Synthesis, crystal structure, vibrational properties and DFT studies of 4-(furan-2-ylmethyl)-1-(thiomorpholinomethyl)-[1,2,4]triazolo[4,3-a]quinazon-5(4H)-one

Article abstract of DOI:10.1016/j.molstruc.2021.131395

In this present research, the title compound 4-(furan-2-ylmethyl)-1-(thiomorpholinomethyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one(1) was synthesized, and its single crystal was produced in acetone. The use of ¹H NMR, ¹³C NMR, FT-

Full text of DOI:10.1016/j.molstruc.2021.131395

Journal of Molecular Structure 1248 (2022) 131395
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, crystal structure, vibrational properties and DFT studies of
4-(furan-2-ylmethyl)-1-(thiomorpholinomethyl)-[1,2,4]triazolo[4,3-
a]quinazon-5(4H)-one
Hong Suna,b,c, Liyuan Dengb,c, Weiyin Hua,c, Tianhui Liaoa,c, Weike Liaod, Huifang Chaie,∗
,
Chunshen Zhaoa,b,c,∗
a School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China
b Guizhou Engineering Laboratory for Synthetic Drugs, Guiyang, 550025, China
c Key Laboratory of Guizhou for Fermentation Engineering and Biomedicine, Guiyang, 550025, China
d Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, PR China
e College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, 550002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this present research, the title compound 4-(furan-2-ylmethyl)-1-(thiomorpholinomethyl)-
[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one(1) was synthesized, and its single crystal was produced
in acetone. The use of 1H NMR, 13 C NMR, FT-IR spectroscopy and MS determined its structure. Using
X-ray diffraction, the single crystal of the title compound was measured. At the same time, the optimized
molecular crystal structure of this small molecule was determined according to DFT calculations adopting
B3LYP/6–311 G (2d, p) basis set. The conformational isomer 1–3 is the most stable conformation and
is consistent with the conformation derived from X-ray diffraction. Hirshfeld surface analysis and 2D
fingerprint were given to support the quantitative analysis of intermolecular interactions and contacts
caused by supramolecular accumulation in crystals.
Received 20 July 2021
Revised 21 August 2021
Accepted 27 August 2021
Available online 30 August 2021
Keywords:
Triazolo[4,3-a]quinazolin
Synthesis
Crystal structure
Vibrational properties
DFT
© 2021 Elsevier B.V. All rights reserved.
Antitumor activity
1. Introduction
structure. Using X-ray diffraction, the single crystal of the title
compound was measured. At the same time, according to DFT cal-
The pharmacology of quinzoline and quinazolinone derivatives
is broad and is shown to possess anti-inflammatory [1,2], an-
tibacterial, antifungal [3,4] anticonvulsant [5,6] antiparasitic, an-
titumor [7], antiepiliepsia [8], antimicrobial [9] and antiulcer
[10]. Triazoloquinazolinone derivatives are an important class of
fused heterocyclic compounds that have attracted a great deal
of interest because of their wide range of biological activities.
Among them, 1-substituted-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-
ones have been shown to possess anti-histaminic [11–14], anticon-
vulsant [15], SHP2 inhibitory [16], antimicrobial [17], antitoxoplas-
mosis [18] and potential antivascular [19] properties.
culations adopting B3LYP/6-311+G (2d, p) basis set, the optimized
molecular crystal structure of this small molecule was determined.
Then using the conformational analysis for the title compound
and comparing the structure of the X-ray measurement with the
structure optimized by adopting the way of DFT, showing that
there was no difference between the two structures. As for the ti-
tle compound’s MEP and FMOs, the next study was carried out by
using DFT, which states that there are certain nucleophilic reactiv-
ity and good chemical stability for the title compound. In addition,
Hirshfeld surface analysis further explored the interactions of title
molecular.
Considering the above viewpoints, 4-(furan-2-ylmethyl)−1-
(thiomorpholinomethyl)-
[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-
2. Experimental
one(1), a novel pyridopyrimidine compound was designed and
synthesized in this study, as shown in Scheme 1. The use of
1H NMR, 13C NMR, FT-IR spectroscopy and MS determined its
2.1. Synthetic procedure
2.1.1. Synthesis of the 2-amino-N-(furan-2-ylmethyl)benzamide (2)
In
a 500 mL single-neck flask, dissolve isatoic anhydride
∗
(50.00 g, 306.50 mmol) in 250 mL of ethyl acetate, and add 2-furan
methylamine (29.76 g, 306.50 mmol) while stirring. After the ad-
Corresponding authors.
E-mail addresses: saieho@126.com (H. Chai), chunshenzhao@163.com (C. Zhao).
https://doi.org/10.1016/j.molstruc.2021.131395
0022-2860/© 2021 Elsevier B.V. All rights reserved.

H. Sun, L. Deng, W. Hu et al.
Journal of Molecular Structure 1248 (2022) 131395
Scheme 1. Synthesis routes of compound 1.
dition, the reaction was heated to 40 °C for 2 h, and the reactional
time was monitored by TLC using mixture of petroleum ether and
ethyl acetate (1:1) and the plates were revealed with sublimated
iodine supported on silica gel. At the end of the reaction, the re-
action solution was brought to room temperature, and the solvent
ethyl acetate was evaporated under reduced pressure to obtain a
white solid. The white solid was immersed in methanol, stirred,
and filtered to remove insoluble impurities. Water was added to
the filtrate for stirring, the solid was extracted, filtered with suc-
tion, the filter cake was washed twice with petroleum ether, and
the crude compound 2 (60.24 g, 90.9%), was obtained by suction
filtration, which was directly transferred to the next step without
treatment.
of petroleum ether and ethyl acetate (2:1) and the plates were re-
vealed with sublimated iodine supported on silica gel. At the end
of the reaction, the reaction solution was cooled to room tempera-
ture, water was added to quench the reaction, the solid was stirred
out, filtered with suction, the filter cake was washed twice with
petroleum ether and twice with methyl tert–butyl ether, and the
crude compound 5 (5.35 g, 87.1%), was obtained by suction filtra-
tion, which was cast directly without treatment step.
