Dihydroquinazolin-4(1H)-one derivatives as novel and potential leads for diabetic management

Article abstract of DOI:10.1007/s11030-021-10196-5

A variety of dihydroquinazolin-4(1H)-one derivatives (1–37) were synthesized via “one-pot” three-component reaction scheme by treating aniline and different aromatic aldehydes with isatoic anhydride in the presence of acetic acid. Chemical structures of c

Full text of DOI:10.1007/s11030-021-10196-5

Molecular Diversity
https://doi.org/10.1007/s11030-021-10196-5
ORIGINAL ARTICLE
Dihydroquinazolin‑4(1H)‑one derivatives as novel and potential leads
for diabetic management
Oluwatoyin Babatunde1,8 · Shehryar Hameed1 · Uzma Salar2 · Sridevi Chigurupati3 · Abdul Wadood4 ·
Ashfaq Ur Rehman4 · Vijayan Venugopal5 · Khalid Mohammed Khan1,6 · Muhammad Taha6 · Shahnaz Perveen7
Received: 12 April 2020 / Accepted: 5 February 2021
© The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature 2021
Abstract
A variety of dihydroquinazolin-4(1H)-one derivatives (1–37) were synthesized via “one-pot” three-component reac-
tion scheme by treating aniline and diferent aromatic aldehydes with isatoic anhydride in the presence of acetic acid.
Chemical structures of compounds were deduced by diferent spectroscopic techniques including EI-MS, HREI-MS, 1H-,
and 13C-NMR. Compounds were subjected to α-amylase and α-glucosidase inhibitory activities. A number of deriva-
tives exhibited signifcant to moderate inhibition potential against α-amylase (IC50 =23.33 0.02—88.65 0.23 μM) and
α-glucosidase (IC50 = 25.01 0.12—89.99 0.09 μM) enzymes, respectively. Results were compared with the standard
acarbose (IC50 =17.08 0.07 μM for α-amylase and IC50 =17.67 0.09 μM for α-glucosidase). Structure–activity relation-
ship (SAR) was rationalized by analyzing the substituents efects on inhibitory potential. Kinetic studies were implemented
to fnd the mode of inhibition by compounds which revealed competitive inhibition for α-amylase and non-competitive
inhibition for α-glucosidase. However, in silico study identifed several important binding interactions of ligands (synthetic
analogues) with the active site of both enzymes.
Keywords Quinazolinone · Dual inhibitors · α-amylase · α-glucosidase · Acarbose · In silico · Kinetic studies ·
Hyperglycemia · Diabetes
Introduction
global health problem, characterized by hyperglycemia
which results from absolute or relative insulin defciency. It
arises when the body is unable to produce sufcient insulin
or cells do not react to the produced insulin for its own need
[1]. Prolonged exposure to elevated blood glucose level is
a foremost reason for renal failure, visual loss, and other
Diabetes mellitus (DM) is a chronic metabolic disorder
which afects the entire metabolism of the body and leads
to the disruption of carbohydrates, proteins, fats, electro-
lytes, and water. DM is the most common and fast-growing
5
* Khalid Mohammed Khan
Faculty of Pharmacy, AIMST University, 08100 Kedah,
khalid.khan@iccs.edu; drkhalidhej@gmail.com
Malaysia
6
Department of Clinical Pharmacy, Institute for Research
1
H. E. J. Research Institute of Chemistry, International Center
and Medical Consultations (IRMC), Imam Abdulrahman
Bin Faisal University, P.O. Box 1982, Dammam 31441,
Saudi Arabia
for Chemical and Biological Sciences, University of Karachi,
Karachi 75270, Pakistan
2
Dr. Panjwani Center for Molecular Medicine and Drug
7
PCSIR Laboratories Complex, Karachi,
Research, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi 75270, Pakistan
Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280,
Pakistan
3
Department of Medicinal Chemistry and Pharmacognosy,
8
Department of Chemical Sciences, Ajayi Crowther
College of Pharmacy, Qassim University, Buraidah 52571,
Saudi Arabia
University, Oyo P.M.B 1066, Nigeria
4
Department of Biochemistry, Computational Medicinal
Chemistry Laboratory, UCSS, Abdul Wali Khan University,
Mardan, Pakistan
Vol.:(0123456789)
1 3

Molecular Diversity
tissue damages. Therefore, a therapeutic approach is always
needed to treat diabetes to reduce the risk of postprandial
hyperglycemia [2]. Type 2 diabetes accounts for 85–90% of
all diabetic patients around the world, while type 1 diabetes
usually occurs in childhood or adolescence [3]. DM causes
signifcant damages, including nephropathy, neuropathy,
retinopathy, and increased risk of cardiovascular diseases
[4, 5]. However, excess thirst, hunger, fatigue, blurry visions,
frequent urination, and weight loss are the common symp-
toms experienced in diabetic patients [6].
quinazolines are classes of fused bicycle heterocyclic com-
pound earlier known as benzo-1,3-diazine [18, 19]. Several
quinazolines and quinazolinone-based molecules possess a
range of biological potentials such as antimicrobial, anti-
malarial, antifungal, antiviral, anti-infammatory, muscle
relaxant, antidepressant, anticancer, antiprotozoal, diuretic,
antitubercular, weedicide, acaricidal, anticonvulsant, and
several others [20–23] (Fig. 1).
Our research group is working on a variety of hetero-
cyclic organic molecules for two decades to discover new
inhibitors for α-amylase, α-glucosidase enzymes [24–31].
We have previously reported quinazoline derivatives as
potent inhibitors of the α-glucosidase enzyme [32].
Therefore, we decided to explore the diversely substituted
dihydroquinazolin-4(1H)-one derivatives for their dual
inhibitory potential against α-amylase and α-glucosidase
enzymes (Fig. 1). Herein, we report the synthesis of
2-aryl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one deriva-
tives (1–37) and their potential inhibitory activity against
α-amylase and α-glucosidase enzyme. To the best of our
knowledge, these compounds are never reported before
structurally as well as biologically.
α-Amylase (EC 3.2.1.1) and α-glucosidase (EC 3.2.1.20)
enzymes are responsible for hydrolyzing carbohydrate
(starches) into glucose monomers [7]. α-Amylase involves
in the breakdown of long-chain carbohydrates, whereas
α-glucosidase breaks down macromolecules such as oli-
gosaccharides, disaccharides, and trisaccharides to mono-
saccharides and other small molecules [8]. α-Amylase
and α-glucosidase enzymes are the potential targets for
the development of lead molecules to treat DM [7]. Since
most of the diabetic patients are treated with hypoglycemic
drugs such as sulfonylureas [9], metformin [10], acarbose
[11], miglitol [12], voglibose [13], biguanide [14], or insu-
lin, these drugs are relatively specifc to the targets but also
known to change some biochemical processes. Therefore,
these drugs lead to specifc adverse efects in the human
body such as abdominal discomfort, diarrhea, and fatulence
which results in discontinuation of therapy. Thus, there is
still a need to design and develop the antidiabetic medicines
to improve the efcacy and decreased the risk of diabetes
mellitus [15, 16].
Results and discussion
Chemistry
Various reports were available on the three-component
synthesis of dihydroquinazolin-4(1H)-one by using dif-
ferent reaction conditions and catalysts [33–37]. A range
of dihydroquinazolin-4(1H)-one derivatives 1–37 were
Heterocyclic scafolds are the core structural feature of
many pharmacological, agrochemical, and veterinary prod-
ucts [17]. Amongst them, 4(3H)-quinazolinones and related
Fig. 1 Some commercially available drugs based on quinazoline scafold as well currently identifed leads for diabetic management
1 3

