Benzoylquinazolinone derivatives as new potential antidiabetic agents: α-Glucosidase inhibition, kinetic, and docking studies

Article abstract of DOI:10.1002/jccs.201900268

Benzoylquinazolinone derivatives 3a–n were synthesized via a simple one-step reaction, and evaluated for in vitro α-glucosidase inhibitory activity. Compounds 3d, 3f–g, 3i, and 3m–n showed more inhibitory activity than standard drug acarbose (IC₅₀ = 750.0 ± 1.5 μM), and among them, compound 3d displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 261.6 ± 0.1 μM). The kinetic analysis of the compound 3d revealed that this compound inhibited α-glucosidase in a competitive manner (K_i = 255 μM). The docking studies were applied to predict binding modes of the synthesized compounds in active site of α-glucosidase.

Full text of DOI:10.1002/jccs.201900268

Received: 4 July 2019
Revised: 30 September 2019
Accepted: 30 September 2019
DOI: 10.1002/jccs.201900268
A R T I C L E
Benzoylquinazolinone derivatives as new potential antidiabetic
agents: α-Glucosidase inhibition, kinetic, and docking studies
Maryam Mohammadi-Khanaposhtani1 | Hoda Yahyavi2 | Somaye Imanparast3
Fereshte Nazemi Harandi4 | Mohammad Ali Faramarzi3 | Alireza Foroumadi2
Bagher Larijani5 | Mahmood Biglar5 | Mohammad Mahdavi5
|
|
1Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
2Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences,
Tehran, Iran
3Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences,
Tehran, Iran
4Biotechnology Group, Chemical Engineering Department, Tarbiat Modares University, Tehran, Iran
5Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences,
Tehran, Iran
Correspondence
Bagher Larijanig and Mohammad Mahdavi,
Abstract
Endocrinology and Metabolism Research
Center, Endocrinology and Metabolism
Clinical Sciences Institute, Tehran
University of Medical Sciences, Tehran,
Iran.
Benzoylquinazolinone derivatives 3a–n were synthesized via a simple one-step
reaction, and evaluated for in vitro α-glucosidase inhibitory activity. Com-
pounds 3d, 3f–g, 3i, and 3m–n showed more inhibitory activity than standard
drug acarbose (IC50 = 750.0 1.5 μM), and among them, compound 3d dis-
played the highest α-glucosidase inhibitory activity (IC50 = 261.6 0.1 μM).
The kinetic analysis of the compound 3d revealed that this compound inhibited
α-glucosidase in a competitive manner (Ki = 255 μM). The docking studies
were applied to predict binding modes of the synthesized compounds in active
site of α-glucosidase.
Email: emrc@tums.ac.ir (B. L.) and
momahdavi@tums.ac.ir (M. M.)
K E Y W O R D S
antidiabetic, benzoylquinazolinone, kinetic analysis, α-glucosidase
delayed digestion and absorption of intestinal carbohydrates
(α-glucosidase inhibitors), suppress hepatic glucose production
1 | INTRODUCTION
The World Health Organization estimates that by 2030, more
than 300 million people will be diagnosed with Type 2 diabe-
tes.[1] Type 2 diabetes results from a combination of resis-
tance to insulin action in body cell, impaired β-cell function,
increased hepatic glucose production, and decreased insulin-
mediated glucose uptake.[2] Current treatment modalities of this
disease include exercise, diet, and various medical treatments.
Available drugs for treatment of Type 2 diabetes act through
(biguanides), stimulate insulin secretion (sulfonylureas and
glinides), and improve insulin sensitivity and peripheral glucose
uptake (thiazolidinediones and metformin). As mentioned, one
way to reduce blood glucose in Type 2 diabetes is to decrease
the absorption of glucose in intestine that is created by interfering
with the action of α-glucosidases present in the small brush bor-
der. Acarbose and miglitol are α-glucosidase inhibitors that are
today used to treat diabetes and are often associated with side
© 2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2019;1–8.
http://www.jccs.wiley-vch.de
1

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MOHAMMADI-KHANAPOSHTANI ET AL.
effects such as abdominal bloating, diarrhea, and flatulence.[3]
On the other hand, there are some reports that show inhibition of
the α-glucosidase can be valuable in the treatment of other
carbohydrate-mediated illnesses such as cancer, viral infections,
and hepatitis.[4–6] Thus, development of safe and effective inhib-
itors for α-glucosidase is an attractive subject for pharmaceutical
chemists.[7–10]
Quinazolinone is an important scaffold with numerous
pharmacological properties such as anticancer, anticon-
vulsant, anti-HIV, central nervous system depressant,
anti-inflammatory, antifungal, antimicrobial activiti-
es.[11–17] Recently, new quinazolinone derivatives have
been reported as potent α-glucosidase inhibitors.[18]
In our continued interest in the development of
α-glucosidase inhibitors, we synthesized and evaluated
benzoylquinazolinone derivatives 3a–n as new inhibitors of
α-glucosidase.[19–21] We also performed a molecular dock-
ing study to further investigate the interaction modes of
these compounds in the active site of α-glucosidase.