2.1.5. Synthesis of the 4-(furan-2-ylmethyl)-1-
(thiomorpholinomethyl)-[1,2,4]triazolo[4,3-a] quinazolin-5(4H)-one
(1)
In a 100 mL single-necked flask, dissolve compound 5 (0.20 g,
0.63 mmol) in 20 mL of acetonitrile, add potassium carbonate
(0.26 g, 1.90 mmol) and thiomorpholine (0.08 g, 0.76 mmol)
under stirring. After the addition, heat the reaction system to
50 °C for 4 h. The reaction progress was monitored by TLC using
a developing solvent of petroleum ether and ethyl acetate (1:2)
and the plates were revealed with sublimated iodine immobi-
lized on silica. And the solvent was evaporated under vacuum
after TLC indicated the reaction was complete. The reaction
solution was cooled to room temperature, water was added
to quench the reaction, the solid was stirred out, filtered with
suction, and the filter cake was washed twice with acetone to
obtain pure compound 1 (0.16 g, 65.2%). 1H NMR (400 MHz,
Chloroform-d) δ 8.45 (d, J = 7.9 Hz, 1H, 2-CH), 8.20 (d, J = 8.4 Hz,
1H, 5-CH), 7.80 (t, J = 7.8 Hz, 1H, 3-CH), 7.56 (t, J = 7.6 Hz,
1H, 4-CH), 7.35 (s, 1H, 12-CH), 6.60 (s, 1H, 11-CH), 6.31 (s, 1H,
10-CH), 5.57 (s, 2H, 15-CH2), 4.03 (s, 2H 18-CH2), 2.90 (s, 4H,
19-CH2,16-CH2), 2.68 (s, 4H, 18-CH2, 17-CH2). 13C NMR (100 MHz,
Chloroform-d) δ 158.21(C7), 156.20(C13), 148.73(C14), 146.19(C9),
144.89(C12), 142.63(C1), 134.74(C3), 133.69(C4), 130.08(C6),
126.95(C2), 117.79(C5), 117.45(C10), 110.63(C11), 110.52(C16),
54.92(C19), 54.50(C8), 39.15(C15), 27.79(C17), 27.64(C18). m/z:
404.12 [M-H]−.
2.1.2. Synthesis of the 3-(furan-2-ylmethyl)-2-thioxo-2,3-
dihydroquinazolin-4(1H)-one (3)
In
a 500 mL single-neck flask, compound 2 (50.00 g,
231.22 mmol) was dissolved in 250 mL of ethanol, potassium hy-
droxide (28.54 g, 508.68 mmol) was added under stirring, and car-
bon disulfide (176.05 g, 2312.2 mmol), after the addition, the re-
action was heated to 55 °C for 16 h, and the reactional time was
monitored by TLC using mixture of petroleum ether and ethyl ac-
etate (2:1) and the plates were revealed with sublimated iodine
supported on silica gel. At the end of the reaction, solids are pre-
cipitated after the reaction solution is reduced to room tempera-
ture. The filter cake was washed once with clear water and once
with acetone. The crude compound 3 (53.03 g, 88.8%), was ob-
tained by suction filtration, and it was directly transferred to the
next step without treatment.
2.1.3. Synthesis of the 3-(furan-2-ylmethyl)-2-hydrazineylidene-2,3-
dihydroquinazolin-4(1H)-one (4)
In a 250 mL single-neck flask, dissolve compound 3 (10.00 g,
38.72 mmol) in 100 mL of isopropanol, add hydrazine hydrate
(29.07 g, 580.8 mmol) under stirring, and after the addition, the
reaction was heat to 90 °C for 16 h. The reactional time was moni-
tored by TLC using mixture of petroleum ether and ethyl acetate
(1:1) and the plates were revealed with sublimated iodine sup-
ported on silica gel. After TLC monitors the completion of the reac-
tion, solids are precipitated after the reaction solution is reduced to
room temperature. The filter cake is washed once with water and
once with ethyl acetate, and the crude compound 4 (8.61 g, 86.6%),
was obtained by suction filtration, which is directly transferred to
the next step without treatment.
The synthesis route of compound 1 is shown in Scheme 1.
2.2. X-ray crystal structure determination
Single crystals of compound 1, were obtained by slow evapo-
ration from acetone, which means that the single crystal of the
title compound, suitable for X-ray crystallographic analysis, was
gained. Using the Bruker D8 VENTURE diffractometer, X-ray diffrac-
tion data of the title compound crystal were recorded. All crystal-
lographic data are shown in Table 1. (CCDC: 2089668).
2.1.4. Synthesis of the 1-(chloromethyl)-4-(furan-2-ylmethyl)-
[1,2,4]triazolo[4,3-a]quinazolin-5 (4H)-one (5)
2.3. Quantum chemical calculations
In a 250 mL single-neck flask, dissolve compound 4 (5.00 g,
19.51 mmol) in 100 mL of N,N-dimethylformamide, slowly add
chloroacetyl chloride dropwise (3.35 g, 29.27 mmol) with stirring
in an ice bath, and after the addition, react for half of the time
in an ice bath, then the reaction system was heated to 100 °C for
5 h, and the reactional time was monitored by TLC using mixture
Quantum chemical calculations were performed in the ground
state with the Gaussian 09 software package [20] using the
B3LYP/6-311+G (2d, p) level of theory. The systematic errors of the
theoretical wavenumbers were reduced by a scaling factor of 0.961
for B3LYP. The Gauss View 6.0 program was used to calculate the
2

H. Sun, L. Deng, W. Hu et al.
Journal of Molecular Structure 1248 (2022) 131395
Table 1
Table 2
Crystallographic characteristics, the X-ray data collection and structure-
Hydrogen-bond geometry of compound 1.
refinement parameters for 1.
˚
˚ ˚
d(D—H) /A d(H…A) /A d(D…A) /A ࢬ(D—H…A) /°
D—H…A
Compound
1
C(5)—H(5)…N(5)
C(8)—H(8B)…O(1)
C(19)—H(19B)…O(1)
0.93
0.97
0.97
2.48
2.39
2.59
3.217(4)
2.759(3)
3.359(3)
136
102
136
CCDC
2,089,668
Molecular formula
Molecular weight
Crystal system
Space group
C19H19N5O2S
381.45
Triclinic
−
1
P
˚
a(A)
7.9535(9)
˚
b(A)
10.5999(12)
˚
c(A)
11.7200(13)
α (o)
β (o)
γ (o)
104.931(2)
104.700(2)
93.119(2)
3
˚
V (A )
915.841(18)
Z
2
N(param)refined
244
μ (mm−1
)
0.20
˚
Radiation λ (A)
Ranges/indices (h, k, l)
θ limit (o)
0.71073
–9 ≤ h ≤ 9, –9 ≤ k ≤ 12, –13 ≤ l ≤ 13
2.005 - 24.997
N(hkl)measured, N(hkl)unique
N(hkl)gt
4711/ 3205[R(int) = 0.0130]
2511
Diffractometer
Scan mode
Bruker APEX II CCD’
ϕ - ω
Programs
SHELXL-2018/3
bond distances and angles and to interpret the output files. The ge-
ometrical parameters, MEP and FMO analyses were conducted by
DFT calculations at the B3LYP/6-311+G (2d, p) level of theory. The
13C chemical shifts of compound 1 were predicted using the gage-
independent atomic orbital (GIAO) method [21].
2.4. Evaluation of cell inhibitory activity
Fig. 1. Crystal structure stacking diagram and hydrogen bonding diagram of com-
pound 1.
A standard MTT bioassay was used to evaluate the antipro-
liferative activity of target compound against human malignant
melanoma cells A375. The cells were divided into three groups: (1)
the normal group; (2) the administration group (200 μM); (3) the
positive control group (SHP244, 200 μM).
structure was confirmed. All information about the spectrogram of
the compound 1 was shown in Supplementary Material Figure S1-
S4.
