X-ray diffraction. Conformer 1–1
calculated by DFT is most similar to the crystal structure, as shown
in Fig. 1. Selected experimental parameters of crystal 1 were com-
pared with the calculated parameters of conformer 1–1. As shown
in Table 4. As expected, most of the X-ray data of title compound
1 is close to the calculated geometry parameters.
α (o)
β (o)
γ (o)
88.407(4)
74.813(4)
70.873(4)
3
˚
V (A )
1402.1(3)
Z
2
N(param)refined
355
μ (mm−1
)
0.179
˚
Radiation λ (A)
Ranges/indices (h, k, l)
θ limit (o)
0.71073
−11 ≤ h ≤ 12, -13 ≤ k ≤ 13, −18≤ l ≤ 17
2.003 - 26.066
T, K
170
N(hkl)measured, N(hkl)unique
N(hkl)gt
15,637 / 5486 [R(int) = 0.0826]
3113
Diffractometer
Scan mode
Bruker APEX II CCD’
ϕ - ω
4.4. Molecular electrostatic potential
Programs
SHELXL-2018/3
Molecular electrostatic potential (MEP) is important for pre-
dicting intermolecular interactions, electrophilic attack and nucle-
ophilic reactions [35,36]. The MEP of 1 was calculated by DFT using
the B3LYP/6–311 G (2d, p) method, and the MEP diagram is shown
in Fig. 5. The MEP diagram gives information on molecular shape,
size, electrostatic potential value and charge distribution [37]. The
were studied using spectroscopy (1H NMR, 13C NMR, MS and FT-
IR) and X-ray crystallography method. As shown in Supplementary
Materials Fig. S1-S4.
−
2
−
– 6.0 e
2. The MEP
MEP was recorded in the region −6.0 e
diagram’s different colors indicate different electrostatic potential
values, electrostatic potential increases in the order of red < or-
ange < yellow < green < blue. Blue represents the strongest pos-
itive potential, and red represents the strongest negative potential.
The positive regions are mainly distributed around the H atoms of
the phenyl, benzyl, piperidinyl and –CH3, and these regions have
a positive potential. The negative potential regions are mainly re-
lated to the N atoms of the triazole ring, the O atoms of –C = O,
–OH and –OCH3, and the Cl atom.
4.2. X-ray crystallography
Crystal
1
is of triclinic system, space group P-1, with
˚
a = 9.7787(12), b = 10.7815(16), c = 14.6154(16) A, V = 1402.1(3)
A , Z = 2, calculated density ρcalc = 1.293 g/cm3, and linear ab-
3
˚
sorption coefficient μ = 0.179 mm−1. For the target compound 1,
ORTEP diagram of the crystal and DFT-optimized structures are
shown in Fig. 2.
The crystallographic and refinement data are shown in Table 1.
Analyze hydrogen bonds to further study the stability of the
crystal structure [33]. For 1, the intramolecular O(3)—H(3)···N(5)
4.5. Frontier molecular orbital
˚
˚
(1.866 A), C(5)—H(5)···N(1) (2.478 A) and C(7)—H(7B)···O(1)
Frontier molecular orbital (FMO) investigation is important
for predicting the reactivity, site selectivity and molecular elec-
tronic transitions [38-40]. The highest occupied molecular orbital
(HOMO) and lowest unoccupied molecular orbital (LUMO) energy
of conformer 1–1 is calculated by DFT using B3LYP/6–311 G (2d,
p). The calculated values described the catalytically and biologi-
cal activity of conformer 1–1. The frontier molecular orbital dia-
gram is shown in Fig. 6. In LUMO, the electron cloud occupies al-
˚
˚
(2.408 A), and the intermolecular O(4)—H(4)···N(3) (2.012 A),
˚
˚
C(13)—H(13)···O(4) (2.447 A), C(23)—H(23B)···O(1) (2.595 A) and
˚
C(27)—H(27)···Cl(1) (2.826 A) hydrogen bonds play a major role
in stabilizing the crystal structure. As shown in Table 2. Fur-
thermore, the crystal structure is further stabilized by the
van der Waals forces and π-π interactions. As shown in
Fig. 3.