2.2 | In vitro α-glucosidase inhibitory activity
α-Glucosidase inhibitory activity of benzoylquinazolinone
derivatives 3a–n was evaluated against α-glucosidase from
Saccharomyces cerevisiae (yeast) and compared with aca-
rbose as a standard drug. Table 1 shows the IC50 values of
the synthesized compounds 3a–n. Among these compounds,
compounds 3d, 3f–g, 3i, and 3m–n displayed high inhibi-
tory activities against α-glucosidase with the IC50 values in
the range of 261.6 0.1–494.1 0.7 μM when compared
with the standard drug acarbose. Compound 3d was found
to be the most potent inhibitor of α-glucosidase with the
IC50 value of 261.6 0.1 μM; compound 3h was as potent
as acarbose against α-glucosidase; and compounds 3a–c, 3e,
and 3j–l did not show any activity (Table 1).
Structure–activity relationship (SAR) analysis indicated
that anti-α-glucosidase activity of this class of compounds
depends mainly on the type and position of substituents on
the aromatic side chain, derived from various acetophenones.
The results showed that the electronic properties of substitu-
ents on the aromatic side chain affect α-glucosidase inhibitory
activity as no activity was observed for un-substituted com-
pound 3a. Compounds with electron-donating groups such as
methyl, hydroxyl, and methoxy in any position of the phenyl
group do not show anti-α-glucosidase activity as observed in
compounds 3b–c, 3j–l. The presence of a halogen atom as
electron-withdrawing substituent on the 4-position of phenyl
group led to increased inhibitory activity and is demon-
strated in compounds 3d (IC50 = 261.6 0.1 μM), 3f
(IC50 = 386.8 0.9 μM), and 3i (IC50 = 494.1 0.7 μM)
in the order of F > Cl > Br. On the other hand, 2-fluro and
2-chloro derivatives 3c and 3e do not show any
α-glucosidase inhibitory activity. Moreover, the introduc-
tion of the second chlorine atom onto the 2-position of phe-
nyl ring in compound 3f (IC50 = 386.8 0.9 μM) led to a
decrease in inhibitory activity as observed in compound 3g
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
The target compounds 3a–n were synthesized by a sim-
ple one-step reaction between acetophenones 1 and
2-aminobenzamide 2 in the presence of iodine in
dimethyl sulfoxide (DMSO) at 100ꢀC (Scheme 1) [22].
The target compounds 3a–n were fully characterized by
physical techniques. For example, nuclear magnetic reso-
nance (NMR) spectra of the compound 3a was assigned, as
shown in Scheme 2.
O
N
O
R
,
NH
NH2
NH2
DM
SO
I2
+
H
C
3
,
100 Ο C 8h
R
(IC50 = 406.5 0.9 μM). 3-Bromo derivative 3h (IC50
=
O
O
-
759.6 0.7 μM) showed inhibitory activity similar to aca-
rbose against α-glucosidase. Interestingly, the second and
the third most potent compounds against α-glucosidase
a n
3
1
2
SCHEME 1 Synthetic protocol of quinolinone derivatives 3a–n
(a)
(b)
8.22
7.73-7.79
8.16
161.1
128.6
122.9
130.9 128.6
12.69
O
N
O
H5
H3'
7.88
134.3
7.59
7.65
128.4
134.1
H2'
H6
H7
H4'
H5'
NH
NH
N
7.73-7.79
H8
H6'
128.6
130.9
147.2
O
O
134.8
126.1
149.0
187.2
7.59
8.16
SCHEME 2 Selected 1H NMR (a) and 1H CNMR (b) data of the compound 3a (unit of numbers in the scheme is ppm)

MOHAMMADI-KHANAPOSHTANI ET AL.
3
TABLE 1 In vitro α-glucosidase
inhibitory activity of the synthesized
compounds 3a–n
O
N
R
NH
O
Compound
R
IC50 (μM)a
NA
Compound
R
IC50 (μM)a
759.6 0.7
494.1 0.7
NA
3a
H
4-CH3
2-F
3h
3-Br
4-Br
3b
NA
3i
3j
3c
NA
4-OH
3-OCH3
4-OCH3
2-NO2
4-NO2
—
3d
4-F
261.6 0.1
NA
3k
NA
3e
2-Cl
4-Cl
3l
NA
3f
386.8 0.9
406.5 0.9
750.0 1.5
3m
368.0 0.9
296.7 0.9
750.0 1.5
3g
2,4-Dichloro
3n
Acarbose
—
Acarbose
Abbreviation: NA, not active.
aValues are mean SD. All experiments were performed at least three times.
FIGURE 1 Kinetic of α-glucosidase inhibition by the compound 3d. (a) The Lineweaver–Burk plot in the absence and presence of different
concentrations of the compound 3d. (b) The secondary plot between Km and various concentrations of the compound 3d
were derivatives 3n (IC50 = 296.7 0.9 μM) and 3m
(IC50 = 368.0 0.9 μM) with strong electron-withdrawing
group NO2, respectively, in 4- and 2-position of pendant
phenyl ring.
that compound 3d acted as a competitive inhibitor of the
α-glucosidase. The Ki (inhibitor constant) was calculated
directly by secondary replot of Lineweaver–Burk plots. The
Ki value of compound 3d was 255 μM.