The specific operation is as follows: (i) 5 mg of the target prod-
uct was dissolved in 200 μL of DMSO solvent and store it in a
frozen state for later use. (ii) In a medium supplemented with 10%
fetal bovine serum (FBS), human malignant melanoma cells A375
were cultured under 37 °C and 5% CO2 of incubator and the cells
grown in logarithm were tested. (iii) Inoculate each well of a 96-
well plate with approximately 4 × 103 cells suspended in DMEM
medium and incubate for 24 h at 37 °C in 5% CO2. (iv) The com-
pound to be tested indicating the final concentration is added to
the culture medium, and the cells are cultured for 72 h. (v) Weigh
0.5 g of MTT and dissolve it in 100 mL of phosphate buffer to ob-
tain a 5 mg/mL MTT solution. (vi) Fresh MTT was added to each
well at a final concentration of 5 mg/mL, and incubated with log-
arithmic growth cells at 37 °C for 4 h. (vii) Finally, the formazan
crystals in each well are dissolved in 100 mL DMSO, and the ab-
sorbance at 492 nm (for MTT methylzan absorption) and 630 nm
(for the reference wavelength) was measured with an Envision en-
zyme marker (PerkinElmer) reader.
3.2. Crystallographic analysis
Employing X-ray diffraction crystal structure analysis, the title
compound 1 was analyzed, which made the structural character-
istics of the synthesized compound further studied. The measu−red
1
values suggest that there is a triclinic crystal system with P
space group for 1. The crystallographic and refinement data are
shown in Table 1.
Hydrogen bonding significantly affects the stability of the crys-
tal structure. The molecule of 1 are connected by three intermolec-
˚
˚
ular C(5)—H(5)…N(5) (2.48 A), C(8)—H(8B)…O(1) (2.39 A), C(19)—
˚
H(19B)…O(1) (2.59 A) hydrogen bonds, as shown in Table 2. The
crystal structure of 1 shows that the intermolecular packing is
stabilized by hydrogen bondings and the Vander Waal forces, as
shown in Fig. 1.
3.3. Conformational determination
Cell survival rate (%) = OD of administered wells / OD of normal
wells × 100. Cell proliferation inhibition (%) = 1-cell survival rate
(%).
Adopting the Spartan 08 program [22] with MMFF [23,24]
(molecular mechanics force field), the title compound
1 was
searched for the initial conformational. Then, adopting DFT/
B3LYP/6-311+G (2d, p) in Gaussian 09 package [25], the geome-
try optimizations and frequency calculation of all the possible con-
formers were performed, and the obtained dominant conformation
is shown in Fig. 2.
3. Results and discussion
3.1. Synthesis and characterization
The synthesis of the title compound 1 involved a five-step reac-
tion. Tested by FT-IR, 1H NMR, 13C NMR spectroscopy and MS, its
According to the relative free energies, each conformer’s
percentage in the equilibrium mixture at room temperature
3

H. Sun, L. Deng, W. Hu et al.
Journal of Molecular Structure 1248 (2022) 131395
Fig. 2. Crystal and DFT-optimized structures of compound 1.
Table 3
Gibbs free energy (G), relative Gibbs free energy (ꢀG) a, and Boltzmann weighting
b
factor (Pi%) of the conformers of compound 1.
Conformer
G (kcal mol−1
)
ꢀG (kcal mol−1
)
Pi%
1–1
1–2
1–3
1–4
1–5
−977,581.4235
−977,581.2722
−977,581.2384
−977,581.2352
−977,580.951
0
27.22
21.03
19.85
19.74
12.16
0.151228922
0.185114241
0.18825177
0.121565088
a
Related to the most stable conformer.
b
Fig. 4. Molecular electrostatic potential diagram of conformer 1–3.
Boltzmann weighting factor (Pi%) based on ꢀG.
3.4. Molecular electrostatic potential (MEP)
(T = 295.15 K) can be predicted. Data about the Gibbs free en-
ergy (G), relative Gibbs free energy ((ꢀG = exp(−Gi/RT )), gas con-
stant R = 8.314 J·(mol·K)−1 and Boltzmann distribution (Boltzmann
Molecular electrostatic potential (MEP) has the important ad-
vantage because it reflects the specific features of the particular
molecule, e.g.lone pairs, strained bonds, π electrons, and so on
[24,26,27], and it can make preliminary judgments on the inter-
action between molecules and molecular recognition. According
to obtain an understanding of the information of the intermolec-
ular interaction area of the title compound 1 and adopting the
B3LYP/6311 G (2d, p) method [28,29], MEP (molecular electrostatic
potential) of the conformer 1–3 was researched (same as the crys-
exp(−Gi/RT )
ꢀ
weighting factor Pi =
× 100%) [18] for different con-
exp(−G j/R)
j
formers of compound 1 are presented in Table 3.
The five conformers of compound 1 are listed in Fig. 3, all
of which are little different. The main reason for the difference
is the torsion of the H(8A)-C(8)-H(8B) connecting the quinazoline
and furan rings, and the torsion of the thiomorpholine ring, es-
pecially the rotation of the angel H(16A)-C(16)-H(16B). It was de-
tected that there are five relatively stable conformers 1–1 (27.22%),
1–2 (21.03%), 1–3 (19.85%), 1–4 (19.74%) and 1–5 (12.16%) for com-
pound 1.
tal structure). In−the MEP dia−gram (as shown in Fig. 4), the range
2
is from −5.0 e
to 5.0 e
2, potentials increase in the order
of red < orange < yellow < green < blue. So the electron-rich
area is located in red, and the electron-deficient area is located in
blue. According to the information in Fig. 4, surrounded by nega-
tive charges is the O (1) atom of the conformational isomer 1–3,
which suggests there are some possible nucleophilic attack sites
for this compound.
Compared to the crystal structure of 1 with the optimized
structure obtained by adopting DFT, it was clear that the calculated
conformational isomer 1–3 through DFT is very little different from
the crystal conformation through X-ray diffraction. And the main
reason for difference of the two conformations for the conjecture
is that there is the inter-molecular π-π bond action (Fig. 1). More
data about the experimental values of crystal 1 and the calculated
values of conformer 1–3 are listed in Table 4, and comparing all
the bond lengths, bond angles and torsion angles of crystal 1–3,
then it is found that 1–3 is roughly consistent with the crystal
data.
3.5. Frontier molecular orbitals (FMOs)
Adopting the B3LYP/6-311+G (2d, p) method [29], the energies
of the highest occupied molecular orbital (EHOMO), the lowest un-
occupied molecular orbital (ELUMO) and their orbital energy gap
Fig. 3. Relatively stable conformers of compound 1.
4

H. Sun, L. Deng, W. Hu et al.
Journal of Molecular Structure 1248 (2022) 131395
Table 4
Bond distances, bond angles and torsion angles for compound 1 and conformer 1–3.