Molecular Diversity
Scheme 1 Synthesis of
2,3-diphenyl-2,3-dihydroquina-
zolin-4(1H)-one derivative 1–37
prepared by treating isatoic anhydride, aniline, and sub-
stitute aldehyde in acetic acid. The reaction was heated at
80–90 °C for 3 h (Scheme 1). Thin-layer chromatography
(TLC; hexane/ethyl acetate (4:6)) was used to monitor the
reaction progress. Molecular structure of all compounds
1–37 was deduced by spectroscopic techniques including
EI-MS, HREI-MS, 1H, and 13C-NMR.
position in compound 1 brought out the slight decline in
the inhibitory potential showed by IC50 values 36.65 0.03
and 37.47 0.13 µM against α-amylase and α-glucosidase
enzymes. This comparison showed that the ortho position is
playing an imperative character in the inhibitory potential.
Another, ortho- and ortho-dichloro-substituted analog 3 with
IC50 values 27.94 0.02; 29.02 0.11 µM for α-amylase and
α-glucosidase, respectively, showed signifcant inhibitory
potential. Slightly less inhibitory potential of compound 3
than compound 4 might be due to the steric efect by sec-
ond ortho-substituted position. However, a combination of
chloro substituents with other groups such as OH and NO2 in
compounds 5, 6, and 7 demonstrated less inhibitory potential
against α-amylase and α-glucosidase enzymes. Compound
27 with para-bromo substitution displayed signifcant activ-
ity against both α-amylase and α-glucosidase enzymes with
IC50 values 27.7 0.06 and 29.97 0.19 µM, respectively,
which showed an active involvement of bromo group in the
inhibitory potential. However, trifuoro-methyl-substituted
compound 28 showed weak α-amylase and α-glucosidase
inhibitory activities with IC50 values 86.65 0.03 and
87.47 0.13 µM, respectively (Fig. 2).
In vitro α‑amylase and α‑glucosidase inhibitory
activities
All new dihydroquinazolin-4(1H)-one analogs 1–37 were
subjected for in vitro α-amylase and α-glucosidase inhibi-
tory activities. These compounds exhibited inhibitory
potential in the ranges of IC50 = 24.13—87.57 µM and
IC50 =25.01–89.99 µM against α-amylase and α-glucosidase
enzymes, respectively. Activity results were compared to the
standard acarbose (IC50 = 17.08 0.07 µM for α-amylase;
IC50 =17.67 0.09 µM for α-glucosidase) (Table 1).
Structure–activity relationship (SAR)
All synthetic compounds 1–37 have almost the same struc-
tural features except diferent aryl ring with varying sub-
stitutions pattern. These substitutions on aryl ring include
electron-withdrawing (EWG), electron-donating (EDG), and
combinations of both. All structural functionalities are tak-
ing part in the inhibition. However, limited structure–activ-
ity relationship (SAR) was rationalized by analyzing the
efect of diferent substitutions at ring “R” on α-amylase
and α-glucosidase inhibitory activities.
Compounds 8–16 bearing methoxy substitutions at dif-
ferent positions of aryl part (R) were found to have varying
degrees of inhibition. Amongst them, compound 9 having
ortho, ortho-dimethoxy substitutions were found signif-
cantly active with IC50s =24.13 0.08; 27.79 0.17 µM for
α-amylase and α-glucosidase enzymes. Surprisingly, its
positional isomer 8 having meta, meta-dimethoxy substitu-
tions was found to be completely inactive. However, com-
pounds 10, 11, and 12, with dimethoxy substitutions at dif-
ferent positions of aryl ring “R,” displayed weak inhibitory
potential against both enzymes.
Compounds 1–7, 27, and 28 were solely substituted with
halogens including Cl, Br, and F. These compounds dis-
played variable inhibition potential against α-amylase and
α-glucosidase enzymes. Amongst them, compound 4 with
ortho and para-dichloro substitutions was found to be the
most potent α-amylase and α-glucosidase inhibitor with IC50
values of 23.33 0.02, 25.01 0.12 µM, respectively. Inhibi-
tory activity comparison of compound 4 with compounds 2
and 1 revealed the efect of position on inhibitory potential.
For instance, lack of chloro at para position in compound 2
did not alter the inhibitory activity as revealed by the IC50
values 25.84 0.03 µM for α-amylase and 26.71 0.11 µM
for α-glucosidase enzymes. Similarly, lack of chloro at ortho
Compounds 15 and 16 bear methoxy and ethoxy substitu-
tions on aryl ring and showed interesting inhibitory poten-
tial. Compound 15 with meta-ethoxy and para-methoxy
substitutions showed signifcant inhibitory activities with
IC50s =28.01 0.07; 29.11 0.15 μM against α-amylase and
α-glucosidase enzymes, respectively. In contrast, compound
16 with reversal of positions of both substitutions showed a
sharp decline in the inhibitory potential as revealed by the
IC50 values 87.52 0.08 and 89.27 0.18 μM, respectively.
In addition to that, trimethoxy-substituted derivatives 13 and
15 were found to be inactive against both enzymes (Fig. 3).
1 3

Molecular Diversity
Table 1 In vitro α-amylase
and α-glucosidase
α
-Amylase inhibitory
activity
α
-Glucosidase inhibitory
activity
Compounds
R
inhibitory activities of new
dihydroquinazolin-4(1H)-ones
1–37
IC50 SEMa
IC50 SEMa
36.65 0.03
25.84 0.03
37.47 0.13
26.71 0.11
1
2
3
4
27.94 0.02
23.33 0.02
29.02 0.11
25.01 0.12
52.91 0.04
70.52 0.08
54.72 0.12
72.27 0.18
5
6
81.7 0.06
NAb
85.97 0.19
NAb
7
8
24.13 0.08
86.33 0.02
27.79 0.17
89.01 0.12
9
10
61.89 0.10
63.51 0.09
11
87.7 0.06
NAb
88.97 0.19
NAb
12
13
NAb
NAb
14
1 3

Molecular Diversity
Table 1 (continued)
α
-Amylase inhibitory
activity
α
-Glucosidase inhibitory
activity
Compounds
R
IC50 SEMa
IC50 SEMa
28.01 0.07
87.52 0.08
84.84 0.03
29.11 0.15
89.27 0.18
83.71 0.11
15
16
17
18
19
78.57 0.17
54.91 0.08
79.68 0.36
55.09 0.17
83.61 0.07
31.89 0.10
83.71 0.15
33.51 0.09
20
21
83.01 0.02
83.12 0.12
22
56.04 0.02
NAb
57.99 0.09
NAb
23
24
NAb
NAb
25
NAb
NAb
26
27
27.7 0.06
29.97 0.19
1 3

Molecular Diversity
Table 1 (continued)
α
-Amylase inhibitory
activity
α
-Glucosidase inhibitory
activity
Compounds
R
IC50 SEMa
IC50 SEMa
86.65 0.03
45.84 0.03
87.47 0.13
46.71 0.11
28
29
88.65 0.23
70.27 0.17
46.7 0.06
89.47 0.03
71.48 0.09
47.97 0.19
30
31
32
29.7 0.06
35.7 0.06
30.97 0.19
76.97 0.19
33
34
42.71 0.04
75.03 0.02
44.79 0.12
75.99 0.09
35
36
37
88.04 0.02
17.08 0.07
89.99 0.09
17.67 0.09
Standardc = Acarbose
aSEM standard error of mean, bNA not active; cStandard (Inhibitor for α-amylase and α-glucosidase
enzymes)
Compounds 17–23 and 31, having combinations of
methoxy/ethoxy with other substitutions such as OH, Cl,
F, and Br, showed moderate inhibitory potential. Amongst
them, compound 21 bearing ortho-fuoro and para-meth-
oxy substitutions were found to have relatively better activ-
ity as compared to other analogues of this group of com-
pounds. Compound 21 displayed IC50 values 31.89 0.10
and 33.51 0.09 µM against α-amylase and α-glucosidase
enzymes, respectively, while its positional isomer 19
showed low inhibitory potential with IC50s =54.91 0.08;
55.09 0.17 µM against α-amylase and α-glucosidase
enzymes, simply due to the change in positions of methoxy
and fuoro groups. Combinations of methoxy with Cl, Br,
and OH as in case of compounds 17, 18, 20, 22, and 31
showed moderate to weak inhibitory potential against both
enzymes. However, compound 23 having ortho-hydroxy and
meta-ethoxy substitutions also showed moderate inhibition
potential against both enzymes (Fig. 4).
Surprisingly, it was observed that benzyloxy-bearing ana-
logues 24–26 did not show α-amylase and α-glucosidase
inhibitory activities which gives a perception that being
bulky in nature benzyloxyl fails to ft into the active site
of the enzyme. Exceptionally, thiophene-substituted ana-
logue 29 showed moderate inhibition against α-amylase
and α-glucosidase with IC50 values 45.84 0.03 and
46.71 0.11 µM, respectively (Fig. 5).
1 3

Molecular Diversity
Fig. 2 Structure–activity relationship (SAR) of compounds 1–7, 27, 28; IC50 +SEM values for α-amylase and α-glucosidase are depicted in blue
and purple, respectively
Mono hydroxy-substituted compounds 32–34 having
hydroxy at the ortho, meta, and para positions showed good
to moderate α-amylase and α-glucosidase inhibitory activi-
ties. Amongst them, molecule 33 with an ortho-hydroxy
group showed better activity with IC50 value 29.7 0.06;
30.97 0.19 µM against α-amylase and α-glucosidase
enzymes. Di hydroxy-substituted compounds 35–37 also
showed moderate to weak inhibitory potential. Amongst
them, meta-, para-dihydroxy-substituted compound 35
showed moderate inhibition with IC50s = 42.71 0.04;
44.79 0.12 µM against α-amylase and α-glucosidase
enzymes. However, compounds 30 and 31 with a combi-
nation of hydroxy with bromo and methoxy, respectively,
showed weak inhibition potential against both enzymes
(Fig. 6).
was interpreted by using various kinetics plots such as
Lineweaver–Burk, Hill, Hanes–Woolf, Eadie–Hofs-
tee, Dixon, and Scatchard models. The kinetic param-
eters Vmax, Km, AICc, and R2 values were calculated
(Table 2). Based on curve fitting model (R2) and low
AICc value, all the selected compounds following com-
petitive type enzyme inhibitor mechanism (Figure S1, see
supplementary file).
Kinetic characterization of α‑glucosidase inhibition
Kinetic studies of selected active α-glucosidase inhibitors 2,
3, 4, 9, 15, 27, and 33 were analyzed to interpret the enzyme
inhibition mechanisms. Rate of the reaction was interpreted
by using various kinetics plots such as Lineweaver–Burk,
Hill, Hanes–Woolf, Eadie–Hofstee, Dixon, and Scatchard
models. The kinetic parameters Vmax, Km, AICc, and R2
values were calculated (Table 3). Based on curve ftting
model (R2) and low AICc value, all the selected compounds
following non-competitive type enzyme inhibitor mecha-
nism (Figure S2, see supplementary fle).
Kinetic characterization of α‑amylase inhibition
Kinetic studies of selected active α-amylase inhibitors
2, 3, 4, 9, 15, 27, and 33 were analyzed to interpret the
enzyme inhibition mechanisms. Rate of the reaction
1 3