2.3 | Kinetic study
2.4 | Docking study
The kinetic study of the most potent compound 3d against
α-glucosidase was performed using a Lineweaver–Burk plot
according to literature procedure (Figure 1a). Figure 1b
shows secondary replot of 1/v versus 1/[S], for the enzyme,
in the presence of compound 3d. The Lineweaver–Burk plot
showed that in the presence of compound 3d, the values of
Vmax remained unchanged, while the values of Km increased
with increasing concentrations of the inhibitor. This indicates
To study the interaction modes of the synthesized compounds
in the active site of α-glucosidase and their related inhibitory
activities, docking study was performed using Auto Dock Tools
(version 1.5.6). Since we used S. cerevisiae α-glucosidase in the
Section 3 and it did not have any crystallographic structure in
the PDB, for docking purposes we applied the crystal structure
of isomaltase (PDB code 3A4A) from S. cerevisiae with 71%
identity and 84% similarity to S. cerevisiae α-glucosidase.[23]

4
MOHAMMADI-KHANAPOSHTANI ET AL.
FIGURE 2 Superimposition of 3d (pink) and acarbose (cyan) in
the α-glucosidase active site
Acarbose, the most potent compound 3d, and inactive com-
pound 3c were docked in the active site of isomaltase.
Figure 2 shows the superposed structure of acarbose as a
standard inhibitor and the most potent compound 3d in the
active site of isomaltase.
The detailed binding mode of acarbose showed that this
drug formed six hydrogen bond interactions with residues
Asp69, Arg213, Glu277, Arg315, Asp352, and Arg442 in
the enzyme active site (Figure 3).
FIGURE 3 Binding mode of acarbose in the in the enzyme
active site
(at 500.1 and 125.8 MHz) with TMS as an internal stan-
dard. Mass spectroscopy was performed on an Agilent
Technology (HP) operating at an ionization potential of
70 eV. Elemental analysis was obtained with an Elementar
Analysen system GmbH VarioEL (CHN mode).
The most active compound 3d established hydrogen
bonds with active site residues Arg213 and Asp352 through
carbonyl and NH unit of quinazolinone moiety (Figure 4). In
addition, this compound formed three π-π interactions with
Tyr72, Phe178, and Tyr158 and three π-anion interactions
with Asp69, Arg442, and Glu411. In addition, 4-fluoro sub-
stituent of pendant phenyl group interacted with Tyr158
(Figure 4). In the case of compound 3c, the presence of a
fluorine atom at the 2-position of pendant benzyl group
leads to the loss of inhibitory activity. This finding can be
reasonably explained by the interaction between 2-flouro
substituent and carbonyl unit attached to quinazolinoe moi-
ety (Figure 4). Although this compound interacts with
important residues Arg213, Glu277, Arg315, Asp352, and
Arg442 in the active site, it appears that internal interaction
of 2-flouro substituent leads to inappropriate interactions of
compound 3c with the active site of enzyme.
3.2 | General procedure for the synthesis of
synthesis of benzoylquinazolinone derivatives
3a–n
Acetophenones 1 (1 mmol) were added to a stirring solution
of 2-aminobenzamide 2 (1 mmol) and iodine (1.2 mmol) in
DMSO (3 ml) in a dropwise manner during 30 min. The reac-
tion mixture was stirred at 100ꢀC for 8 hr. After reaction com-
pletion, the reaction mixture was poured into cold water and
excess iodine was neutralized with sodium thiosulfate. Then,
the mixture was extracted using dichloromethane (2 × 25 ml)
and the solvent was evaporated under reduced pressure.
Finally, the residue was purified using recrystallization from
ethyl acetate to obtain pure products 3a–n (75–85%).
3.3 | Spectral data
3.3.1 | 2-benzoylquinazolin-4(3H)-one (3a)
3 | EXPERIMENTAL
3.1 | General
White powder, yield: 84%, mp 184–186ꢀC, IR (KBr)
(νmax/cm−1): 3,175, 3,063, 3,232, 2,918, 1,704, 1,680, 1,593,
1,447, 1,305, 1,242, 893, 776, 689. 1H NMR (500 MHz,
DMSO-d6): 7.59 (t, J = 7.5 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H),
7.73–7.79 (m, 2H), 7.88 (t, J = 7.5 Hz, 1H), 8.16 (t, J = 8 Hz,
2H), 8.22 (d, J = 8 Hz, 1H), 12.69 (s, NH). 13C NMR
(125 MHz, DMSO-d6): δ 122.9 (C–CO), 126.1 (CH), 128.4
(CH), 128.6 (3CH), 130.9 (2CH), 134.1 (CH), 134.3 (C–CO),
134.8 (CH), 147.2 (C–N), 149.0 (N–C–N), 161.1 (C=O),
All chemicals were purchased from Merck (Germany) and
were used without further purification. Melting points
were measured on an Electro thermal 9100 apparatus and
are uncorrected. IR spectra were recorded on a Shimadzu
1
IR-460 spectrometer. H and 13C NMR spectra were mea-
sured (DMSO solution) with Bruker DRX-500 AVANCE

MOHAMMADI-KHANAPOSHTANI ET AL.