˚
˚
Bond distance (A)
Exp.a
Calcd.b
Difference
Bond distance (A)
Exp.a
1.298(3)
Calcd.b
Difference
C(1)-C(6)
C(1)-C(7)
C(2)-C(3)
C(2)-H(2)
C(3)-C(4)
C(3)-H(3)
C(4)-C(5)
C(4)-H(4)
C(5)-C(6)
C(5)-H(5)
C(6)-N(2)
C(7)-O(1)
C(7)-N(1)
C(8)-C(9)
C(8)-N(1)
C(8)-H(8A)
C(8)-H(8B)
C(9)-C(10)
C(9)-O(2)
C(10)-C(11)
C(10)-H(10)
C(11)-C(12)
C(11)-H(11)
C(12)-O(2)
C(12)-H(12)
1.392(3)
1.404
1.484
1.383
1.082
1.395
1.083
1.386
1.083
1.395
1.078
1.408
1.217
1.391
1.488
1.482
1.088
1.088
1.359
1.370
1.430
1.077
1.356
1.078
1.360
1.076
0.012
0.007
0.009
0.152
0.02
C(13)-N(3)
1.306
1.376
1.374
1.303
1.400
1.495
1.467
1.100
1.094
1.467
1.523
1.103
1.100
1.828
1.091
1.092
1.521
1.830
1.090
1.092
1.469
1.102
1.092
1.381
0.008
0.002
−0.003
0.007
0.104
0.199
0.008
−8.87
0.124
0.004
0.009
0.133
0.13
1.477(3)
1.374(3)
0.9300
C(13)-N(2)
1.374(2)
1.377(3)
1.296(3)
1.296(3)
1.296(3)
1.459(3)
9.9700
C(13)-N(1)
C(14)-N(4)
1.375(3)
0.9300
C(14)-N(2)
0.153
0.004
0.153
0.009
0.148
−0.007
0
C(14)-C(15)
C(15)-N(5)
1.382(3)
0.9300
C(15)-H(15A)
C(15)-H(15B)
C(16)-N(5)
1.386(3)
0.9300
0.9700
1.463(3)
1.514(3)
0.9700
1.415(2)
1.217(2)
1.381(3)
1.480(3)
1.486(2)
0.9700
C(16)-C(17)
C(16)-H(16A)
C(16)-H(16B)
C(17)-S(1)
0.01
0.9700
0.008
−0.004
0.118
0.118
0.024
0.004
0.019
0.147
0.042
0.148
−0.014
0.146
1.790(3)
0.9700
0.038
0.121
0.122
0.016
0.027
0.12
C(17)-H(17A)
C(17)-H(17B)
C(18)-C(19)
C(18)-S(1)
0.9700
0.9700
1.505(3)
1.803(2)
0.9700
1.335(3)
1.366(3)
1.411(3)
0.9300
C(18)-H(18A)
C(18)-H(18B)
C(19)-N(5)
0.9700
0.122
−0.001
0.132
0.122
−0.016
1.470(3)
0.9700
1.314(3)
0.9300
C(19)-H(19A)
C(19)-H(19B)
N(3)-N(4)
0.9700
1.374(3)
0.9300
1.397(3)
Bond angle (°)
Exp.a
Calcd.b
Difference
Bond angle (°)
Exp.a
Calcd.b
Difference
C(2)-C(1)-C(6)
119.28(18)
117.85(18)
122.86(18)
120.3(2)
119.8
119.40
118.17
122.42
120.61
121.74
117.65
119.46
120.24
120.29
121.00
119.95
119.04
119.43
120.44
120.04
120.06
123.09
116.84
121.54
123.04
115.42
114.02
109.37
107.09
110.33
105.91
109.99
109.81
133.04
117.16
106.54
125.54
127.91
106.13
126.42
127.45
110.52
133.52
115.95
111.89
126.34
121.77
109.24
122.55
0.12
0.32
N(2)-C(14)-C(15)
N(5)-C(15)-C(14)
N(5)-C(15)-H(15A)
C(14)-C(15)-H(15A)
N(5)-C(15)-H(15B)
C(14)-C(15)-H(15B)
H(15A)-C(15)-H(15B)
N(5)-C(16)-C(17)
N(5)-C(16)-H(16A)
C(17)-C(16)-H(16A)
N(5)-C(16)-H(16B)
C(17)-C(16)-H(16B)
H(16A)-C(16)-H(16B)
C(16)-C(17)-S(1)
C(16)-C(17)-H(17A)
S(1)-C(17)-H(17A)
C(16)-C(17)-H(17B)
S(1)-C(17)-H(17B)
H(17A)-C(17)-H(17B)
C(19)-C(18)-S(1)
C(19)-C(18)-H(18A)
S(1)-C(18)-H(18A)
C(19)-C(18)-H(18B)
S(1)-C(18)-H(18B)
H(18A)-C(18)-H(18B)
N(5)-C(19)-C(18)
N(5)-C(19)-H(19A)
C(18)-C(19)-H(19A)
N(5)-C(19)-H(19B)
C(18)-C(19)-H(19B)
H(19A)-C(19)-H(19B)
C(13)-N(1)-C(7)
126.89(19)
113.78(17)
108.8
128.09
114.77
112.21
105.20
107.92
109.56
106.91
112.35
111.42
109.45
107.76
108.45
107.22
112.59
110.03
106.03
110.4
1.20
0.99
C(2)-C(1)-C(7)
C(6)-C(1)-C(7)
−0.44
0.31
3.41
C(3)-C(2)-C(1))
C(3)-C(2)-H(2)
C(1)-C(2)-H(2)
C(2)-C(3)-C(4)
108.8
−3.60
−0.88
0.76
1.94
108.8
119.8
−2.15
−0.34
0.14
108.8
119.8(2)
120.1
107.7
−0.79
0.93
C(2)-C(3)-H(3)
C(4)-C(3)-H(3)
C(3)-C(4)-C(5)
111.42(17)
109.3
120.1
0.19
2.12
121.27(19)
119.4
−0.27
0.55
109.3
0.15
C(3)-C(4)-H(4)
C(5)-C(4)-H(4)
C4)-C(5)-C(6)
109.3
−1.54
−0.85
−0.78
0.18
119.4
−0.36
0.42
109.3
119.01(19)
120.5
108.0
C(4)-C(5)-H(5)
C(6)-C(5)-H(5)
C(5)-C(6)-C(1))
C(5)-C(6)-N(2))
C(1)-C(6)-N(2))
O(1)-C(7)-N(1))
O(1)-C(7)-C(1))
N(1)-C(7)-C(1))
C(9)-C(8)-N(1)
C(9)-C(8)-H(8A)
N(1)-C(8)-H(8A)
C(9)-C(8)-H(8B)
N(1)-C(8)-H(8B)
H(8B)-C(8)-H(8A)
C(10)-C(9)-O(2)
C(10)-C(9)-C(8)
O(2)-C(9)-C(8)
C(9)-C(10)-C(11)
C(9)-C(10)-H(10)
C(11)-C(10)-H(10)
C(12)-C(11)-C(10)
C(12)-C(11)-H(11)
C(10)-C(11)-H(11)
C(11)-C(12)-O(2)
C(11)-C(12)-H(12)
O(2)-C(12)-H(12)
N(3)-C(13)-N(2)
N(3)-C(13)-N(1)
N(2)-C(13)-N(1)
N(4)-C(14)-N(2)
N(4)-C(14)-C(15)
−0.06
−0.46
−0.22
−0.34
0.56
112.41(17)
109.1
120.5
0.93
120.28(17)
123.43(18)
116.28(17)
121.01(19)
123.3(2)
115.65(18)
113.15(16)
108.9
109.1
−3.07
1.30
109.1
109.1
109.24
108.37
112.50
110.00
105.91
110.55
109.30
108.41
112.27
110.88
109.61
107.98
108.76
107.18
122
0.14
0.53
107.9
0.47
−0.26
−0.23
0.87
112.61(16)
109.1
−0.11
0.90
109.1
−3.19
1.45
0.47
109.1
108.9
−1.81
1.43
109.1
0.20
108.9
107.8
0.61
108.9
−2.99
2.19
112.77(19)
109.0
−0.5
1.88
107.8
109.08(19)
133.0(2)
117.96(19)
107.9(2)
126.1
0.73
109.0
0.61
0.04
109.0
−1.02
−0.24
−0.62
−0.09
−0.03
1.99
−0.8
109.0
−1.36
−0.56
1.81
107.8
122.09(16)
118.01(17)
118.01(17)
103.29(16)
121.75(16)
134.95(17)
105.36(16)
109.19(17)
110.01(16)
110.64(18)
112.34(16)
105.89(18)
95.84(11)
126.1
C(13)-N(1)-C(8)
117.98
120
106.2(2)
126.9
−0.07
−0.48
0.55
C(7)-N(1)-C(8)
C(13)-N(2)-C(14)
C(13)-N(2)-C(6)
103.34
121.5
0.05
126.9
−0.25
0.21
111.0(2)
124.5
−0.48
9.02
C(14)-N(2)-C(6)
135.16
106.17
109.34
110.33
111.47
112.23
107
C(13)-N(3)-N(4)
0.81
124.5
−8.55
−0.64
0.16
C(14)-N(4)-N(3)
0.15
112.53(18)
126.18(18)
121.28(17)
109.63(18)
123.45(19)
C(15)-N(5)-C(16)
C(15)-N(5)-C(19)
C(16)-N(5)-C(19)
C(9)-O(2)-C(12)
0.32
0.83
0.49
−0.11
1.11
−0.39
−0.90
C(17)-S(1)-C(18)
96.6
0.76
(continued on next page)
5