4

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
Table 2
The hydrogen-bond geometry parameters of 1.
˚
˚
˚
D—H···A
d(D—H) /A
d(H···A) /A
d(D···A) /A
ࢬ(D—H···A) /°
O(3)—H(3)···N(5)
O(4)—H(4)···N(3)
C(5)—H(5)···N(1)
0.84
0.84
0.95
0.99
0.95
0.98
1.00
1.866
2.012
2.478
2.408
2.447
2.595
2.826
2.614(4)
2.820(4)
2.840(5)
2.760(5)
3.348(5)
3.534(5)
3.675(4)
148
161
103
100
158
160
143
i
C(7)—H(7B)···O(1)
C(13)—H(13)···O(4)
ii
iii
C(23)—H(23B)···O(1)
C(27)—H(27)···Cl(1)
iv
Symmetry code: (i) 1-x,1-y,-z; (ii) 2-x,−1-y,-z; (iii) 1-x,2-y, l-z; (iv) 1 + x,- l + y, - l + z.
Fig. 3. The Crystal structure stacking (a) and hydrogen bond distance (b) diagram of 1.
Fig. 4.. Relatively stable conformers of 1.
Table 3
a
Gibbs free energy (G), relative Gibbs free energy (ꢀG) and Boltzmann weighting
b
factor (Pi%) of the conformers of 1.
Conformer
G (kcal mol−1
)
ꢀG (kcal mol−1
)
Pi%
1–1
1–2
1–3
1–4
1–5
1–6
1–7
1–8
1,353,439.156
1,353,437.751
1,353,437.701
1,353,437.550
1,353,437.531
1,353,437.486
1,353,437.404
1,353,437.234
0
69.10
6.28
5.76
4.46
4.32
4.00
3.48
2.60
1.406
1.456
1.606
1.625
1.670
1.752
1.922
a
Related to the most stable conformer.
b
Boltzmann weighting factor (Pi%) based on ꢀG.
Fig. 5. Molecular electrostatic potential diagram of conformer 1–1.
most the entire title molecule, and in HOMO, the electron cloud
is mainly distributed on the triazole ring and the 1-substituted
benzene ring. For conformer 1–1, the energy values of EHOMO
and ELUMO are −5.9699 and −1.9410 eV, respectively. The HOMO-
LUMO orbital energy gap (ꢀE = EHOMO - ELUMO) is an important
parameter for quantum chemistry [41]. The larger ꢀE indicates
higher chemical stability, and the smaller indicates higher reactiv-
ity [40]. For conformer 1–1, The orbital energy gap ꢀE = EHOMO
- ELUMO = −4.0289 eV. Furthermore, the electron affinity and
ionization energy of conformer 1–1 can be calculated as: A = -
5

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
Table 4
Selected experimental and calculated geometry parameters for 1 and conformer 1–1.
a
b
Exp.a
Calcd.b
Difference
Bond Distances (A)
Exp.
Calcd.
Difference
˚
˚
Bond Distances (A)
Cl(1)-C(1)
1.741(4)
1.370(4)
1.429(5)
0.840
1.763
1.359
1.420
0.992
1.351
0.964
1.427
1.218
1.376
1.408
1.404
1.379
1.391
1.465
1.472
1.474
1.470
1.384
1.302
1.304
1.413
1.388
1.399
1.396
1.405
1.395
1.513
1.472
1.515
1.396
1.393
1.389
1.403
1.083
1.081
1.483
Calcd.