5
(a)
(b)
FIGURE 4 Docking poses of the compounds 3d (a) and 3c (b) in the active site of enzyme
187.2 (C=O). MS (70 eV): m/z = 250 (M+). C15H10N2O2
(250.25): calcd. C 71.99, H 4.03, N 11.19; found C 71.84, H
4.12, N 11.01.
(CH), 134.9 (C–CO), 135.6 (J = 33 Hz,CH), 147.1 (C–N),
148.9 (N–C–N), 160.8 (J = 1,010 Hz, C–F), 161.0 (C=O),
186.1 (C=O). C15H9FN2O2 (268.24): calcd. C 67.16, H
3.38, N 10.44; found C 67.24, H 3.55, N 10.31.
3.3.2 | 2-(4-methylbenzoyl)quinazolin-4(3H)-
one (3b)
3.3.4 | 2-(4-Fluorobenzoyl)quinazolin-4(3H)-
one (3d)
White powder, yield: 82%, mp 225–229ꢀC, IR (KBr)
(νmax/cm−1): 3,171, 3,134, 3,090, 3,070, 2,918, 1,666, 1,601,
Yellow powder, yield: 81%, mp 232–235ꢀC, IR (KBr)
1
1,464, 1,436, 1,335, 1,288, 1,157, 1,099, 898, 769. H NMR
(νmax/cm−1): 3,187, 3,072, 2,921, 1,681, 1,596, 1,506,
1
(500 MHz, DMSO-d6): 2.42 (s, 3H), 7.11 (d, J = 9 Hz, 2H),
7.64 (t, J = 7.5 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.88 (t,
J = 7.5 Hz, 1H), 8.19 (m, 3H), 12.68 (s, NH). 13C NMR
(125 MHz, DMSO-d6): δ 55.8 (OCH3), 114.1 (2CH), 122.7
(C–CO), 126.0 (CH), 126.4 (CH), 128.2 (CH), 128.4 (CH),
133.5 (2CH), 134.8 (C–CO), 147.2 (C–N), 149.6 (N–C–N),
161.1 (C=O), 164.3 (OCH3), 186.7 (C=O). MS (70 eV): m/
z = 264 (M+). C16H12N2O2 (264.28): calcd. C 72.72, H 4.58,
N 10.60; found C 72.91, H 4.34, N 10.49.
1,447, 1,438, 1,336, 1,230, 1,158, 1,100, 900, 843, 771. H
NMR (500 MHz, DMSO-d6): 7.42 (t, J = 8.5 Hz, 2H), 7.65
(t, J = 7 Hz, 1H), 7.78 (d, J = 8 Hz, 2H), 7.88 (t, J = 7.5 Hz,
1H), 8.21 (d, J = 7.5 Hz, 1H), 8.28 (t, J = 7 Hz, 2H), 12.68
(s, NH). 13C NMR (125 MHz, DMSO-d6): δ 115.8 (2CH,
J = 87.5 Hz), 122.8 (C–CO), 126.1 (CH), 128.5 (2CH,
J = 124.5 Hz), 130.8 (CH), 134.1 (CH, J = 37.5 Hz), 134.7
(C–CO), 147.1 (C–N), 149.0 (N–C–N), 161.3 (C=O), 165.6
(C–F, J = 1,010 Hz), 185.7 (C=O). C15H9FN2O2 (268.24):
calcd. C 67.16, H 3.38, N 10.44; found C 66.95, H 3.51,
N 10.32.
3.3.3 | 2-(2-fluorobenzoyl)quinazolin-4(3H)-
one (3c)
3.3.5 | 2-(2-chlorobenzoyl)quinazolin-4(3H)-
one (3e)
White powder, yield: 79%, mp 244–248ꢀC, IR (KBr)
(νmax/cm−1): 3,174, 3,035, 2,917, 1,697, 1,606, 1,488,
1,449, 1,313, 1,227, 1,176, 1,100, 899, 751. 1H NMR
(500 MHz, DMSO-d6): 7.40 (m, 2H), 7.66 (t, J = 8 Hz, 4H),
7.71 (d, J = 8 Hz, 1H), 7.73–7.75 (m, 1H), 7.86 (t, J = 8 Hz,
1H), 7.90 (t, J = 7 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 12.81
(s, NH). 13C NMR (125 MHz, DMSO-d6): δ 116.5
(J = 85 Hz, CH), 122.9 (C–CO), 123.8 (J = 45 Hz, C–F),
124.7 (CH), 126.2 (CH), 128.4 (CH), 128.9 (CH), 132.0
Yellow powder, yield: 76%, mp 245–247ꢀC, IR (KBr)
(νmax/cm−1): 3,172, 2,915, 1,709, 1,608, 1,529, 1,447,
1,343, 1,239, 1,128, 869, 769. 1H NMR (500 MHz, DMSO-
d6): 7.51 (t, J = 7.5 Hz, 1H), 7.60–7.69 (m, 4H), 7.79 (d,
J = 7.5 Hz, 1H), 7.84 (t, J = 8 Hz, 1H), 8.21 (d, J = 7.5 Hz,
1H), 12.78 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ
123.0 (C–CO), 126.2 (CH), 127.2 (CH), 128.6 (C), 129.2

6
MOHAMMADI-KHANAPOSHTANI ET AL.