Molecular Diversity
Fig. 3 Structure–activity relationship (SAR) of compounds 8–16; IC50 +SEM values for α-amylase and α-glucosidase are depicted in blue and
purple, respectively
Fig. 4 Structure–activity relationship (SAR) of compounds 17–23, and 31; IC50 +SEM values for α-amylase and α-glucosidase are depicted in
blue and purple, respectively
1 3

Molecular Diversity
Fig. 5 Structure–activity relationship (SAR) of compounds 24–26 and 29; IC50 +SEM values for α-amylase and α-glucosidase are depicted in
blue and purple, respectively
Fig. 6 Structure–activity relationship (SAR) of compounds 30–37; IC50 +SEM values for α-amylase and α-glucosidase are depicted in blue and
purple, respectively
Table 2 Kinetic studies of
active compounds for α-amylase
inhibition
Compounds
Vmax (µM/min)1
Km (mM)
AICc
R2
Type of inhibition
2
3
4
9
15
27
33
1252.2
1256.8
1625.4
1502.2
1240.2
1455.1
1412.5
0.5
0.6
0.6
0.6
0.5
0.6
0.6
194.2
181.8
133.5
205.1
189.2
150.1
182.2
0.912
0.941
0.989
0.941
0.915
0.902
0.922
Competitive type
Competitive type
Competitive type
Competitive type
Competitive type
Competitive type
Competitive type
1 3

Molecular Diversity
Table 3 Kinetic studies
of active compounds for
α-glucosidase inhibition
Compounds
Vmax (µM/min)1
Km (mM)
AICc
R2
Type of inhibition
2
3
4
9
15
27
33
1825.3
1289.6
1919.7
1506.2
1512.1
1562.4
1411.2
0.7
0.9
0.9
0.9
0.8
0.8
0.9
160.4
168.4
139.0
158.2
155.1
181.2
162.5
0.914
0.916
0.985
0.902
0.923
0.904
0.944
Non-competitive type
Non-competitive type
Non-competitive type
Non-competitive type
Non-competitive type
Non-competitive type
Non-competitive type
Fig. 7 a The PLI profle for synthesized compounds against the
α-amylase enzyme. a The surface representation of the active site of
the α-amylase enzyme (PDB ID 3BAJ), reddish color contour indi-
cates the active site pocket. b The binding mode of the most potent
compound 4. c The binding mode of compound 9; π-stacking is rep-
resented by a double-sided arrow
compound revealed numerous favorable interaction with cat-
alytic residues which had a vital role in enhancing the inhibi-
tory activity of the enzyme. Catalytic site residues include
the acidic amino acid with negatively charged side chain
Asp300 and Glu233, also, some other side chain acceptor
polar residues Tyr62 and His305, and the hydrophobic resi-
due Ile235 (Fig. 7b). Also, the high potency may be due to
the mechanism of the electron-withdrawing efect of chlo-
rine (Cl) from the benzene ring via inductive efect which
triggers the partial positive charge over benzene, and hence,
benzene adopted π-stacking interaction with the polar resi-
due His305 to stabilize in the reaction center. The electron
withdrawal by the -ortho and -para Cl from the benzene
ring further donated the electron to acceptor acidic residue
Asp300. Interesting, we have noticed that the bond among
the acidic residue Asp300 and the EWG-Cl also stabilized
by the hydrophobic residue Trp58. Also, the hydrophobic
residue Ile235 and polar residue Tyr62 adopted π-stacking
interaction with the 6-ring of the compound 4. In case of
second-ranked compound, 10 (IC50 = 24.13 0.08 μM) in
the series bearing the -ortho EDGs also showed favorable
interactions with the active site residues including the acidic
residue Asp300, the basic side chain donor residue Lys200,
the polar residue Tyr151 via π-stacking interaction and with
the hydrophobic residue Ile235 as shown in Fig. 7c. The high
potency of this compound compared with the highly potent
Ligand docking studies
α‑amylase inhibition
Small-molecule or ligand docking approach was applied
to explore the binding mode of the synthetic compounds
that showed α-amylase inhibitory activity. The structure
coordinated for the α-amylase enzyme was retrieved from
the RCSB database using PDB code 3BAJ. The active site
residues encompass Tyr62, Trp58, Lys200, Glu233, Ile235,
Asp300, His305 (Fig. 7a). Generally, it was noticed from
the docking results that all the compounds showed dif-
ferent binding modes; it might be due to the variation in
the substituted groups (from EWGs to EDGs vice versa)
attached at various positions (-ortho, -meta, and -para). In
this series, most of the compounds bearing electron-with-
drawing (EWGs) as compared to electron-donating groups
(EDGs). The instant variation in the position of these substi-
tuted groups ultimately alters the entire enzymatic activity at
a diferent level. The docking results revealed that all those
compounds bearing EWGs showed favorable interaction
with active site residues of the enzyme which witness the
high potency of the corresponding compound. In case of the
most potent compound, 4 in the series showed best inhibi-
tory activity (IC50 =23.33 0.02 μM) against the α-amylase
enzyme. The protein–ligand interaction (PLI) profle of this
1 3

Molecular Diversity
Fig. 8 The PLI profle for synthesized compounds against the
pound 4 in the series. c The binding mode of compound 2; double-
α-glucosidase enzyme.
a
The surface representation of the
sided arrow represents the π-stacking
α-glucosidase enzyme. b The binding mode of the most potent com-
compound 4 might be due to the occupation of the EDGs
over benzene ring which triggers partial positive charge at
benzene ring and hence compels the benzene ring to inter-
act via π-stacking with another molecule to gain stability
and thus enhance the enzymatic activity of the enzyme.
Overall, the correlation of docking and enzymatic results
delineates that the compounds bearing EWG over benzene
rings showed a well-ft pattern of binding, while others that
possess EDG also showed enough enzymatic activity against
the corresponding enzyme.
showed favorable interactions with the catalytic residues
including the acidic residue Glu276, the hydrophobic side
chain residues Phe300 and Phe157 (Fig. 8c).
Molecular dynamics simulation
It has been earlier described in the ligand docking part that
compound 4 showed the highest activity against both the
targets enzymes and showed a best fll-well pattern of bind-
ing in the active site. Furthermore, we performed molecu-
lar dynamics simulation for the evaluation of the docked
complex of compound 4 against both the targeted enzymes
using the molecular dynamic stability criteria using AMBER
v2018 software package. Similarly, the ligand or small-mol-
ecule docking simulation results revealed that compound 4
showed a very stable molecular dynamic behavior during
molecular dynamics time. The deviation of backbone atoms
was examined by the root-mean-square-deviation (RMSd) to
validate the stability of the complex.
α‑glucosidase inhibition
Ligand docking approach was applied to explore the binding
mode of the synthetic compounds that showed α-glucosidase
inhibitory activity at a diferent level. The described homol-
ogy model by Guerreiro et al. was used as a target model
for the ligand docking approach (Fig. 8a). Diferent binding
modes for all compounds were noted, which might be the
consequences of the variation in the attached groups at the
various position. The almost same pattern was observed that
compounds bearing electron-withdrawing groups (EWGs)
showed good inhibitory activity both in vitro and in silico,
while compounds bearing electron-donating groups (EDGs)
showed slight activity. Also, the variation in the position of
substituted groups alters the entire enzymatic activity at a
diferent level. The protein–ligand interaction (PLI) profle
of most potent compound 4 (IC50 =25.01 0.12 μM) is an
evidence of its best activity, adopted numerous favorable
interactions with catalytic residues including acidic residues
Asp68, Asp214 and Glu276 (Fig. 8b).
The results demonstrate that the RMSd curve for com-
pound 4, in the case of α-amylase, was initially in range of
around 1–2 Å; later, this deviation gradually increased till
2.4 Å and then oscillated around 2.45 Å during molecular
docking simulation time, while the compound 4 against the
α-glucosidase showed a high fuctuation initially till 50 ns;
afterward, this compound gained a stabilized pattern and
oscillated around 2 Å which indicated the similar dynamics
behavior of the compounds in the active site (Fig. 9a, b).
These RMSd results indicated that this potent compound
remained stable in the active site for longer, though ini-
tially, fuctuated, later on, it gained a stable behavior which
is indicative of their potency, which tightly bound in the
substrate site and this way enhanced the enzymatic activity,
respectively.
Interestingly, the polar uncharged residue Qln181 bridged
the acidic residue Asp68 with the EWGs of the compound.
Moreover, an additional hydrophobic interaction was
adopted by the compound with the Phe300 via π-stacking
interaction. The high potency might be due to the electron-
withdrawing efect on benzene by EWGs. Compound 2
(IC50 =26.71 0.11 μM) which also bears the -ortho EWGs
To understand the fluctuation of the individual
residues followed by compound 4 binding in the
active site of both the enzymes. We analyzed the
1 3