118.3
106.3
109.0
121.4
103.3
135.0
121.8
118.5
119.6
111.9
111.0
111.5
106.3
109.3
121.5
112.0
126.4
115.4
124.9
119.7
118.2
122.1
119.8
123.3
116.7
119.9
119.8
120.5
119.6
127.2
109.1
123.7
119.9
122.9
117.2
119.6
0.022
−0.011
−0.009
0.152
−0.004
−0.124
0.000
−0.001
0.012
0.005
0.011
−0.001
0.005
0.000
0.008
0.001
−0.002
−0.016
−0.011
−0.001
0.006
0.006
0.005
−0.004
0.009
0.007
−0.009
−0.007
−0.006
0.006
0.006
0.013
0.007
0.133
0.131
0.000
Difference
1.1
C(12)-H(12)
0.950
1.078
1.387
1.397
1.090
1.089
1.091
1.104
1.527
1.387
1.096
1.100
1.094
1.095
1.528
1.082
1.383
1.100
1.522
1.083
1.395
1.092
1.104
1.527
1.082
1.390
1.083
1.094
1.095
1.089
1.094
1.092
1.082
1.389
1.083
1.389
1.083
Calcd.
110.3
110.0
119.7
118.1
122.2
113.4
111.3
106.6
109.6
108.9
106.8
109.1
109.9
107.5
110.9
110.5
108.8
117.6
120.6
121.7
112.6
109.4
107.3
108.8
111.0
108.7
118.9
121.1
120.0
110.2
108.2
111.4
107.1
111.0
109.9
119.1
0.128
0.009
0.012
0.100
0.099
0.101
0.114
0.009
0.006
0.106
0.110
0.104
0.105
0.015
0.132
−0.012
0.100
0.011
0.133
0.013
0.102
0.114
0.014
0.132
0.008
0.133
0.114
0.115
0.109
0.104
0.102
0.132
0.007
0.133
0.017
0.133
Difference
0.6
O(2)-C(21)
C(12)-C(13)
1.378(5)
1.385(5)
0.990
O(2)-C(23)
C(10)-C(15)
O(3)-H(3)
C(7)-H(7A)
O(3)-C(20)
1.355(4)
0.840
C(7)-H(7B)
0.990
O(4)-H(4)
C(25)-H(25A)
0.990
O(4)-C(27)
1.427(4)
1.219(4)
1.364(4)
1.403(5)
1.393(4)
1.380(4)
1.386(5)
1.465(4)
1.464(5)
1.473(4)
1.472(5)
1.400(4)
1.313(5)
1.305(5)
1.407(5)
1.382(5)
1.394(5)
1.400(5)
1.396(5)
1.388(5)
1.522(5)
1.479(5)
1.521(5)
1.390(5)
1.387(5)
1.376(5)
1.396(5)
0.950
C(25)-H(25B)
0.990
O(1)-C(9)
C(25)-C(26)
1.518(5)
1.381(6)
0.990
N(4)-C(8)
C(1)-C(2)
N(4)-C(11)
C(24)-H(24A)
N(4)-C(16)
C(24)-H(24B)
0.990
N(1)-C(8)
C(26)-H(26A)
0.990
N(1)-C(9)
C(26)-H(26B)
0.990
N(1)-C(7)
C(26)-C(27)
1.513(5)
0.950
N(5)-C(25)
C(15)-H(15)
N(5)-C(24)
C(15)-C(14)
1.395(6)
1.000
N(5)-C(29)