(CH), 130.0 (CH), 131.3 (2CH), 133.2 (CH), 134.9 (C–CO),
135.5 (CH), 147.1 (C–N), 148.3 (N–C–N), 161.1 (C=O),
188.8 (C=O). C15H9ClN2O2 (284.70): calcd. C 63.28, H
3.19, N 9.84; found C 63.41, H 3.35, N 10.07.
DMSO-d6): 7.59 (t, J = 7.5 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H),
7.73–7.79 (m, 2H), 7.88 (t, J = 7.5 Hz, 1H), 8.16 (t, J = 8 Hz,
2H), 8.22 (d, J = 8 Hz, 1H), 12.69 (s, NH). 13C NMR
(125 MHz, DMSO-d6): δ 122.8 (C–CO), 125.9 (CH), 126.0
(CH), 128.4 (CH), 131.5 (2CH), 132.6 (CH), 132.8 (2CH),
133.1 (CH), 134.7 (C–CO), 146.9 (C–N), 148.4 (N–C–N),
160.9 (C=O), 186.0 (C=O). MS (70 eV): m/z = 329 (M+).
C15H9BrN2O2 (329.15): calcd. C 54.74, H 2.76, N 8.51;
found C 54.86, H 2.68, N 8.34.
3.3.6 | 2-(4-chlorobenzoyl)quinazolin-4(3H)-
one (3f)
White powder, yield: 83%, mp 238–240ꢀC, IR (KBr)
(νmax/cm−1): 3,173, 3,095, 1,662, 1,586, 1,465, 1,336,
1
1,286, 1,148, 1,091, 898, 848, 772. H NMR (500 MHz,
3.3.10 | 2-(4-hydroxybenzoyl)quinazolin-4
(3H)-one (3j)
DMSO-d6): 7.60–7.66 (m, 3H), 7.91 (t, J = 7.5 Hz, 1H),
8.30 (t, J = 8 Hz, 2H), 8.43 (d, J = 8 Hz, 1H), 11.25 (s,
NH). C15H9ClN2O2 (284.70): calcd. C 63.28, H 3.19, N
9.84; found C 63.06, H 3.26, N 10.11.
Yellow powder, yield: 75%, mp 226–230ꢀC, IR (KBr)
(νmax/cm−1): 3,247, 1,683, 1,650, 1,604, 1,512, 1,462,
1
1,440, 1,300, 1,225, 1,163, 902, 768. H NMR (500 MHz,
DMSO-d6): 6.93 (d, J = 8.5 Hz, 2H), 7.62 (t, J = 7 Hz, 1H),
7.77 (d, J = 8 Hz, 1H), 7.86 (t, J = 7 Hz, 1H), 8.09 (d,
J = 7 Hz, 2H), 8.20 (d, J = 8 Hz, 1H), 12.61 (s, NH). 13C
NMR (125 MHz, DMSO-d6): δ 115.5 (2CH), 122.6 (C–CO),
125.2 (CH), 126.0 (CH), 128.2 (CH), 133.5 (CH), 133.8
(2CH), 134.7 (C–CO), 147.3 (C–N), 149.9 (N–C–N), 161.1
(C=O), 163.6 (C–OH), 185.1 (C=O). C15H10N2O3 (266.25):
calcd. C 67.67, H 3.79, N 10.52; found C 67.48, H 3.85,
N 10.73.
3.3.7 | 2-(2,5-dichlorobenzoyl)quinazolin-4
(3H)-one (3g)
White powder, yield: 84%, mp 243–245ꢀC, IR (KBr)
(νmax/cm−1): 3,175, 3,093, 1,661, 1,588, 1,467, 1,335, 1,287,
1,148, 1,090, 896, 848, 771. 1H NMR (500 MHz, DMSO-d6):
7.62–7.70 (m, 3H), 7.82–7.86 (m, 3H), 8.21 (d, J = 7.5 Hz,
1H), 12.90 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 123.1
(C–CO), 126.2 (CH), 127.4 (CH), 128.6 (C), 129.3 (CH),
129.5 (CH), 132.4 (CH), 132.7 (C), 134.3 (CH), 134.8 (C–
CO), 136.9 (CH), 146.9 (C–N), 147.9 (N–C–N), 161.0 (C=O),
187.7 (C=O). C15H8Cl2N2O2 (319.14): calcd. C 56.45, H 2.53,
N 8.78; found C 56.57, H 2.74, N 8.59.