Molecular Diversity
Fig. 9 The post-dynamics
simulation result; a, b the
root-mean-square-deviation
(RMSd) of compound 4 against
both the targets; α-amylase and
α-glucosidase. c, d Repre-
sent the root-mean-square-
fuctuation (RMSf) graph for
compound 4 against both the
targets. The highlighted region
indicative of the binding site of
compound 4
root-mean-square-fuctuations (RMSf), which further pro-
vides the high or less fexibility of the protein structure
(Fig. 9c, d) [38–40]. The results revealed a similar observa-
tion, and in agreement with the interaction analysis, that
compound stabilized the active site and remain stable;
Compound 4 against both the enzymes showed local resi-
dues fuctuation, while the binding site of both the targets,
where compound 4 bonded, showed high fuctuation. The
residues numbering is according to the AMBER standard.
These results demonstrate the stabilized behavior as from
the dynamics behavior prospective, which is indicative of
their potency against both the targets.
α-glucosidase inhibitors for the development of insulin-
independent antidiabetic agents.
Future perspective
In the near future, we intended to use a range of substituted
aniline in combination to some selectively substituted alde-
hyde and isatoic anhydride to synthesize dihydroquinazo-
lin-4(1H)-one derivative and their evaluation for diferent
antidiabetic activities including α-amylase α-glucosidase
inhibitory as well as antiglycation activities.
Experimental
Conclusion
Materials and methods
Thirty-seven 2,3-diphenyl-2,3-dihydroquinazolin-4(1H)-one
derivatives (1–37) were frst time synthesized and evalu-
ated for their in vitro α-amylase and α-glucosidase inhibi-
tory activity. All analogs except few exhibited good to weak
inhibitory activity as compared to standard inhibitor acar-
bose against α-amylase and α-glucosidase enzymes. The
limited structure–activity relationship was established for
knowing the involvement of various groups in the inhibitory
potential. The kinetic studies were performed on some active
compounds to decipher the mode of inhibition. In silico
study has identifed several structural features that involves
binding interaction with the active site of both enzymes.
This study has identifed new lead candidates based on
quinazolinone scafold in search of potent α-amylase and
All reagents were purchased from Merck (Germany) and
Sigma-Aldrich (USA). Enzymes, α-amylase from Aspergil-
lus oryzae and α-glucosidase from Saccharomyces cerevi-
siae were obtained from Sigma-Aldrich Co. LLC (St. Louis,
MO). Thin-layer chromatography was carried out on pre-
coated silica gel, GF-254 (Merck, Germany). Spots were
visualized under ultraviolet light at 254, 366 nm or iodine
vapors. EI- and HREI-MS spectra were recorded on MAT
312 and MAT 113D mass spectrometers. The 1H-, 13C-NMR
were recorded on a Bruker AM spectrometers, operating at
300 and 400 MHz. The chemical shift values are presented
in ppm (δ), relative to tetramethylsilane (TMS) as an internal
standard, and the coupling constant (J) is in Hz.
1 3

Molecular Diversity
H-3′, H-5′), 7.28 (t, J3,2/3,4 = 8.0 Hz, 1H, H-3), 7.22 (d,
J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.21 (t, J4′,3′/4′,5′ =7.6 Hz,
1H, H-4′), 7.20 (d, J=2.0 Hz, CH), 7.14 (ovp, 1H, H-4"),
6.65 (d, J4,3 = 8.8 Hz, 1H, H-4), 6.61 (t, J2,1/2,3 = 7.6 Hz,
1H, H-2), 6.50 (d, J=2.4 Hz, 1H, NH); EI MS m/z (% rel.
abund.): 368 (M+, 21), 370 (M+2, 14), 372 (M+4, 3), 278
(62), 276 (98), 223 (100), 105 (37), 77 (35).
General procedure for the syntheses of new dihyd‑
roquinazolin‑4(1H)‑ones (1–37)
Isatoic anhydride, aniline, and substituted aldehyde
(0.5 mmol each) were mixed in acetic acid in a round-bot-
tomed fask (100 mL) and heated with continuous stirring
at 80–90 °C for 3 h. Reaction progression was examined by
thin-layer chromatography (TLC) in hexane: ethyl acetate
solvent system. On completion, reaction was cooled to room
temperature and added to an ice cold water to form precipi-
tate. Precipitates were fltered and washed with excess water
to remove water soluble impurities. Solid product was dried,
weighed, and crystallized from ethanol. Molecular structures
of all compounds 1–37 were identifed by EI-MS, HREI-MS,
1H-, and 13C-NMR.
2‑(2,4‑Dichlorophenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (4)
Solid; yield: 66; 1HNMR (400 MHz, DMSO-d6): δ
7.84 (dd, J1,2 = 7.6 Hz, J1,3 = 1.2 Hz, 1H, H-1), 7.65 (d,
J2",3" = 8.4 Hz, 1H, H-2"), 7.39 (d, J5",3" = 2 Hz, 1H,
H-5"), 7.32 (t, J3′,2′/3′,4′/5′,6′/5′,4′ = 7.6 Hz, 2H, H-3′, H-5′),
7.29 (t, J3,2/3,4 =8 Hz, 1H, H-3), 7.27 (s, 1H, CH), 7.26 (t,
J4′,3′/4′,5′ = 7.6 Hz, 1H, H-4′), 7.23 (d, J3",5" = 8.4 Hz, 1H,
H-3"), 7.19 (d, J2′,3′/6′,5′ = 7.6 Hz, 2H, H-2′, H-6′), 6.81 (t,
J2,1/2,3 = 7.6 Hz, 1H, H-2), 6.72 (d, J4,3 = 8 Hz, 1H, H-4),
6.62 (s, 1H, NH); EI MS m/z (% rel. abund.): 368 (M+, 21),
370 (M+2, 10), 372 (M+4, 3) 276 (100), 248 (6), 223 (73),
186 (11).
2‑(4‑Chlorophenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (1)
1
Solid; yield: 77%; HNMR (400 MHz, DMSO-d6): δ
7.71 (d, J1,2 = 7.6 Hz, 1H, H-1), 7.63 (d, J= 2.4 Hz, CH),
7.39 (d, J2",3"/6",5" = 8.7 Hz, 2H, H-2", H-6"), 7.34 (d,
J3"2"/5",6" =8.4 Hz, 2H, H-3", H-5"), 7.32 (t, J3′,2′/3′,4′/5′,4′/5′,6′
= 7.6 Hz, 2H, H-3′, H-5′), 7.29 (t, J3,2/3,4 = 8.0 Hz, 1H,
H-3), 7.25 (d, J2′,3′/6′,5′ = 7.6 Hz, 2H, H-2′, H-6′), 7.16 (t,
J4′,5′/4′,3′ =7.6 Hz, 1H, H-4′), 6.76 (d, J4,3 =8.4 Hz, 1H, H-4),
6.72 (t, J2,1/2,3 =7.6 Hz, 1H, H-2), 6.31 (d, J=2.4 Hz, 1H,
NH); EI MS m/z (% rel. abund.): 334 (M+, 50), 336 (M+2,
17) 331 (21), 242 (100), 152 (19), 77 (20).
2‑(3,5‑Dichloro‑2‑hydroxyphenyl)‑3‑phenyl‑2,3‑dihydro‑
quinazolin‑4(1H)‑one (5)
1
Solid; yield: 71%; HNMR (300 MHz, DMSO-d6): δ
10.12 (s, 1H, OH), 7.75 (d, J1,2 = 7.6 Hz, 1H, H-1), 7.45
(d, J4″,6″ =2.4 Hz, 1H, H-4″), 7.33 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =8 H
z, 2H, H-3′, H-5′), 7.28 (t, J3,2/3,4 =8 Hz, 1H, H-3), 7.26 (s,
1H, CH), 7.22 (d, J2′,3′/6′,5′ = 7.6 Hz, 2H, H-2′, H-6′), 7.20
(t, J4′,3′/4′,5′ =7.2 Hz, 1H, H-4′), 7.16 (d, J6″,4″ =2.4 Hz, 1H,
H-6″), 6.79 (d, J4,3 =8 Hz, 1H, H-4), 6.75 (t, J2,1/2,3 =7.2 Hz,
1H, H-2), 6.50 (s, 1H, NH); EI MS m/z (% rel. abund.): 384
(M+, 78), 386 (M +2, 45), 388 (M +4, 17), 292 (89), 263
(45), 223 (100), 120 (37).
2‑(2‑Chlorophenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (2)
Solid; yield: 68%; 1HNMR (400 MHz, DMSO-d6): δ 7.75
(d, J1,2 = 7.6 Hz, 1H, H-1), 7.58 (t, J4",5"/4",3" = 8 Hz, 1H,
H-4"), 7.45 (d, J=2 Hz, 1H, CH), 7.38 (t, J5",4"/5",6" =8 Hz,
1H, H-5"), 7.30 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =8 Hz, 2H, H-3′, H-5′),
7.28 (t, J3,2/3,4 = 8 Hz, 1H, H-3), 7.27 (ovp, 2H, H-3",
H-6"), 7.20 (d, J2′,3′/6′,5′ = 7.6 Hz, 2H, H-2′, H-6′), 7.16 (t,
J4′,3′/4′,5′ =7.2 Hz, 1H, H-4′), 6.76 (d, J4,3 =8 Hz, 1H, H-4),
6.73 (t, J2,1/2,3 = 7.2 Hz, 1H, H-2), 6.58 (d, J = 2 Hz, 1H,
NH); EI MS m/z (% rel. abund.): 334 (M+, 20), 336 (M+2,
7), 242 (100), 223 (97), 214 (7), 152 (11).
2‑(2‑Chloro‑5‑nitrophenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (6)
Solid; yield: 79%; 1H-NMR (400 MHz, CDCl3-d1): δ 8.44
(d, J6",4" = 2.4 Hz, 1H, H-6"), 8.09 (dd, J4",3" = 8.8 Hz,
J4",6" = 2.4 Hz, 1H, H-4"), 8.07 (dd, J1,2 = 7.2 Hz,
J1,3 =2.0 Hz, 1H, H-1), 7.53 (d, J3",4" =8.8 Hz, 1H, H-3"),
7.35 (t, J3′,2′/3′,4′/5′,4′/5′,6′ = 7.6 Hz, 2H, H-3′, H-5′), 7.31 (t,
J3,2/3,4 = 8.0 Hz, 1H, H-3), 7.29 (d, J2′,3′/6′,5′ = 7.6 Hz, 2H,
H-2′, H-6′), 7.22 (d, J4′,5′/4′,3′ = 7.2 Hz, 1H, H-4′), 6.93 (t,
J2,1/2,3 =7.6 Hz, 1H, H-2), 6.59 (d, J4,3 =8.0 Hz, 1H, H-4),
6.53 (s, 1H, CH), 5.11 (s, 1H, NH); EI-MS m/z (% rel.
abund.): 379 (M+, 17), 381(M+2, 6), 287 (88), 241 (20),
223 (100), 178 (11), 77 (26).
2‑(2,6‑Dichlorophenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (3)
Solid; yield: 76%; 1H-NMR (400 MHz, DMSO-d6): δ 7.66
(d, J1,2 = 7.6 Hz, 1H, H-1), 7.39 (d, J3",4"/5",4" = 7.2 Hz,
2H, H-3", H-5"), 7.33 (t, J3′,2′/3′,4′/5′,4′/5′,6′ = 7.6 Hz, 2H,
1 3