C(27)-H(27)
N(2)-N(3)
C(27)-C(28)
1.511(5)
0.950
N(2)-C(8)
C(13)-H(13)
N(3)-C(16)
C(13)-C(14)
1.382(5)
0.990
C(21)-C(20)
C(29)-H(29A)
C(21)-C(22)
C(29)-H(29B)
0.990
C(20)-C(19)
C(29)-C(28)
1.513(5)
0.950
C(11)-C(12)
C(5)-H(5)
C(11)-C(10)
C(5)-C(4)
1.382(6)
0.950
C(19)-C(18)
C(14)-H(14)
C(19)-C(24)
C(23)-H(23A)
0.980
C(16)-C(17)
C(23)-H(23B)
0.980
C(6)-C(7)
C(23)-H(23C)
0.980
C(6)-C(1)
C(28)-H(28A)
0.990
C(6)-C(5)
C(28)-H(28B)
0.990
C(17)-C(18)
C(2)-H(2)
0.950
C(17)-C(22)
C(2)-C(3)
1.382(6)
0.950
C(18)-H(18)
C(3)-H(3A)
C(22)-H(22)
0.950
C(3)-C(4)
1.372(6)
0.950
C(9)-C(10)
1.483(5)
C(4)-H(4A)
a
b
a
b
Bond angle [°]
C(21)-O(2)-C(23)
C(20)-O(3)-H(3)
C(27)-O(4)-H(4)
C(8)-N(4)-C(11)
C(8)-N(4)-C(16)
C(16)-N(4)-C(11)
C(8)-N(1)-C(9)
C(8)-N(1)-C(7)
C(9)-N(1)-C(7)
C(25)-N(5)-C(24)
C(25)-N(5)-C(29)
C(29)-N(5)-C(24)
C(8)-N(2)-N(3)
C(16)-N(3)-N(2)
N(4)-C(8)-N(1)
N(2)-C(8)-N(4)
N(2)-C(8)-N(1)
O(2)-C(21)-C(20)
O(2)-C(21)-C(22)
C(22)-C(21)-C(20)
O(3)-C(20)-C(21)
O(3)-C(20)-C(19)
C(19)-C(20)-C(21)
C(12)-C(11)-N(4)
C(10)-C(11)-N(4)
C(10)-C(11)-C(12)
C(20)-C(19)-C(24)
C(18)-C(19)-C(20)
C(18)-C(19)-C(24)
N(4)-C(16)-C(17)
N(3)-C(16)-N(4)
N(3)-C(16)-C(17)
C(1)-C(6)-C(7)
C(5)-C(6)-C(7)
C(5)-C(6)-C(1)
C(18)-C(17)-C(16)
Exp.
Bond angle [°]
C(26)-C(25)-H(25A)
C(26)-C(25)-H(25B)
C(6)-C(1)-Cl(1)
C(2)-C(1)-Cl(1)
C(2)-C(1)-C(6)
N(5)-C(24)-C(19)
N(5)-C(24)-H(24A)
N(5)-C(24)-H(24B)
C(19)-C(24)-H(24A)
C(19)-C(24)-H(24B)
H(24A)-C(24)-H(24B)
C(25)-C(26)-H(26A)
C(25)-C(26)-H(26B)
H(26A)-C(26)-H(26B)
C(27)-C(26)-C(25)
C(27)-C(26)-H(26A)
C(27)-C(26)-H(26B)
C(10)-C(15)-H(15)
C(10)-C(15)-C(14)
C(14)-C(15)-H(15)
O(4)-C(27)-C(26)
O(4)-C(27)-H(27)
O(4)-C(27)-C(28)
C(26)-C(27)-H(27)
C(28)-C(27)-C(26)
C(28)-C(27)-H(27)
C(12)-C(13)-H(13)
C(12)-C(13)-C(14)
C(14)-C(13)-H(13)
N(5)-C(29)-H(29A)
N(5)-C(29)-H(29B)
N(5)-C(29)-C(28)
H(29A)-C(29)-H(29B)
C(28)-C(29)-H(29A)
C(28)-C(29)-H(29B)
C(6)-C(5)-H(5)
Exp.