3.3.11 | 2-(3-methoxybenzoyl)quinazolin-4
(3H)-one (3k)
Yellow powder, yield: 83%, mp 186–190ꢀC, IR (KBr)
(νmax/cm−1): 3,070, 2,965, 1,699, 1,674, 1,595, 1,486, 1,445,
1,332, 1,230, 1,158, 1,100, 900, 843, 771. 1H NMR (500 MHz,
DMSO-d6): 3.82 (s, OCH3), 7.30 (d, J = 7.5 Hz, 1H), 7.49 (t,
J = 8 Hz, 1H), 7.63 (t, J = 7 Hz, 1H), 7.70(s, 1H), 7.74 (d,
J = 7.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.86 (t, J = 7.5 Hz,
1H), 8.21 (d, J = 8 Hz, 1H), 12.67 (s, NH). 13C NMR
(125 MHz, DMSO-d6): δ 55.4 (OCH3), 114.9 (CH), 120.3
(CH), 122.9 (C–CO), 123.6 (CH), 126.0 (CH), 128.3 (CH),
128.6 (CH), 129.7 (CH), 134.8 (C–CO), 135.3 (CH), 147.1 (C–
N), 149.0 (N–C–N), 159.1 (C–OCH3), 161.1 (C=O), 186.7
(C=O). C16H12N2O3 (280.28): calcd. C 68.56, H 4.32, N 9.99;
found C 68.41, H 4.19, N 10.13.
3.3.8 | 2-(3-bromobenzoyl)quinazolin-4(3H)-
one (3h)
White powder, yield: 77%, mp 220–223ꢀC, IR (KBr)
(νmax/cm−1): 3,175, 3,091, 1,660, 1,582, 1,464, 1,438, 1,336,
1,283, 1,146, 1,010, 896, 771. 1H NMR (500 MHz, DMSO-d6):
7.55 (t, J = 7.5 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.79
(d, J = 8 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 7.94 (d, J = 8 Hz,
1H), 8.16 (d, J = 7.5 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.34
(s, 1H), 12.68 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ
121.5 (C–Br), 123.0 (C–CO), 126.0 (CH), 128.4 (CH), 128.8
(CH), 129.8 (CH), 130.7 (CH), 133.3 (CH), 134.8 (C–CO),
136.2 (CH), 136.5 (CH), 148.4 (C–N), 149.9 (N–C–N), 161.1
(C=O), 185.8 (C=O). C15H9BrN2O2 (329.15): calcd. C 54.74, H
2.76, N 8.51; found C 54.59, H 2.65, N 8.38.
3.3.12 | 2-(4-methoxybenzoyl)quinazolin-4
(3H)-one (3l)
Yellow powder, yield: 85%, mp 186–190ꢀC, IR (KBr)
(νmax/cm−1): 3,170, 3,061, 2,963, 2,840, 1,677, 1,601, 1,505,
1,445, 1,339, 1,241, 1,162, 1,028, 897, 778. 1H NMR
(500 MHz, DMSO-d6): 3.88 (s, 3H, OCH3), 7.11 (d, J = 8 Hz,
2H), 7.64 (t, J = 7.5 Hz, 1H), 7.77 (d, J = 8 Hz, 2H), 7.87
(t, J = 7.5 Hz, 1H), 8.07 (d, J = 8 Hz, 2H), 8.21 (d, J = 7.5 Hz,
3.3.9 | 2-(4-bromobenzoyl)quinazolin-4(3H)-
one (3i)
White powder, yield: 79%, mp 275–277ꢀC, IR (KBr)
(νmax/cm−1): 3,176, 3,091, 1,662, 1,580, 1,465, 1,438,
1
1,336, 1,284, 1,147, 1,011, 897, 770. H NMR (500 MHz,

MOHAMMADI-KHANAPOSHTANI ET AL.
7
1H), 12.62 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 21.4
(CH3), 122.8 (C–CO), 126.1 (CH), 128.3 (CH), 128.5 (CH),
129.2 (2CH), 131.0 (2CH), 131.5 (CH), 134.8 (C–CO), 145.2
(C–CH3), 147.2 (C–N), 149.3 (N–C–N), 161.1 (C=O), 186.7
(C=O).). C16H12N2O3 (280.28): calcd. C 68.56, H 4.32, N
9.99; found C 68.32, H 4.03, N 9.78.
15 min at 30ꢀC. The reaction was then initiated by adding
different concentrations of p-nitrophenyl glucopyranoside
(1–4 mM) as substrate, and change in absorbance was deter-
mined for 20 min at 405 nm by using the spectrophotometer
(Gen5, Power wave xs2, BioTek, America).