H. Sun, L. Deng, W. Hu et al.
Journal of Molecular Structure 1248 (2022) 131395
Table 4 (continued)
˚
˚
Bond distance (A)
Exp.a
Calcd.b
Difference
Bond distance (A)
Exp.a
0.3
Calcd.b
Difference
C(6)-C(1)-C(2)-H(2)
C(6)-C(1)-C(2)-C(3)
C(7)-C(1)-C(2)-H(2)
C(7)-C(1)-C(2)-C(3)
C(2)-C(1)-C(6)-C(5)
C(2)-C(1)-C(6)-N(2)
C(7)-C(1)-C(6)-C(5)
C(7)-C(1)-C(6)-N(2)
C(2)-C(1)-C(7)-N(1)
C(2)-C(1)-C(7)-O(1)
C(6)-C(1)-C(7)-N(1)
C(6)-C(1)-C(7)-O(1)
C(1)-C(2)-C(3)-H(3)
C(1)-C(2)-C(3)-C(4)
H(2)-C(2)-C(3)-H(3)
H(2)-C(2)-C(3)-C(4)
C(2)-C(3)-C(4)-H(4)
C(2)-C(3)-C(4)-C(5)
H(3)-C(3)-C(4)-H(4)
H(3)-C(3)-C(4)-C(5)
C(3)-C(4)-C(5)-H(5)
C(3)-C(4)-C(5)-C(6)
H(4)-C(4)-C(5)-H(5)
H(4)-C(4)-C(5)-C(6)
C(4)-C(5)-C(6)-C(1)
C(4)-C(5)-C(6)-N(2)
H(5)-C(5)-C(6)-C(1)
H(5)-C(5)-C(6)-N(2)
C(1)-C(6)-N(2)-C(13)
C(1)-C(6)-N(2)-C(14)
C(5)-C(6)-N(2)-C(13)
C(5)-C(6)-N(2)-C(14)
C(1)-C(7)-N(1)-C(8)
C(1)-C(7)-N(1)-C(13)
O(1)-C(7)-N(1)-C(8)
O(1)-C(7)-N(1)-C(13)
H(8A)-C(8)-C(9)-C(10)
H(8A)-C(8)-C(9)-O(2)
H(8B)-C(8)-C(9)-C(10)
H(8B)-C(8)-C(9)-O(2)
N(1)-C(8)-C(9)-C(10)
N(1)-C(8)-C(9)-O(2)
H(8A)-C(8)-N(1)-C(7)
H(8A)-C(8)-N(1)-C(13)
H(8B)-C(8)-N(1)-C(7)
H(8B)-C(8)-N(1)-C(13)
C(9)-C(8)-N(1)-C(7)
C(9)-C(8)-N(1)-C(13)
C(8)-C(9)-C(10)-H(10)
C(8)-C(9)-C(10)-C(11)
O(2)-C(9)-C(10)-H(10)
O(2)-C(9)-C(10)-C(11)
C(8)-C(9)-O(2)-C(12)
C(10)-C(9)-O(2)-C(12)
C(9)-C(10)-C(11)-H(11)
C(9)-C(10)-C(11)-C(12)
H(10)-C(10)-C(11)-H(11)
H(10)-C(10)-C(11)-C(12)
C(10)-C(11)-C(12)-H(12)
C(10)-C(11)-C(12)-O(2)
H(11)-C(11)-C(12)-H(12)
H(11)-C(11)-C(12)-O(2)
C(11)-C(12)-O(2)-C(9)
H(12)-C(12)-O(2)-C(9)
N(2)-C(13)-N(1)-C(7)
−178.7
1.3
180.0
−0.4
1.3
1.7
1.5
1.8
3.2
2.8
3.3
2.9
3.5
4.4
3.7
3.5
0.3
0.7
0
N(3)-C(13)-N(1)-C(8)
0.3
1.2
0
N(1)-C(13)-N(2)-C(6)
1.3
−179.4
−179.5
−0.2
0.1
1.1
0
0.0
−1.5
N(1)-C(13)-N(2)-C(14)
N(3)-C(13)-N(2)-C(6)
−178.3
180.0
−1.2
178.2
2.0
−179.5
1.0
N(3)-C(13)-N(2)-C(14)
N(1)-C(13)-N(3)-N(4)
1.2
1.0
1.1
5.3
2.8
3.0
3.0
0.6
0.7
1.4
2.9
0.6
0.8
2.1
0.2
1.9
2.5
0.4
1.1
1.0
1.6
5.7
7.6
4.5
7.0
9.1
5.8
3.7
5.7
2.5
1.2
0.1
0.6
0.7
2.8
1.6
3.5
5.4
4.5
5.1
4.6
2.7
3.0
2.4
0.5
1.7
1.1
0.8
3.1
4.1
2.1
3.7
2.8
2.0
1.0
2.3
1.4
0.5
0.1
1.0
178.5
−179.8
−0.2
−178.8
−176.5
2.7
179.5
0.3
178.5
−0.8
N(2)-C(13)-N(3)-N(4)
N(2)-C(14)-C(15)-H(15A)
N(2)-C(14)-C(15)-H(15B)
N(2)-C(14)-C(15)-N(5)
N(4)-C(14)-C(15)-H(15A)
N(4)-C(14)-C(15)-H(15B)
N(4)-C(14)-C(15)-N(5)
C(15)-C(14)-N(2)-C(6)
C(15)-C(14)-N(2)-C(13)
N(4)-C(14)-N(2)-C(6)
−168.8
−51.7
69.7
−163.5
−48.9
72.7
−176.1
3.8
−179.6
−0.6
2.6
−1.1
9.1
12.1
−177.5
179.5
−0.4
178.0
179.8
−1.1
126.1
−112.4
−2.8
126.7
−111.7
−4.2
−0.5
−0.5
178.1
179.1
−0.0
175.2
179.7
−0.8
179.5
179.5
−0.5
178.5
−178.3
1.0
1.0
2.2
1.5
1.2
0.5
3.3
0.1
2.7
0.6
1.8
1.8
5.6
4.0
0.9
2.6
1.4
3.1
1.6
2.6
2.5
3.5
37.7
9.9
14.4
13.7
12.1
11.4
1.5
2.4
1.4
2.4
1.3
2.2
0.4
0.9
1.1
0.2
0.6
0
N(4)-C(14)-N(2)-C(13)
C(15)-C(14)-N(4)-N(3)
N(2)-C(14)-N(4)-N(3)
−178.0
0.2
−175.9
0.4
−0.4
0.8
179.6
−179.4
0.6
−179.9
−176.1
0.5
C(14)-C(15)-N(5)-C(16)
C(14)-C(15)-N(5)-C(19)
H(15A)-C(15)-N(5)-C(16)
H(15A)-C(15)-N(5)-C(19)
H(15B)-C(15)-N(5)-C(16)
H(15B)-C(15)-N(5)-C(19)
H(16A)-C(16)-C(17)-H(17A)