117.2(3)
109.5
109.7
−3.2
−0.5
−0.1
−0.7
−0.5
0.7
109.7
0.3
109.5
118.6(3)
118.8(3)
122.6(4)
112.0(3)
109.2
1.1
121.5(3)
104.0(3)
134.5(3)
121.1(3)
118.2(3)
120.7(3)
112.4(3)
109.6(3)
112.6(3)
104.9(3)
109.4(3)
121.9(3)
112.6(3)
125.5(3)
115.4(3)
124.4(3)
120.2(3)
117.4(3)
122.7(3)
119.9(3)
123.0(3)
117.1(3)
119.8(4)
120.5(3)
118.8(3)
120.6(3)
126.8(3)
109.1(3)
124.0(3)
120.6(3)
122.6(3)
116.7(4)
119.7(3)
−0.7
−0.4
1.4
2.1
0.3
109.2
−2.6
0.4
−1.1
−0.5
1.4
109.2
109.2
−0.3
−1.1
−0.2
0.6
107.9
−1.1
1.4
109.3
109.3
−0.1
−0.4
−0.6
0.9
108.0
−0.5
−0.5
1.2
111.4(3)
109.3
109.3
−0.5
−2.2
0.2
0.0
119.8
0.5
120.4(4)
119.8
−0.5
0.8
1.9
111.8(3)
108.9
0.8
−0.6
−0.1
0.3
0.5
106.8(3)
108.9
0.5
−0.1
−0.4
−0.2
−0.8
0.4
−0.4
0.1
111.4(3)
108.9
−0.7
1.7
119.7
120.7(4)
119.7
−1.0
0.4
0.3
109.8
0.4
0.0
109.8
−1.6
2.1
−0.3
−0.7
0.3
109.3(3)
108.3
−1.2
1.2
109.8
0.5
109.8
0.1
−0.1
119.4
−0.3
(continued on next page)
6

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
Table 4 (continued)
a
b
Exp.a
Calcd.b
Difference
Bond Distances (A)
Exp.
Calcd.
Difference
˚
˚
Bond Distances (A)
C(18)-C(17)-C(22)
C(22)-C(17)-C(16)
C(19)-C(18)-H(18)
C(17)-C(18)-C(19)
C(17)-C(18)-H(18)
C(21)-C(22)-C(17)
C(21)-C(22)-H(22)
C(17)-C(22)-H(22)
O(1)-C(9)-N(1)
119.8(3)
120.4(3)
119.2
119.3
121.0
119.7
121.0
119.4
120.6
120.0
119.3
121.3
123.2
115.5
120.4
119.5
120.1
122.3
119.5
118.1
114.6
107.3
106.6
109.7
109.6
108.7
108.5
109.9
111.0
107.0
−0.5
−0.4
0.5
C(4)-C(5)-C(6)
121.2(4)
119.4
121.5
119.3
120.3
119.4
120.3
105.8
111.5
111.4
109.3
109.4
109.4
111.2
108.6
109.9
109.9
109.8
107.4
119.6
119.4
121.0
119.7
119.7
120.6
119.7
120.0
120.3
0.3
C(4)-C(5)-H(5)
−0.1
0.2
C(15)-C(14)-H(14)
C(13)-C(14)-C(15)
C(13)-C(14)-H(14)
O(2)-C(23)-H(23A)
O(2)-C(23)-H(23B)
O(2)-C(23)-H(23C)
H(23A)-C(23)-H(23B)
H(23A)-C(23)-H(23C)
H(23B)-C(23)-H(23C)
C(27)-C(28)-C(29)
C(27)-C(28)-H(28A)
C(27)-C(28)-H(28B)
C(29)-C(28)-H(28A)
C(29)-C(28)-H(28B)
H(28A)-C(28)-H(28B)
C(1)-C(2)-H(2)
120.1
121.6(4)
119.2
−0.6
0.2
119.7(4)
120.1
−0.3
0.2
119.6(3)
120.2
1.0
109.5
−3.7
2.0
−0.2
−0.9
0.8
109.5
120.2
109.5
1.9
120.5(3)
123.4(4)
116.1(3)
120.1
109.5
−0.2
−0.1
−0.1
−0.9
−0.6
0.7
O(1)-C(9)-C(10)
−0.2
−0.6
0.3
109.5
N(1)-C(9)-C(10)
109.5
C(11)-C(12)-H(12)
C(13)-C(12)-C(11)
C(13)-C(12)-H(12)
C(11)-C(10)-C(9)
C(15)-C(10)-C(11)
C(15)-C(10)-C(9)
N(1)-C(7)-C(6)
112.1(3)
109.2
119.8(4)
120.1
−0.3
0.0
109.2
121.7(3)
119.5(3)
118.7(3)
112.6(3)
109.1
0.6
109.2
0.7
0.0
109.2
0.6
−0.6
2.0
107.9
−0.5
−0.8
0.2
120.4
N(1)-C(7)-H(7A)
N(1)-C(7)-H(7B)
C(6)-C(7)-H(7A)
C(6)-C(7)-H(7B)
H(7A)-C(7)-H(7B)
N(5)-C(25)-H(25A)
N(5)-C(25)-H(25B)
N(5)-C(25)-C(26)