Molecular Diversity
2‑(5‑Chloro‑2‑hydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquina‑
zolin‑4(1H)‑one (7)
2‑(2‑Bromo‑4,5‑dimethoxyphenyl)‑3‑phenyl‑2,3‑dihyd‑
roquinazolin‑4(1H)‑one (11) Solid; yield: 78%; 1HNMR
(400 MHz, DMSO-d6): δ 7.74 (d, J1,2 =7.6 Hz, 1H, H-1),
7.33 (s, 1H, H-3"), 7.29 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz, 2H,
H-3′, H-5′), 7.24 (t, J3,2/3,4 =7.6 Hz, 1H, H-3), 7.18 (d,
J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.15 (s, 1H, CH), 7.13
(t, J4′,3′/4′,5′ =7.6 Hz, 1H, H-4′), 6.98 (s, 1H, H-6"), 6.79 (d,
J4,3 =8 Hz, 1H, H-4), 6.75 (t, J2,1/2,3 =8.4 Hz, 1H, H-2),
6.52 (d, J=1.6 Hz, 1H, NH), 3.69 (s, 3H, CH3), 3.59 (s,
3H, CH3); 13C NMR (75 MHz, DMSO-d6): δ 162.7, 149.7,
148.0, 146.9, 139.9, 133.8, 129.7, 128.5, 127.8, 127.6,
126.7, 117.7, 115.0, 114.8, 114.7, 112.5, 111.6, 72.7; EI
MS m/z (% rel. abund.): 438 (M+, 40), 440 (M+2, 26),
348 (93), 320 (6), 223 (100), 216 (17); HREI-MS Calcd for
C22H19N2O3Br: m/z=438.0579, found; 438.0556.
1
Solid; yield: 85%; HNMR (400 MHz, DMSO-d6): δ
10.27 (s, 1H, OH), 7.75 (d, J1,2 = 7.6 Hz, 1H, H-1), 7.35
(t, J3′,2′/3′,4′/5′,6′/5′,4′ = 7.6 Hz, 2H, H-3′, H-5′), 7.28 (t,
J3,2/3,4 = 7.6 Hz, 1H, H-3), 7.25 (d, J6",4" = 2.4 Hz, 1H,
H-6"), 7.23 (d, J2′,3′/6′,5′ = 8 Hz, 2H, H-2′, H-6′), 7.15 (t,
J4′,3′/4′,5′ = 8 Hz, 1H, H-4′), 7.13 (s, 1H, CH), 7.12 (d,
J4",3" =8.4 Hz, 1H, H-4"), 6.81 (d, J3″,4″ =8.4 Hz, 1H, H-3"),
6.77 (d, J4,3 =8 Hz, 1H, H-4), 6.72 (t, J2,1/2,3 =7.2 Hz, 1H,
H-2), 6.36 (s, 1H, NH); EI MS m/z (% rel. abund.): 350 (M+,
100), 352 (M+2, 46), 258 (86), 229 (69), 223 (88), 214 (52).
2‑(3,5‑Dimethoxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (8)
2‑(2,4‑Dimethoxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (12) Solid; yield: 71%; HNMR (400 MHz,
1
1
Solid; yield: 63%; HNMR (400 MHz, DMSO-d6): δ
7.70 (d, J1,2 =7.6 Hz, 1H, H-1), 7.60 (s, 1H, CH), 7.34 (t,
J3′,2′/3′,4′/5′,6′/5′,4′ =8 Hz, 2H, H-3′, H-5′), 7.28 (t, J3,2/3,4 =8 Hz,
1H, H-3), 7.24 (d, J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.19 (t,
J4′,3′/4′,5′ =7.2 Hz, 1H, H-4′), 6.75 (d, J4,3 =8 Hz, 1H, H-4),
6.68 (t, J2,1/2,3 =7.2 Hz, 1H, H-2), 6.50 (d, J6″,4″/2″,4″ =2.4 Hz,
2H, H-6″, H-2″), 6.38 (s, 1H, NH), 6.17 (d, J4″,6″ =2.4 Hz,
1H, H-4″), 3.64 (s, 6H, CH3); EI MS m/z (% rel. abund.): 360
(M+, 29), 268 (100), 223 (80), 196 (3), 130 (8).
DMSO-d6): δ 7.72 (d, J1,2 =7.6 Hz, 1H, H-1), 7.31
(t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz, 2H, H-3′, H-5′), 7.28 (t,
J3,2/3,4 =7.6 Hz, 1H, H-3), 7.23 (d, J2′,3′/6′,5′ =7.6 Hz, 2H,
H-2′, H-6′), 7.21 (d, J6″,5″ =8.4 Hz, 1H, H-6"), 7.15 (t,
J4′,3′/4′,5′ =7.6 Hz, 1H, H-4′), 7.09 (d, J=2 Hz, 1H, CH), 6.75
(d, J4,3 =8 Hz, 1H, H-4), 6.69 (t, J2,1/2,3 =7.6 Hz, 1H, H-2),
6.50 (d, J3″,5″ =2 Hz, 1H, H-3"), 6.41 (dd, J5″,6″ =8.4 Hz,
J5″,3″ =2.4 Hz, 1H, H-5"), 6.30 (d, J=2.4 Hz, 1H, NH), 3.72
(s, 3H, CH3), 3.68 (s, 3H, CH3); EI MS m/z (% rel. abund.):
360 (M+, 76), 327 (4), 268 (100), 240 (5), 223 (30), 149
(60).
2‑(2,6‑Dimethoxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (9)
Solid; yield: 72%; 1HNMR (400 MHz, DMSO-d6): δ 7.75
(d, J1,2 = 7.6 Hz, 1H, H-1), 7.23 (t, J3′,2′/3′,4′/5′,6′/5′,4′ = 8 Hz,
2H, H-3′, H-5′), 7.19 (t, J3,2/3,4 = 8 Hz, 1H, H-3), 7.15 (d,
J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.11 (t, J4′,3′/4′,5′ =7.2 Hz,
1H, H-4′), 7.05 (ovp, 1H, H-4″), 6.93 (s, 1H, CH), 6.81 (d,
J=2 Hz, 1H, NH), 6.62 (t, J2,1/2,3 =7.2 Hz, 1H, H-2), 6.58
(d, J4,3 = 8 Hz, 1H, H-4), 6.52 (t, J3″,4″/5″,4″ = 8.4 Hz, 2H,
H-3″, H-5″), 3.50 (s, 6H, CH3); EI MS m/z (% rel. abund.):
360 (M+, 75), 268 (100), 223 (63), 196 (12), 149 (44), 120
(36).
3‑Phenyl‑2‑(3,4,5‑trimethoxyphenyl)‑2,3‑dihydro‑
quinazolin‑4(1H)‑one (13) Solid; yield: 74%; 1H-NMR
(400 MHz, DMSO-d6): δ 7.73 (d, J1,2 =7.6 Hz, 1H, H-1),
7.30 (t, J3′,2′/3′,4′/5′,4′/5′,6′ =7.2 Hz, 2H, H-3′, H-5′), 7.25 (t,
J3,2/3,4 =8.4Hz, 1H, H-3), 7.20(d, J2′,3′/6′,5′ =7.6Hz, 2H, H-2′,
H-6′), 7.18 (s, 2H, H-2", H-6"), 7.03 (d, J4′,5′/4′,3′ =8.8 Hz,
1H, H-4′), 6.75 (d, J4,3 =8.0 Hz, 1H, H-4), 6.71 (s, 1H, CH),
6.69 (t, J2,1/2,3 =8.4 Hz, 1H, H-2), 6.33 (d, J=2.8 Hz, 1H,
H-NH), 3.71 (s, 3H, 3"-OCH3), 3.67 (s, 3H, 5"-OCH3), 3.63
(s, 3H, 4"-OCH3); EI-MS m/z (% rel. abund.): 390 (M+, 25),
388 (17), 298 (100), 223 (32), 195 (25), 178 (30), 132 (18).
2‑(3,4‑Dimethoxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
lin‑4(1H)‑one (10) Solid; yield: 60%; HNMR (400 MHz,
3‑Phenyl‑2‑(2,3,4‑trimethoxyphenyl)‑2,3‑dihydroquinazo‑
1
DMSO-d6): δ 7.69 (d, J1,2 =7.6 Hz, 1H, H-1), 7.52 (s, 1H,
CH), 7.32 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz, 2H, H-3′, H-5′), 7.29
(t, J3,2/3,4 =8 Hz, 1H, H-3), 7.24 (d, J2′,3′/6′,5′ =7.6 Hz, 2H,
H-2′, H-6′), 7.17 (t, J4′,3′/4′,5′ =7.2 Hz, 1H, H-4′), 6.99 (d,
J6″,5″ =8.4 Hz, 1H, H-6"), 6.82 (d, J5″,6″ =8.4 Hz, 1H, H-5"),
6.79 (s, 1H, H-2"), 6.74 (d, J4,3 =8 Hz, 1H, H-4), 6.70 (t,
J2,1/2,3 =7.2 Hz, 1H, H-2), 6.19 (s, 1H, NH), 3.66 (s, 3H,
CH3), 3.64 (s, 3H, CH3); EI MS m/z (% rel. abund.): 360
(M+, 75), 283 (9), 268 (100), 240 (11), 223 (64), 130 (22).
lin‑4(1H)‑one (14) Solid; yield: 67%; H-NMR (400 MHz,
DMSO-d6): δ 7.75 (d, J1,2 =7.6 Hz, 1H, H-1), 7.31 (t,
J3′,2′/3′,4′/5′,6′/5′,4′ =8 Hz, 2H, H-3′, H-5′), 7.27 (t, J3,2/3,4 =8 Hz,
1H, H-3), 7.23 (d, J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.20 (d,
J6″,5″ =8 Hz, 1H, H-6″), 7.16 (t, J4′,3′/4′,5′ =7.2 Hz, 1H, H-4′),
7.03 (d, J5″,6″ =8 Hz, 1H, H-5″), 6.76 (d, J4,3 =8 Hz, 1H,
H-4), 6.71 (d, J=2 Hz, 1H, CH), 6.68 (t, J2,1/2,3 =7.2 Hz,
1H, H-2), 6.32 (d, J=2 Hz, 1H, NH), 3.71 (s, 3H, 4″-OCH3),
3.67 (s, 3H, 3″-OCH3), 3.63 (s, 3H, 2″-OCH3); EI MS m/z
1 3