H(16A)-C(16)-C(17)-H(17B)
H(16A)-C(16)-C(17)-S(1)
H(16B)-C(16)-C(17)-H(17A)
H(16B)-C(16)-C(17)-H(17B)
H(16B)-C(16)-C(17)-S(1)
N(5)-C(16)-C(17)-H(17A)
N(5)-C(16)-C(17)-H(17B)
N(5)-C(16)-C(17)-S(1)
H(16A)-C(16)-N(5)-C(15)
H(16A)-C(16)-N(5)-C(19)
H(16B)-C(16)-N(5)-C(15)
H(16B)-C(16)-N(5)-C(19)
C(17)-C(16)-N(5)-C(15)
C(17)-C(16)-N(5)-C(19)
C(16)-C(17)-S(1)-C(18)
H(17A)-C(17)-S(1)-C(18)
H(17B)-C(17)-S(1)-C(18)
H(18A)-C(18)-C(19)-H(19A)
H(18A)-C(18)-C(19)-H(19B)
H(18A)-C(18)-C(19)-N(5)
H(18B)-C(18)-C(19)-H(19A)
H(18B)-C(18)-C(19)-H(19B)
H(18B)-C(18)-C(19)-N(5)
S(1)-C(18)-C(19)-H(19A)
S(1)-C(18)-C(19)-H(19B)
S(1)-C(18)-C(19)-N(5)
H(18A)-C(18)-S(1)-C(17)
H(18B)-C(18)-S(1)-C(17)
C(19)-C(18)-S(1)-C(17)
C(18)-C(19)-N(5)-C(15)
C(18)-C(19)-N(5)-C(16)
H(19A)-C(19)-N(5)-C(15)
H(19A)-C(19)-N(5)-C(16)
H(19B)-C(19)-N(5)-C(15)
H(19B)-C(19)-N(5)-C(16)
C(13)-N(3)-N(4)-C(14)
N(2)-C(13)-N(1)-C(8)
−168.1
67.1
−170.0
64.6
70.4
70.0
0.6
3.3
−54.4
−46.6
−171.4
64.2
−55.5
−47.6
−173.0
58.5
−179.5
0.3
179.9
−2.1
−179.4
−179.8
0.6
178.8
174.6
−4.6
−53.4
−174.6
−177.8
64.7
−61.0
−179.1
175.2
55.6
−1.8
−2.7
179.2
177.8
−1.1
176.6
176.4
−4.2
−56.6
−56.8
−174.4
64.4
−62.4
−60.5
179.9
61.9
178.9
−3.2
−179.5
−0.6
−1.1
1.4
52.0
50.8
176.9
−14.9
164.1
−132.3
46.8
−179.6
−52.6
154.2
−146.7
33.1
175.7
−66.0
57.7
175.8
−66.6
58.4
173.0
−63.2
−55.1
66.1
170.2
−64.8
−51.4
71.6
106.4
−74.6
−139.4
42.5
94.3
−86.0
−140.9
40.1
−176.3
−61.3
56.1
−171.8
−56.2
60.7
−22.1
159.9
99.3
−23.5
157.5
98.0
177.4
−178.9
−61.4
59.9
−179.9
−175.9
−59.0
60.4
−78.8
−1.1
−81.0
−1.5
178.9
179.8
−0.2
179.8
178.7
−0.0
59.9
61.6
177.4
−61.3
174.8
−67.6
53.6
178.5
−62.1
171.7
−71.7
51.5
−179.3
0.0
−179.9
−0.0
−179.7
0.3
−179.9
0.1
0.2
0.2
1.1
1.1
0.7
0.2
0.6
0.3
0.1
0.3
0.9
−174.4
62.2
−170.7
65.0
0.3
1.4
−179.7
179.6
−0.3
−178.6
−179.7
−0.1
64.4
66.4
−59.0
−53.1
−176.5
−0.3
−58.0
−50.8
−175.1
0.2
−0.4
0.2
179.6
0.2
179.9
0.1
179.4
−177.7
179.5
−178.7
−179.8
1.4
179.9
0.5
N(3)-C(13)-N(1)-C(7)
a
Experimental geometry parameters for molecule 1.
Calculated geometry parameters for conformer 1–3.
b
(ꢀE) were measured to research the chemical stability and activ-
ity of conformer 1–3 (same as the crystal structure) [30–32]. The
electrons in the EHOMO are the “valence” electrons of the molecule.
They have the highest energy and are the least bound, so they are
the easiest to be pushed during the reaction, while the ELUMO is
the easiest to accept in chemical reactions. The pictorial illustra-
tion of the FMOs and two colors are shown in Fig. 5. And the red
color indicates their positive areas, and the green color indicates
their negative areas. Comparing the values of EHOMO (−6.3397 eV)
and ELUMO (−1.9426 eV) with the value of the energy separation
6

H. Sun, L. Deng, W. Hu et al.
Journal of Molecular Structure 1248 (2022) 131395
between the HOMO and LUMO is 4.3917 eV for conformer 1–3, it
is able to find that there is a large HOMO-LUMO energy gap, which
suggests the calculated conformer has the properties of high exci-
tation energy of the excited state, good chemical stability.