H(25A)-C(25)-H(25B)
−1.8
−2.5
0.6
C(1)-C(2)-C(3)
119.2(4)
120.4
109.1
C(3)-C(2)-H(2)
0.6
109.1
C(2)-C(3)-H(3)
120.3
−0.6
0.3
109.1
0.5
C(4)-C(3)-C(2)
119.4(4)
120.3
107.8
0.9
C(4)-C(3)-H(3)
0.3
109.7
−1.2
0.2
C(5)-C(4)-H(4)
119.6
0.1
109.7
C(3)-C(4)-C(5)
120.9(4)
119.6
−0.9
0.7
109.6(3)
108.2
0.4
C(3)-C(4)-H(4)
−1.2
a: Experimental geometry parameters for molecule 1;.
b: Calculated geometry parameters for conformer 1–1.
4.6.1. –OH vibration
The –OH vibrations are expected in the region of 3500 – 3100
cm−1 [43]. For 1, the –OH vibration was observed at 3355.05 cm−1
.
4.6.2. C–H vibration
The C–H asymmetric stretch vibrations frequencies of the
methyl group and methylene group are expected in the region of
3009 – 2908 cm−1 [44]. The out-of-plane bending vibrations of the
substituted benzene rings C–H are expected in the region of 900 –
730 cm−1. For, the methyl and methylene group’s C–H stretching
mode were observed at 2941.39 cm−1, and the out-of-plane bend-
ing vibration of Ar–H was observed at 759.33 cm−1
.
4.6.3. C = O vibration
The C = O stretching vibrations are expected in the region of
1870 – 1540 cm−1 [45]. For 1, the C = O vibration was observed at
1684.52 cm−1
.
Fig. 6. The HOMO and LUMO of conformer 1–1.
4.6.4. C = C vibration
The C = C stretching vibrations of the substituted benzene ring
are expected in the region of 1620 – 1450 cm−1 [29]. For 1, the
aromatic C = C vibrations are observed at 1613.16 cm−1, 1597.74
ELUMO = 1.9410 eV and I = -EHOMO = 5.9699 eV. The chemical po-
tential and global hardness are given by using the relation μ = -
(I + A)/2 = −3.9555 eV, η = (I-A)/2 = 2.0145 eV and electrophilic-
ity index (ω) = μ2/2η = 3.8832 eV.
cm−1, 1563.99 cm−1, 1496.01 cm−1 and 1470.46 cm−1
.
3.6.5. C–Cl vibration
The C–Cl stretching vibrations are expected in the region of 760
– 505 cm−1 [46]. The C–Cl absorption frequencies may appear to
shift because of the vibrational coupling with the neighboring C
4.6. Vibrational assignment
Based on the characteristic vibrations of –OH, C–H, C = O, C = C
and C–Cl, the vibrational analysis of 1 was carried out. The title
molecule 1 has 67 atoms in total, so the normal vibration mode is
3∗n - 6 = 195. The theoretical wavenumbers are higher than the
experimental wavenumbers, since non-harmonic vibrations were
ignored [42]. The theoretical errors were corrected using a scal-
ing factor of 0.961 for B3LYP. The experimental wavenumbers were
recorded in the region of 4000 – 400 cm−1 using Bruker IFS-55 V
IR spectrometer. As shown in Fig.S4.
group. For 1, the C–Cl vibration was observed at 683.16 cm−1
.