Molecular Diversity
(% rel. abund.): 390 (M+, 57), 298 (100), 223 (45), 179 (97),
168 (16), 151 (15).
2‑(4‑Fluoro‑3‑methoxyphenyl)‑3‑phenyl‑2,3‑dihyd‑
roquinazolin‑4(1H)‑one (19) Solid; yield: 80%; 1H-
NMR (400 MHz, DMSO-d6): δ 7.72 (d, J1,2 = 7.6 Hz,
1H, H-1), 7.57 (s, 1H, H-2"), 7.32 (t, J3′,2′/3′,4′/5′,4′/5′,6′
= 7.6 Hz, 2H, H-3′, H-5′), 7.28 (t, J3,2/3,4 = 8.0 Hz,
1H, H-3), 7.24 (d, J2′,3′/6′,5′ = 7.6 Hz, 2H, H-2′, H-6′),
7.18 (d, J6″,5″/5″,6″ = 7.6 Hz, 2H, H-5", H-6"), 7.18 (t,
J4′,5′/4′,3′ = 7.6 Hz, 1H, H-4′), 6.89 (d, J = 2.0 Hz, 1H, CH),
6.77 (d, J4,3 = 8.4 Hz, 1H, H-4), 6.72 (t, J2,1/2,3 = 7.6 Hz,
1H, H-2), 6.27 (d, J = 1.6 Hz, 1H, NH), 3.73 (s, 3H,
O-CH3); EI-MS m/z (% rel. abund.): 348 (M+, 86), 345
(36), 257 (67), 256 (100), 223 (100), 130 (17), 77 (23).
2‑(3‑Ethoxy‑4‑methoxyphenyl)‑3‑phenyl‑2,3‑dihydro‑
quinazolin‑4(1H)‑one (15) Solid; yield: 78%; 1H-NMR
(400 MHz, DMSO-d6): δ 7.70 (d, J1,2 =7.6 Hz, 1H, H-1),
7.52 (d, J=2.0 Hz, CH), 7.33 (t, J3′,2′/3′,4′/5′,4′/5′,6′ =7.2 Hz,
2H, H-3′, H-5′), 7.29 (t, J3,2/3,4 =8.0 Hz, 1H, H-3), 7.25 (d,
J2′,3′/6′,5′ =7.2 Hz, 2H, H-2′, H-6′), 7.03 (t, J4′,5′/4′,3′ =7.2 Hz,
1H, H-4′), 6.97 (s, 1H, H-6"), 6.82 (s, 2H, H-2", H-5"),
6.74 (d, J4,3 =8.0 Hz, 1H, H-4), 6.70 (t, J2,1/2,3 =7.6 Hz, 1H,
H-2), 6.18 (d, J=2.4 Hz, 1H, NH), 3.86 (q, J=7.2 Hz, 2H,
O-CH2), 3.66 (s, 3H, O-CH3), 1.24 (t, J=7.2 Hz, 3H, CH3);
EI-MS m/z (% rel. abund.): 374 (M+, 27), 372 (50), 343
(21), 282 (100), 223 (27), 119 (57).
2‑(5‑Bromo‑2‑methoxyphenyl)‑3‑phenyl‑2,3‑dihyd‑
roquinazolin‑4(1H)‑one (20) Solid; yield: 69%; 1H-
NMR (400 MHz, CDCl3-d1): δ 8.01 (dd, J1,2 =8.0 Hz,
J1,3 =1.2 Hz, 1H, H-1), 7.50 (d, J6″,4″ =2.0 Hz, 1H, H-6"),
7.34 (d, J4″,6″ =2.4 Hz, 1H, H-4"), 7.32 (t, J3′,2′/3′,4′/5′,4′/5′,6′
=7.4 Hz, 2H, H-3′, H-5′), 7.22 (d, J2′,3′/6′,5′ =7.2 Hz, 2H,
H-2′, H-6′), 7.20 (t, J4′,5′/4′,3′ =7.2 Hz, 1H, H-4′), 7.19 (t,
J3,2/3,4 =8.0 Hz, 1H, H-3), 6.85 (t, J2,1/2,3 =7.6 Hz, 1H, H-2),
6.75 (d, J3″,4″ =8.8 Hz, 1H, H-3"), 6.53 (d, J4,3 =8.0 Hz, 1H,
H-4), 6.29 (s, 1H, CH), 3.90 (s, 3H, O-CH3); EI-MS m/z (%
rel. abund.): 408 (M+, 34), 410 (M+2, 29), 316 (93), 223
(100), 120 (18).
2‑(4‑Ethoxy‑3‑methoxyphenyl)‑3‑phenyl‑2,3‑dihydro‑
quinazolin‑4(1H)‑one (16) Solid; yield: 73%; 1H-NMR
(400 MHz, DMSO-d6): δ 7.71 (d, J1,2 = 7.6 Hz, 1H, H-1),
7.52 (d, J = 1.6 Hz, 1H, CH), 7.33 (t, J3′,2′/3′,4′/5′,6′/5′,4′
= 7.6 Hz, 2H, H-3′, H-5′), 7.29 (t, J3,2/3,4 = 8.0 Hz, 1H,
H-3), 7.25 (d, J2′,3′/6′,5′ = 7.6 Hz, 2H, H-2′, H-6′), 7.18 (t,
J4′,5′/4′,3′ = 7.2 Hz, 1H, H-4′), 6.98 (s, 1H, H-6"), 6.80 (s,
2H, H-2", H-5"), 6.76 (d, J4,3 = 8.0 Hz, 1H, H-4), 6.70 (t,
J2,1/2,3 = 7.2 Hz, 1H, H-2), 6.18 (d, J = 2.4 Hz, 1H, NH),
3.93 (q, J = 6.8 Hz, 2H, CH2), 3.64 (s, 3H, O-CH3), 1.25
(t, J = 6.8 Hz, 3H, CH3); EI MS m/z (% rel. abund.): 374