3.6 | Docking study
3.3.13 | 2-(2-nitrobenzoyl)quinazolin-4(3H)-
Docking studies were performed using Auto Dock Tools
(version 1.5.6) on the pdb structure of 3A4A that was taken
from the Brookhaven protein database (http://www.rcsb.
org). The 3D structures of the selected compounds 3c and
3d were created by MarvineSketch 5.8.3, 2012, ChemAxon
(http://www.chemaxon.com) and converted to pdbqt form
using Auto Dock Tools. Also, the pdbqt form of protein was
procured using the same software. Before preparation of
Auto Dock format of enzyme, the additional molecules
(water molecules and the inhibitors) were removed from
it. Then, polar hydrogen atoms were added, Koullman char-
ges were assigned, and the obtained protein was used as an
input file for the AUTOGRID program. In AUTOGRID for
each atom type in the ligand, maps were determined with
0.375 Å spacing between grid points, and the coordinates x,
y, and z for the center of grid box were 22.625, −8.069,
24.158, respectively. The dimensions of the grid box were
set at 50 × 50 × 50 Å. Flexible ligand dockings were
accomplished for the selected inhibitors. For each docked
system 50 runs of the AUTODOCK search by the Lamarck-
ian genetic algorithm was carried. The best pose of each
ligand was selected for analyzing the interactions between
α-glycosidase and the ligand and visualized using Discovery
Studio 4.0 Client.
one (3m)
Yellow powder, yield: 75%, mp 300ꢀC, IR (KBr) (νmax/cm−1):
3,172, 2,915, 1,709, 1,608, 1,529, 1,447, 1,343, 1,239, 1,128,
1
869, 769. H NMR (500 MHz, DMSO-d6): 7.51(d, J = 7 Hz,
2H), 7.63 (t, J = 7.5 Hz, 1H), 7.80–7.95 (m, 3H), 7.99
(t, J = 7.5 Hz, 1H), 8.18 (d, J = 7 Hz, 1H), 8.27 (d, J = 7.5 Hz,
2H), 13.00 (s, NH). 13C NMR (125 MHz, DMSO-d6): δ 123.0
(C–CO), 123.9 (CH), 126.3 (CH), 128.4 (CH), 129.3 (CH),
130.4 (CH), 132.3 (CH), 132.5 (CH), 135.0 (C–CO), 135.1
(CH), 146.7 (C–NO2), 147.5 (C–N), 147.9 (N–C–N), 160.0
(C=O), 187.2 (C=O). MS (70 eV): m/z = 295 (M+).
C15H9N3O4 (295.25): calcd. C 61.02, H 3.07, N 14.23; found
C 60.89, H 3.21, N 14.07.
3.3.14 | 2-(3-nitrobenzoyl)quinazolin-4(3H)-
one (3n)
Yellow powder, yield: 78%, mp 272–275ꢀC, IR (KBr)
(νmax/cm−1): 3,048, 2,923, 1,708, 1,681, 1,607, 1,530,
1,447, 1,352, 1,242, 1,129, 1,096, 918, 771. 1H NMR
(500 MHz, DMSO-d6): 7.67 (t, J = 7.5 Hz, 2H), 7.78 (d,
J = 7.5 Hz, 1H), 7.85–7.90 (m, 2H), 7.88 (t, J = 7.5 Hz,
1H), 8.22 (d, J = 7.5 Hz, 1H), 8.53 (d, J = 7.5 Hz, 1H), 8.58
(d, J = 7.5 Hz, 1H), 8.99 (s, 1H), 12.77 (s, NH). 13C NMR
(125 MHz, DMSO-d6): δ 122.1 (C–CO), 125.7 (CH), 125.8
(CH), 126.1 (CH), 128.5 (CH), 129.0 (CH), 130.1 (CH),
134.8 (CH), 135.6 (CH), 137.0 (C–CO), 146.9 (C–N), 147.4
(C–NO2), 148. 1 (N–C–N), 161.2 (C=O), 185.1 (C=O). MS
(70 eV): m/z = 295 (M+). C15H9N3O4 (295.25): calcd. C
61.02, H 3.07, N 14.23; found C 61.24, H 2.91, N 14.44.
4 | CONCLUSIONS
In conclusion, a series of benzoylquinazolinone derivatives
3a–n was introduced as α-glucosidase inhibitor. 4-fluoro
derivative 3d was the most active compound, being around
three times more potent than reference drug acarbose.
Kinetic study of compound 3d revealed that this compound
inhibited α-glucosidase in a competitive manner. Further-
more, a docking study showed that the most active com-
pound 3d interacted properly with important amino acids in
the active site of the enzyme. Due to the significant inhibi-
tory activity of the compound 3d against α-glucosidase,
in vivo evaluation of this compound on streptozotocin-
diabetic rats will be done in the future.
3.4 | α-Glucosidase inhibition assay
Determination of α-glucosidase inhibitory activity of synthe-
sized compounds 3a–n was performed exactly based on our
previous report [21].
3.5 | Kinetic study
Kinetic study was carried out to determine the inhibition
mode of the title compounds. Twenty microliters of enzyme
solution (1 U/ml) was incubated with concentrations 0, 170,
240, and 260 μM of the most potent compound 3d for
ORCID
Mohammad Mahdavi https://orcid.org/0000-0003-0256-
3352

8
MOHAMMADI-KHANAPOSHTANI ET AL.
[17] P. M. Bedi, V. Kumar, M. P. Mahajan, Bioorg. Med. Chem. Lett.
2004, 14, 5211.
[18] M. Wei, W. M. Chai, R. Wang, Q. Yang, Z. Deng, Y. Peng, Bio-
org. Med. Chem. Lett. 2017, 25, 1303.