4.7. 13 C NMR spectral analysis
NMR spectroscopy is widely used to confirm the structure of
the compound [47–49]. For 1, the theoretical 13C NMR chemical
shifts were calculated using the DFT/GIAO method [30], and the
experimental spectrum was recorded on a Bruker ACF-400 spec-
trometer. The calculated and experimental 13C NMR chemical shifts
7

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
Table 5
4.8. Molecular docking analysis
Calculated and experimental 13 C chemical shifts (ppm) of 1.
Assignments
Calc.
Exp.
Molecular docking plays a vital role in computer-aided drug de-
sign and the development of new chemotherapeutic drugs [50,51].
Molecular docking aims to understand the interaction mechanisms
between ligand molecules and target proteins by analyzing vari-
ous structural parameters, and find out the binding sites and op-
timized conformations of ligand molecules with proteins [52–54].
Docking of reference compound (SHP244) and 1 with SHP2 pro-
tein were carried out using the Surflex-Dock (SFXC) docking mode
in the SYBYL-X 2.0 software [55,56], to understand the mode of
interaction and binding site position. The docking interactions be-
tween SHP244 and 1 with SHP2 protein were compared, as shown
in Table 6.
C9
164.75
157.06
156.32
154.28
153.56
144.67
141.37
139.55
138.83
134.69
134.39
132.80
131.30
131.09
130.13
129.24
127.16
125.85
122.80
121.26
114.48
73.50
158.88
149.17
148.89
148.69
148.20
135.04
134.65
133.43
132.20
129.80
129.73
129.39
127.86
127.79
127.10
123.98
123.13
118.40
117.69
116.29
112.86
65.91
C20
C16
C8
C21
C1
C11
C13
C6
C15
C2
C3
C4
C14
C19
C5
The docking scores of SHP244 and 1 with SHP2 protein were
8.30 and 7.43, respectively. SHP244 and 1 bound to residues R265,
Q269 and Q79 of SHP2 protein; SHP244 bound to residue L262,
and compound 1 also bound to residue K266 of the same pro-
tein, as shown in Fig. 8. The docking structure was different from
the crystal structure and DFT-optimized 1–1 conformation, which
may be caused by the interaction between 1 and the amino acid
residues of SHP2. For SHP244 and 1, the N-2 atom of the triazole
ring formed a hydrogen bond with residue R265, the N-3 atom of
the triazole ring formed a hydrogen bond with residue Q269. For
SHP244, the O atom of the phenolic hydroxyl group formed a hy-
drogen bond with residues Q79, L262 and R265, and the O atom
of the methoxy group was combined with residue Q79 through
hydrogen bonding mediated by a water molecule (H2O 899). For
1, the N-2 atom of the triazole ring also formed a hydrogen bond
with residue Q269, the N-3 atom of the triazole ring also formed a
hydrogen bond with residue R265, and the O atoms of the methoxy
and hydroxypiperidine rings form hydrogen bonds with residues
K266 and Q79, respectively. In summary, compound 1 not only re-
tains the original main amino acid residues that can form hydrogen
bonds with the SHP2 protein, but also adds the amino acid residue
K266.
C18
C17
C10
C12
C22
C27
C24
C23
C29
C25
C7
62.22
59.03
56.15
56.41
55.61
50.68
51.79
50.68
47.66
44.25
C26
C28
38.83
34.64
36.66
34.64
Numbering is according to Fig. 2.