(M+, 54), 282 (100), 254 (18), 223 (49), 130 (17), 77 (14).
2‑(2‑Fluoro‑4‑methoxyphenyl)‑3‑phenyl‑2,3‑dihydroquina‑
zolin‑4(1H)‑one (21) Solid; yield: 61%; 1H-NMR (400 MHz,
CDCl3-d1): δ 8.01 (dd, J1,2 =7.6 Hz, J1,3 =1.2 Hz, 1H,
H-1), 7.37 (s, 1H, H-3"), 7.35 (t, J3′,2′/3′,4′/5′,4′/5′,6′ =7.2 Hz,
2H, H-3′, H-5′), 7.30 (t, J3,2/3,4 =8.0 Hz, 1H, H-3), 7.23 (d,
J2′,3′/6′,5′ =7.2 Hz, 2H, H-2′, H-6′), 7.18 (t, J4′,5′/4′,3′ =7.2 Hz,
1H, H-4′), 6.85 (t, J2,1/2,3 =7.6 Hz, 1H, H-2), 6.60 (d,
J4,3 =8.4 Hz, 1H, H-4), 6.55 (d, J6″,5″/5″,6″ =8.4 Hz, 2H,
H-5", H-6"), 6.35 (s, 1H, CH), 3.86 (s, 3H, O-CH3); EI-MS
m/z (% rel. abund.): 348 (M+, 65), 256 (100), 223 (31), 130
(14), 105 (12), 77 (20).
2‑(4‑Hydroxy‑3,5‑dimethoxyphenyl)‑3‑phenyl‑2,3‑di‑
hydroquinazolin‑4(1H)‑one (17) Solid; yield: 77%;
1HNMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H, OH),
7.71 (d, J1,2 = 7.6 Hz, 1H, H-1), 7.45 (s, 1H, CH), 7.32
(t, J3′,2′/3′,4′/5′,6′/5′,4′ = 7.6 Hz, 2H, H-3′, H-5′), 7.28 (t,
J3,2/3,4 = 7.6 Hz, 1H, H-3), 7.23 (d, J2′,3′/6′,5′ = 7.6 Hz, 2H,
H-2′, H-6′), 7.15 (t, J4′,3′/4′,5′ = 7.6 Hz, 1H, H-4′), 6.77 (d,
J4,3 = 7.6 Hz, 1H, H-4), 6.71 (t, J2,1/2,3 = 8 Hz, 1H, H-2),
6.61 (s, 2H, H-2", H-6"), 6.15 (s, 1H, NH), 3.61 (s, 6H,
CH3); EI MS m/z (% rel. abund.): 376 (M+, 77), 284 (100),
268 (6), 240 (7), 223 (81), 130 (32).
2‑(2‑Chloro‑3‑methoxyphenyl)‑3‑phenyl‑2,3‑dihydro‑
quinazolin‑4(1H)‑one (22) Solid; yield: 70%; 1H-NMR
(400 MHz, DMSO-d6): δ 7.76 (d, J1,2 =8.0 Hz, 1H, H-1),
7.43 (d, J=2.4 Hz, 1H, CH), 7.32 (d, J4″,5″ =8.0 Hz,
1H, H-4"), 7.30 (t, J5″,6″/5″,4″ =7.6 Hz, 1H, H-5"), 7.26
(t, J3′,2′/3′,4′/5′,4′/5′,6′ =7.6 Hz, 2H, H-3′, H-5′), 7.21 (d,
J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.19 (t, J3,2/3,4 =8.0 Hz,
1H, H-3), 7.13 (d, J6″,5″ =7.6 Hz, 1H, H-6"), 7.07 (d,
J4′,5′/4′,3′ =7.6 Hz, 1H, H-4′), 6.76 (d, J4,3 =8.0 Hz, 1H, H-4),
6.73 (t, J2,1/2,3 =7.6 Hz, 1H, H-2), 6.57 (d, J=2.8 Hz, NH),
3.80 (s, 3H, O-CH3); 13C-NMR (75 MHz, DMSO-d6): δ
162.1, 154.8, 145.9, 140.3, 138.5, 133.8, 128.7, 127.8, 127.7,
126.5, 119.3, 119.2, 117.6, 114.9, 114.6, 112.6, 70.1, 56.2;
EI-MS m/z (% rel. abund.): 364 (M+, 54), 366 (M+2, 17),
2‑(4‑Bromo‑3,5‑dimethoxyphenyl)‑3‑phenyl‑2,3‑dihyd‑
1
roquinazolin‑4(1H)‑one (18) Solid; yield: 76%; H-NMR
(400 MHz, DMSO-d6): δ 7.73 (d, J1, 2 = 7.6 Hz, 1H,
H-1), 7.57 (d, J = 2.0 Hz, CH), 7.35 (t, J3′,2′/3′,4′/5′,4′/5′,6′
= 7.2 Hz, 2H, H-3′, H-5′), 7.30 (t, J3,2/3,4 = 8.0 Hz, 1H,
H-3), 7.27 (d, J2′,3′/6′,5′ = 7.2 Hz, 2H, H-2′, H-6′), 7.19 (d,
J4′,5′/4′,3′ = 7.2 Hz, 1H, H-4′), 6.79 (d, J4,3 = 8.0 Hz, 1H,
H-4), 6.73 (s, 2H, H-2", H-6"), 6.72 (t, J2,1/2,3 = 7.4 Hz, 1H,
H-2), 6.29 (d, J = 2.0 Hz, 1H, NH), 3.69 (s, 6H, O-CH3);
EI-MS m/z (% rel. abund.): 438 (M+, 42), 440 (M + 2, 18),
348 (90), 346 (100), 223 (93), 77 (13).
1 3