3.6. Hirshfeld analysis
Hirshfeld surface analysis and 2D fingerprint plots were ob-
tained using CrystalExplorer 17.5 to examine the interactions in the
crystal structure of 1. The dnorm Hirshfeld curvatures for crystal
structure of 1 was displayed using a red-blue-white color scheme
in Fig. 6 where red highlights shorter contacts. And the red and
blue areas proving the existence of N—H···N and C—H···O hydro-
gen bonds, white indicates that there is a weaker and farther con-
tact between the molecules, rather than hydrogen bonding. 2D fin-
gerprint plots of the crystal structure show that the interactions
of C···H, H···H, N···H, O···H and S···H play a major contributor in
crystal packings. Among them, the proportions of C···H, H···H, N···H
and O···H in crystal structure of 1 are 8.4%, 43.3%, 4.5%, 6.1%, 2.8%.
These interactions ensure the stability of the crystal.
3.7. Vibrational analysis
The theoretical and experimental IR spectra of title compound
are shown in Fig. 7, the theoretical wavenumbers were scaled with
0.9618 respectively [33]. The measured IR and calculated vibra-
tional wavenumbers of title compound along with assignments are
given in Table 5.
3.8. In vitro antitumor activity analysis
Using an MTT assay, the antitumor activity of 1 was evaluated
in human melanoma cells A375; SHP244 (an inhibitor of SHP2)
[16] was selected as the control compound. The results are shown
Fig. 5. The HOMO and LUMO of conformer 1–3.
Fig. 6. (a) Hirshfeld surface analyses of 1 mapped with dnorm (b) 2D-fingerprint plots for 1 resolved into C···H contacts. (c) 2D-fingerprint plots for 1 resolved into H···H
contacts. (d) 2D-fingerprint plots for 1 resolved into N···H contacts. (e) 2D-fingerprint plots for 1 resolved into O···H contacts. (f) 2D-fingerprint plots for 1 resolved into S···H
contacts.
7

H. Sun, L. Deng, W. Hu et al.
Journal of Molecular Structure 1248 (2022) 131395
Table 5
Experimental and theoretical vibrational wavenumbers (cm−1) and vibrational assignments of the
compound 1.
Mode
Experimental
2927
Theoretical (Unsalced)
Theoretical (Salceda)
Assignments
1
3099
3095
3070
3047
2973
2943
2931
1727
1647
1627
1625
1587
1554
1522
1513
1507
1491
1482
1473
1454
1428
1424
1373
1372
1358
1193
1191
1182
785
2980.6182
2976, 771
2952.726
v(-CH2)
2
3
4
2930.6046
2859.4314
2830.5774
2819.0358
1661.0286
1584.0846
1564.8486
1562.925
5
2815
1686
1562
1490
1452
1413
1328
1145
759
6
7
8
v(-C = O)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
V(benzene ring)
1526.3766
1494.6372
1463.8596
11,455.2034
1449.4326
1434.0438
1425.3876
1416.7314
1398.4572
1373.4504
1369.6032
1320.5514
1319.5896
1306.1244
1147.4274
1145.5038
1136.8476
755.013
v(C–N)
v(C–H)
v(C–S)
774
744.4332
766
736.7388
673
691
664.6038
683
656.9094
679
653.0622
was synthesized through adopting a five-step reaction. Employ-
ing the spectral techniques, MS and X-ray single crystal diffraction,
its structure was determined. Also, the title compound molecules
have undergone the crystallographic studies and conformational
analysis. And there is consistence between the molecular structure
optimized by DFT and the crystal structure determined by X-ray
diffraction. Also, the physical and chemical properties of the title
compound were analyzed by using MEP and FMOs. In addition, it
was found that the title compound has certain anti-tumor activity
in A375.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
CRediT authorship contribution statement
Hong Sun: Writing – original draft, Data curation, Methodology,
Writing – review & editing. Liyuan Deng: Writing – review & edit-
ing. Weiyin Hu: Writing – review & editing. Tianhui Liao: Writ-
ing – review & editing. Weike Liao: Writing – review & editing.
Huifang Chai: Supervision, Writing – review & editing. Chunshen
Zhao: Software, Supervision, Writing – review & editing.
Fig. 7. Theoretical and experimental IR spectra of compound 1.
that their inhibition rate are 17.79% (compound 1) and 13.84% (the
control), so it can be found that 1 has certain anti-tumor activ-
ity by comparing with the reference compound SHP244 in A375,
which may be due to 1 has better physical and chemical proper-
ties.
Acknowledgment
4. Conclusion
This work has been awarded the Guizhou University of Tra-
ditional Chinese Medicine 2018 annual academic new seedling
cultivation and innovation exploration special project cultivation
project plan (Qiankehe platform talent [2018]5766-14).
In this research, a new compound, 4-(furan-2-ylmethyl)−1-
(thiomorpholinomethyl)- [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one
8

H. Sun, L. Deng, W. Hu et al.
Journal of Molecular Structure 1248 (2022) 131395
Supplementary materials
[16] M. Fodor, E. Price, P. Wang, H.Y. Lu, A. Argintaru, Z.L. Chen, Allosteric Inhibition
of SHP2 Phosphatase, ACS Chem Biol. 13 (2018) 647.
[17] S. Danylchenko, O. Drushlyak, S. Kovalenko, S. Kovalenko, A. Elliott, Primary
antimicrobial screening of novel [1,2,4]triazolo [4,3-a]quinazolin-5(4H)-one
derivatives, ScienceRise 4 (21) (2016) 59–64.
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131395.
[18] A.A. El-Tombary, K.A. Ismail, O.M. Aboulwafa, et al., Novel tria-
ꢁ
zolo[4,3-a]quinazolinone and bis-triazolo [4,3-a:4,3 -c]quinazolines: synthesis
References
and antitoxoplasmosis effect, Farmaco 54 (7) (1999) 486–495.
[19] M. Driowya, J. Leclercq, V. Verones, A. Barczyk, Synthesis of triazoloquinazoli-
none based compounds as tubulin polymerization inhibitors and vascular dis-
rupting agents, Eur. J. Med. Chem. 115 (2016) 393–405.
[1] R.A. Smits, M. Adami, E.P. Istyastono, O.P. Zuiderveld, et al., Synthesis and QSAR
of quinazoline sulfonamides as highly potent human histamine H4 receptor
inverse agonists, J. Med. Chem. 53 (2010) 2390–2400.
[20] M. Dinçer, D. Avcı, M. S¸ ekerci, Y. Atalay, Molecular structure and vi-
brational and chemical shift assignments of 5-(2-Hydroxyphenyl)-
4-(p-tolyl)-2,4-dihydro-1,2,4-triazole-3-thione by DFT and ab initio HF calcula-
tions, J. Mol. Model. 14 (9) (2008) 823–832.
[2] V. Alagarsamy, V. Raja Solomon, M. Murugan, K. Dhanabal, P. Parthiban,
G.V. Anjana, Design and synthesis of 3-(4-ethylphenyl)-2-substituted
amino-3H-quinazolin-4-ones as
a novel class of analgesic and anti-in-
flammatory agents, J. Enzyme Inhib. Med. Chem. 23 (2008) 839–847.
[3] G. Grover, S.G. Kini, Synthesis and evaluation of new quinazolone derivatives
of nalidixic acid as potential antibacterial and antifungal agents, Eur. J. Med.
Chem. 41 (2006) 256–262.
[21] Jane S. Murray, Peter Poitzer, The electrostatic potential: an overview. The elec-
trostatic potential: an overview, Wiley Son. 1 (2011) 153–163.