[19] M. Mohammadi-Khanaposhtani, H. Yahyavi, E. Barzegaric,
S. Imanparast, M. M. Heravi, M. A. Faramarzi, A. Foroumadi,
H. Adibi, B. Larijani, M. Mahdavi, Polycycl. Aromat. Comp. 2018, 1.
(in press)
[20] M. Mohammadi-Khanaposhtani, S. Rezaei, R. Khalifeh,
S. Imanparast, M. A. Faramarzi, S. Bahadorikhalili, M. Safavi,
F. Bandarian, E. N. Esfahani, M. Mahdavi, B. Larijani, Bioorg.
Chem. 2018, 80, 288.
[21] M. Adib, F. Peytam, M. Rahmanian-Jazi, M. Mohammadi-
Khanaposhtani, S. Mahernia, H. R. Bijanzadeh, M. Jahani,
S. Imanparast, M. A. Faramarzi, M. Mahdavi, B. Larijani, New
J. Chem. 2018, 42, 17268.
[22] Y. P. Zhu, Z. Fei, M. C. Liu, F. C. Jia, A. X. Wu, Org. Lett. 2012,
15, 378.
[23] H. Sun, W. Ding, X. Song, D. Wang, M. Chen, K. Wang,
Y. Zhang, P. Yuan, Y. Ma, R. Wang, R. H. Dodd, Bioorg. Med.
Chem. Lett. 2017, 27, 3226.
REFERENCES
[1] K. Ogurtsova, J. D. da Rocha Fernandes, Y. Huang,
U. Linnenkamp, L. Guariguata, N. H. Cho, D. Cavan, J. E. Shaw,
L. E. Makaroff, Diabetes Res. Clin. Pract. 2017, 128, 40.
[2] S. H. Havale, M. Pal, Bioorg. Med. Chem. 2009, 17, 1783.
[3] R. Coniff, A. Krol, Clin. Ther. 1997, 19, 16.
[4] M. J. Humphries, K. Matsumoto, S. L. White, K. Olden, Cancer
Res. 1986, 46, 5215.
[5] H. Park, K. Y. Hwang, K. H. Oh, Y. H. Kim, J. Y. Lee, K. Kim,
Bioorg. Med. Chem. 2008, 16, 284.
[6] S. J. Storr, L. Royle, C. J. Chapman, U. M. A. Hamid,
J. F. Robertson, A. Murray, R. A. Dwek, P. M. Rudd, Gly-
cobiology 2008, 18, 456.
[7] O. U. R. Abid, M. Ayaz, W. Rehman, K. Mehdi, A. Ali, A. Wadood,
F. Rahim, A. Sultan, M. Ghufran, S. Mir, M. T. Qureshi, J. Chin.
Chem. Soc. 2016, 63, 1015.
[8] S. Hameed, F. Seraj, R. Rafique, S. Chigurupati, A. Wadood,
A. U. Rehman, V. Venugopal, U. Salar, M. Taha, K. M. Khan,
Eur. J. Med.Chem. 2019, 183, 111677.
[9] M. Taha, S. Sultan, S. Imran, F. Rahim, K. Zaman, A. Wadood,
A. U. Rehman, N. Uddin, K. M. Khan, Bioorg. Med. Chem. 2019,
27, 4081.
[10] G. Lavanya, K. Venkatapathy, C. J. Magesh, M. Ramanathan,
R. Jayasudha, Bioorg. Chem. 2019, 84, 125.
SUPPORTING INFORMATION
[11] K. M. Chang, L. C. Chen, C. C. Tzeng, Y. H. Lu, I. L. Chen,
S. H. Juang, T. C. Wang, J. Chin. Chem. Soc. 2018, 65,
1110.
Additional supporting information may be found online in
the Supporting Information section at the end of this article.
[12] H. Georgey, N. Abdel-Gawad, S. Abbas, Molecules 2008, 13, 2557.
[13] C. E. Brown, T. Kong, J. McNulty, L. D'Aiuto, K. Williamson,
L. McClain, P. Piazza, V. L. Nimgaonkar, Bioorg. Med. Chem.
Lett. 2017, 27, 4601.
[14] S. K. Kashaw, V. Kashaw, P. Mishra, N. K. Jain, Arkivoc 2008, 14, 17.
[15] V. Alagarsamy, V. Raja Solomon, R. V. Sheorey, R. Jayakumar,
Chem. Biol. Drug. Des. 2009, 73, 471.
How to cite this article: Mohammadi-
Khanaposhtani M, Yahyavi H, Imanparast S, et al.
Benzoylquinazolinone derivatives as new potential
antidiabetic agents: α-Glucosidase inhibition, kinetic,
and docking studies. J Chin Chem Soc. 2019;1–8.
https://doi.org/10.1002/jccs.201900268
[16] J. Zhang, J. Liu, Y. Ma, D. Ren, P. Cheng, J. Zhao, F. Zhang,
Y. Yao, Bioorg. Med. Chem. Lett. 2016, 26, 2273.