4.9. Molecular dynamics analysis
We further ran MD simulation based on docked data to ver-
ify the results of molecular docking. In order to evaluate the dy-
namic stability of the 1-SHP2 complex, the time dependence of
the root mean square deviation (RMSD) of the MD simulation for
all atomic position of the 1-SHP2 complex relative to those of the
initial structures are studied. The MD trajectory of SHP2 protein,
˚
˚
sharply to 19.38 A within 100 ps then averages at 20.97 A after
200 ps, as shown in Fig. 9. For 1-SHP2 complex rises, sharply to
˚
˚
19.36 A within 100 ps then averages at 21.13 A after 200 ps.
We also further used MD to simulate the interaction between
SHP2 protein and compound 1, as shown in Fig. 10. In the triazole
ring of compound 1, the N-2 atom formed a hydrogen bond with
the residue R265, and the N-4 atom formed a hydrogen bond with
the residues R265 and K266, respectively. The N-4 atom of the
triazole ring formed an electrostatic interaction with the residue
Q79, and the Cl atom also formed an electrostatic interaction with
the residue K266. The triazole ring formed Pi–cation interactions
with residues R265 and K266, respectively; in addition, the ben-
zene ring and ketone ring of quinazolinone also formed Pi–cation
interactions with residue K266.
Fig. 7. Linear relationship between calculated and experimental 13 C NMR chemical
shift of 1.
of 1 were listed in Table 5. Different hybrid degree of carbon atom
will cause different chemical shift [29]. The conjugation action can
lead to an increase in the chemical shifts of carbon atom [49].
For 1, the C atoms’ calculated chemical shifts attached to the N, O
and Cl heteroatoms are in the region of 164.75 – 47.66 ppm. Fur-
thermore, the calculated chemical shifts of aromatic and aliphatic
C atoms are in the region of 157.06 – 114.48 ppm and 73.50 –
36.66 ppm, respectively.
4.10. SHP2 enzyme inhibitory activity
The linear correlations between calculated and experimental
data of 13C NMR spectrum were meaned with the equation:
δcal = 1.029δexp + 1.6095 (correlation coefficient R2 = 0.9977). We
can observe good correlations between the calculated and experi-
mental chemical shifts, as shown in Fig. 7.
The SHP2 enzyme inhibitory activity of 1 was evaluated at
10 μM, SHP244 (SHP2 inhibitor) [11] was used as a reference com-
pound. The SHP2 enzyme inhibitory activity of 1 (inhibition rate:
23.33%) is better than SHP244 (19.67%).
8

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
Table 6
Docking scoring results and hydrogen bondings of compounds with SHP2 protein.
Compound
PDB
Total Score
Hydrogen-bonding residues
Number of Hydrogen-bonding
SHP244
1
6BMR
6BMR
8.30
7.43
Q79/R265/Q269/L262
Q79/R265/Q269/K266
7
7
Fig. 8. Docking diagram of SHP244 (A) and 1 (B) with SHP2 protein (PDB: 6BMR), (hydrogen bond: light blue dashed line).
Fig. 9. RMSD plots for the simulation of 1-SHP2.
Fig. 10. MD simulation diagram of the interaction between compound 1 and SHP2
protein (PDB: 6BMR).
9

Q. Wu, Z. Zheng, W. Ye et al.
Journal of Molecular Structure 1247 (2022) 131367
5. Conclusions
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The authors declare that they have no known competing finan-
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curation, Writing – review & editing. Wenjun Ye: Writing – review
& editing. Qian Guo: Writing – review & editing. Tianhui Liao:
Writing – review & editing. Di Yang: Writing – review & editing.
Chunshen Zhao: Writing – review & editing. Weike Liao: Writing
– review & editing. Huifang Chai: Supervision, Writing – review
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Acknowledgments
We want to thank the Guizhou Provincial Natural Science
Foundation ([2020]1Y393), the Science and Technology Fund of
Guizhou Provincial Health Department (gzwjkj2020–1–238) and
the Guizhou University of Traditional Chinese Medicine 2018 an-
nual academic new seedling cultivation and innovation exploration
special project cultivation project plan (Qiankehe platform talent
[2018]5766–14) for financial support.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131367.
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