[22] B.J. Deppmeier, A.J. Driessen, T.S. Hehre, et al., Structural evidence that
alkoxy substituents adopt electronically preferred pseudoaxial orientations in
six-membered ring dioxocarbenium ions, J. Am. Chem. Soc. 127 (15) (2005)
5322–5323.
[23] H.H. Brintzinger, M.H. Prosenc, F. Schaper, A. Weeber, U. Wieser, Alternative
force field models for ansa-zirconocene complexes-vibrational and structural
studies on Me2Si-bridged and tert-butyl-substituted representatives, J. Mol.
Struct. (1999) 485–486.
[4] S.R. Kanth, G. Venkat Reddy, K.Hara Kishore, P. Shanthan Rao, B. Narsa-
iah, U. Surya Narayana Murthy, Convenient synthesis of novel 4- substi-
tutedamino-5-triuoromethyl-2,7-disubstituted pyrido [2,3-d] pyrimidines and
their antibacterial activity, Eur. J. Med. Chem. 41 (2006) 1011–1016.
[5] H. Georgey, N. Abdel-Gawad, S. Abbas, Synthesis and anticonvulsant activity of
some quinazolin-4-(3H)-one derivatives, Molecules 13 (2008) 2557–2569.
[6] V. Jatav, P. Mishra, S. Kashaw, J.P. Stables, CNS depressant and anticonvulsant
activities of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quina-
zoline-4(3H)-ones, Eur. J. Med. Chem. 43 (2008) 1945–1954.
[24] N. Huang, C. Kalyanaraman, K. Bernacki, M.P. Jacobson, Molecular mechanics
methods for predicting protein–ligand binding, Phys. Chem. Chem. Phys. 8 (44)
(2006) 5166–5177.
[25] A.V. Ivachtchenko, P.M. Yamanushkin, O.D. Mitkin, Bromination of in-
domethacin, Mendeleev Commun. (20) (2010) 111–112.
[7] A. Rosowsky, A.T. Papoulis, R.A. Forsch, S.F. Queener, Synthesis and
antiparasitic and antitumor activity of 2, 4-diamino-6-(arylmethyl)-5,6,7,
8-tetrahydroquinazoline analogues of piritrexim, J. Med. Chem. 42 (1999)
1007–1017.
[8] J. Rémi, A. Hüttenbrenner, B. Feddersen, S. Noachtar, Carbamazepine but not
pregabalin impairs eye control: a study on acute objective CNS side effects in
healthy volunteers, Epilepsy Res 88 (2010) 145–150.
[26] N. Kanagathara, F. MaryAnjalin, V. Ragavendran, et al., Experimental and theo-
retical (DFT) investigation of crystallographic, spectroscopic and Hirshfeld sur-
face analysis of anilinium arsenate, J. Mol. Struct. 1223 (1) (2020) 128965.
[27] P. Zhou, W.Y. Qiu, S.B. Liu, N.Z. Jin, Halogen as halogen-bonding donor and hy-
drogen-bonding acceptor simultaneously in ring-shaped H3N·X(Y)·HF (X = Cl,
[9] A. Abdel-Aziem, M.S. El-Gendy, A.O. Abdelhamid, Synthesis and antimicrobial
activities of pyrido[2,3-d]pyrimidine, pyridotriazolopyrimidine, triazolopyrimi-
dine, and pyrido[2,3-d:6,5d’]dipyrimidine derivatives, Eur. J. Chem. 3 (4) (2012)
455–460.
[10] H. Hafez, H.A. Abbas, A.R. El-Gazzar, Synthesis and evaluation of anal-
gesic, anti-inammatory and ulcerogenic activities of some triazolo-and 2-pyra-
zolylpyrido [2,3-d]-pyrimidines, Acta Pharm. 58 (2008) 359–378.
[11] V. Alagarsamy, M. Rupeshkumar, K. Kavitha, et al., Synthesis and phar-
macological investigation of novel 4-(2-methylphenyl)-1-substituted-4H-
[1,2,4]triazolo[4,3-a]quinazolin- 5-ones as new class of H1-antihistaminic
agents, Eur. J. Med. Chem. 43 (2008) 2331.
[12] M. Gobinath, N. Subramanian, V. Alagarsamy, Design, synthesis and
H1-antihistaminic activity of novel 1-substituted-4-(3-chlorophenyl)-
[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones, J. Saudi Chem. Soc. 19 (3) (2015)
282–286.
[13] M. Gobinath, N. Subramanian, V. Alagarsamy, et al., Design and synthesis of
1-substituted-4-(4-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones as
Br and
Y
=
F, Cl, Br) complexes, Phys. Chem. Chem. Phys. 13 (16) (2011)
7408–7418.
[28] Ç.K. Atay, T. Tilki, B. Dede, JDesign and synthesis of novel ribofuranose nucleo-
side analogues as antiproliferative agents: a molecular docking and DFT study,
J. Mol. Liq. 269 (2018) 315–326.
[29] J.S. Zhao, P. Jin, N. Xi, D.D. Wei, J. LI, D. Wei, C.H. Hu, Design, synthesis and
crystal structure of the antitumor agent N1-(2-(4-Methoxy-2-nitrophenoxy)-
2-dimethyl acyloxymethyl)-5-fluorouracil, J. Struct. Chem. 36 (6) (2017)
937–942.
[30] H.H. Greenwood, Molecular orbital theory of reactivity in aromatic hydrocar-
bons, J. Chem. Phys. 20 (10) (1952) 1653.
[31] M.D. Rozeboom, I.M. Tegmo-Larsson, K.N. Houk, Frontier molecular orbital the-
ory of substitutent effects on regioselectivities of nucleophilic additions and
cycloadditions to benzoquinones and naphthoquinones, J. Org. Chem. 46 (11)
(1981) 2338–2345.
[32] Q.M. Wu, Y.M. Chen, D.M. Chen, Z.X. Zhou, Synthesis, crystal struc-
ture and vibrational properties studies of 2-((4-(4,4,5,5-tetramethyl-1,
3,2-dioxaborolan-2-yl)phenoxy)methyl)benzonitrile and N-(3-bromobenzyl)-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, J. Mol. Struct. 1229 (2021)
129782.
a
new class of antihistaminic agents, Russ. J. Bioorg. Chem. 46 (3) (2020)
403–408.
[14] V. Alagarsamy, V.R. Solomon, M. Murugan, Bioorg, Synthesis and pharmaco-
logical investigation of novel 4-benzyl-1-substituted-4H-[1,2,4]triazolo[4,3-a]
quinazolin-5-ones as new class of H1-antihistaminic agents, Bioorg. Med.
Chem. 15 (12) (2007) 4009–4015.
[33] B.G. Johnson, P.M.W. Gill, J.A. Pople, The performance of a family of density
functional methods, J. Chem. Phys. 98 (1993) 5612.
[15] N.M. Abdel Gawad, H.H. Georgey, R.M. Youssef, N.A. El Sayed, Design, synthesis,
and anticonvulsant activity of novel quinazolinone analogues, Med. Chem. Res.
20 (8) (2010) 1280–1286.
9