Molecular Diversity
274 (61), 272 (91), 223 (100), 105 (20), 77 (23); HR-EIMS
Calcd for C21H17N2O2Cl: 364.0973, found=364.0974.
H-5"’), 7.35 (m, 1H, H-4"’), 7.33 (t, J3′,2′/3′,4′/5′,4′/5′,6′ =7.6 H
z, 2H, H-3′, H-5′), 7.31 (t, J3,2/3,4 =8.0 Hz, 1H, H-3), 7.28 (d,
J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.24 (d, J2",3"/6",5" =8.0 Hz,
2H, H-2", H-6"), 7.19 (d, J4′,5′/4′,3′ =7.6 Hz, 1H, H-4′), 6.92
(d, J3",2"/5",6" =8.4 Hz, 2H, H-3", H-5"), 6.74 (d, J4,3 =8.4 Hz,
1H, H-4), 6.70 (t, J2,1/2,3 =7.6 Hz, 1H, H-2), 6.20 (s, 1H,
NH), 5.01 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6):
δ 162.3, 158.2, 146.6, 140.8, 136.7, 133.7, 132.8, 128.5,
128.4, 127.9, 127.8, 127.7, 126.3, 125.9, 117.4, 115.3,
114.7, 114.4, 72.2, 69.1; EI-MS m/z (% rel. abund.): 406
(M+, 28), 314 (98), 223 (28), 167, (11), 91 (100); HREI-MS
Calcd for C27H22N2O2: m/z=406.1676, Found 406.1667.
2‑(3‑Ethoxy‑2‑hydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquina‑
1
zolin‑4(1H)‑one (23) Solid; yield: 71; HNMR (400 MHz,
DMSO-d6): δ 8.89 (s, 1H, OH), 7.72 (d, J1,2 =7.6 Hz, 1H,
H-1), 7.31 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz, 2H, H-3′, H-5′), 7.28
(t, J3,2/3,4 =7.6 Hz, 1H, H-3), 7.20 (d, J2′,3′/6′,5′ =7.6 Hz, 2H,
H-2′, H-6′), 7.15 (t, J4′,3′/4′,5′ =7.6 Hz, 1H, H-4′), 7.07 (s, 1H,
CH), 6.82 (ovp, 2H, H-5", H-6"), 6.76 (d, J4″,5″ =8.4 Hz, 1H,
H-4"), 6.69 (d, J4,3 =8 Hz, 1H, H-4), 6.63 (t, J2,1/2,3 =8.4 Hz,
1H, H-2), 6.40 (d, J=1.6 Hz, 1H, NH), 3.98 (q, J=6.8 Hz,
2H, CH2), 1.30 (t, J=6.8 Hz, 3H, CH3); 13C NMR (75 MHz,
DMSO-d6): δ 194.2, 146.6, 143.2, 140.8, 133.5, 128.5,
127.7, 126.2, 126.1, 118.6, 118.3, 117.3, 114.9, 112.7, 68.0,
64.0, 14.6; EI MS m/z (% rel. abund.): 360 (M+, 100), 345
(29), 268 (63), 252 (49), 223 (84), 211 (16); HREI-MS
Calcd for C22H20N2O3: m/z=360.1468, Found 360.1457.
2‑(4‑Hydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
lin‑4(1H)‑one (27) Solid; yield: 62%; HNMR (400 MHz,
DMSO-d6): δ 9.43 (s, 1H, OH), 7.69 (d, J1,2 =7.6 Hz, 1H,
H-1), 7.46 (s, 1H, CH), 7.31 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz,
2H, H-3′, H-5′), 7.27 (t, J3,2/3,4 =8 Hz, 1H, H-3), 7.24 (d,
J2′,3′/6′,5′ =8 Hz, 2H, H-2′, H-6′), 7.18 (t, J4′,3′/4′,5′ =7.2 Hz,
1H, H-4′), 7.15 (d, J2",3"/6",5" =8.8 Hz, 2H, H-2", H-6"), 6.73
(d, J4,3 =8 Hz, 1H, H-4), 6.69 (t, J2,1/2,3 =7.2 Hz, 1H, H-2),
6.62 (d, J3",2"/5",6" =8.4 Hz, 2H, H-3", H-5"), 6.13 (s, 1H,
NH); EI MS m/z (% rel. abund.): 316 (M+, 66), 224 (100),
196 (29), 167 (17), 141 (13), 130 (27).
2‑(2‑(Benzyloxy)phenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
lin‑4(1H)‑one (24) Solid; yield: 79%; H-NMR (400 MHz,
DMSO-d6): δ 7.74 (d, J1,2 =7.6 Hz, 1H, H-1), 7.38 (d,
J2"’,3"’/6"’,5"’ =7.6 Hz, 2H, H-2"’, H-6"’), 7.35 (ovp, 2H,
H-3"’, H-5"’), 7.33 (ovp, 1H, H-4"’), 7.30 (d, J6",5" =8.0 Hz,
1H, H-6"), 7.27 (t, J3′,2′/3′,4′/5′,4′/5′,6′ =7.4 Hz, 2H, H-3′, H-5′),
7.25 (t, J3,2/3,4 =8.0 Hz, 1H, H-3), 7.22 (d, J5",6" =8.0 Hz,
1H, H-5"), 7.19 (d, J2′,3′/6′,5′ =7.4 Hz, 2H, H-2′, H-6′), 7.16
(d, J4′,5′/4′,3′ =7.4 Hz, 1H, H-4′), 7.12 (d, J=2.0 Hz, CH),
7.03 (d, J4,3 =8.0 Hz, 1H, H-4), 6.87 (t, J2,1/2,3 =7.2 Hz,
1H, H-2), 6.77 (d, J3",4" =8.0 Hz, 1H, H-3"), 6.71 (t,
J4",3"/4",5" =7.6 Hz, 1H, H-4"), 6.52 (d, J=2.4 Hz, 1H, NH),
5.18 (dd, 2H, CH2); EI MS m/z (% rel. abund.): 406 (M+,
61), 315 (55), 223 (100), 212 (48), 195 (90), 167 (60), 120
(36), 91 (96), 77 (27).
3‑Phenyl‑2‑(4‑(trifluoromethyl)phenyl)‑2,3‑dihydro‑
quinazolin‑4(1H)‑one (28) Solid; yield: 74%; 1HNMR
(400 MHz, DMSO-d6): δ 7.71 (d, J3",2"/5",6" =8 Hz, 2H,
H-3", H-5"), 7.69 (d, J2",3"/6",5" =8.4 Hz, 2H, H-2", H-6"),
7.60 (d, J1,2 =7.6 Hz, 1H, H-1), 7.57 (d, J=2 Hz, 1H, CH),
7.36 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz, 2H, H-3′, H-5′), 7.30 (t,
J3,2/3,4 =7.6 Hz, 1H, H-3), 7.26 (d, J2′,3′/6′,5′ =7.6 Hz, 2H,
H-2′, H-6′), 7.19 (t, J4′,3′/4′,5′ =8 Hz, 1H, H-4′), 6.76 (d,
J4,3 =8 Hz, 1H, H-4), 6.71 (t, J2,1/2,3 =7.2 Hz, 1H, H-2),
6.41 (d, J=2 Hz, 1H, NH); 13C NMR (100 MHz, DMSO-
d6): δ 162.0, 146.2, 145.2, 140.5, 133.9, 130.0, 128.9, 128.7,
128.6, 128.5, 128.0, 127.4, 126.1, 126.0, 125.5, 125.4,
125.3, 121.0, 117.8, 115.3, 115.1, 114.8, 71.8; EI MS m/z
(% rel. abund.): 368 (M+, 34), 276 (100), 248 (8), 223
(73), 201 (10), 152 (6); HREI-MS Calcd for C21H15F3N2O:
m/z=368.1131, Found 368.1143.
2‑(3‑(Benzyloxy)‑4‑methoxyphenyl)‑3‑phenyl‑2,3‑dihyd‑
1
roquinazolin‑4(1H)‑one (25) Solid; yield: 72%; H-NMR
(400 MHz, DMSO-d6): δ 7.71 (d, J1,2 =7.6 Hz, 1H, H-1),
7.50 (d, J=2.0 Hz, CH), 7.36 (ovp, 2H, H-2"’, H-6"’),
7.35 (ovp, 2H, H-3"’, H-5"’), 7.33 (ovp, 1H, H-4"’),
7.31 (t, J3′,2′/3′,4′/5′,4′/5′,6′ =7.2 Hz, 2H, H-3′, H-5′), 7.29 (t,
J3,2/3,4 =8.0 Hz, 1H, H-3), 7.20 (d, J2′,3′/6′,5′ =7.2 Hz, 2H,
H-2′, H-6′), 7.16 (d, J4′,5′/4′,3′ =7.4 Hz, 1H, H-4′), 7.11 (s, 1H,
H-6"), 6.84 (s, 2H, H-2", H-5"), 6.74 (d, J4,3 =8.0 Hz, 1H,
H-4), 6.71 (t, J2,1/2,3 =7.2 Hz, 1H, H-2), 6.16 (d, J=2.0 Hz,
1H, NH), 4.95 (dd, 2H, CH2), 3.67 (s, 3H, O-CH3); EI MS
m/z (% rel. abund.): 436 (M+, 61), 434 (24), 344 (79), 254
(29), 223 (31), 91 (100), 77 (13).
3‑Phenyl‑2‑(thiophen‑2‑yl)‑2,3‑ dihydroquinazo‑
1
lin‑4(1H)‑one (29) Solid; yield: 81%; HNMR (400 MHz,
DMSO-d6): δ 7.71 (dd, J1,2 =7.6 Hz, J1,3 =1.2 Hz, 1H,
H-1), 7.56 (d, J=2.8 Hz, 1H, CH), 7.43 (dd, J5",4" =4.8 Hz,
J5",3" =2.8 Hz, 1H, H-5"), 7.36 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz,
2H, H-3′, H-5′), 7.32 (t, J3,2/3,4 =8 Hz, 1H, H-3), 7.30 (d,
J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.27 (dd, J4",3" =6 Hz,
J4",5" =4.8 Hz, 1H, H-4"), 7.19 (t, J4′,3′/4′,5′ =7.2 Hz, 1H,
H-4′), 7.03 (dd, J3",4" =5.2 Hz, J3",5" =1.2 Hz, 1H, H-3"),
6.77 (d, J4,3 =8 Hz, 1H, H-4), 6.72 (t, J2,1/2,3 =7.2 Hz, 1H,
H-2), 6.27 (d, J=2.8 Hz, 1H, NH); 13C NMR (100 MHz,
2‑(4‑(Benzyloxy)phenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
lin‑4(1H)‑one (26) Solid; yield: 68%; H-NMR (400 MHz,
DMSO-d6): δ 7.71 (d, J1,2 =7.6 Hz, 1H, H-1), 7.53 (s, 1H,
CH), 7.39 (ovp, 2H, H-2"’, H-6"’), 7.37 (ovp, 2H, H-3"’,
1 3

Molecular Diversity
DMSO-d6): δ 161.9, 146.6, 142.4, 140.7, 133.6, 128.6,
127.9, 126.9, 126.1, 126.0, 123.5, 117.6, 115.5, 114.9,
69.3; EI MS m/z (% rel. abund.): 306 (M+, 98), 275 (3), 223
(49), 214 (100), 186 (39), 130 (40); HREI-MS Calcd for
C18H14N2OS: m/z=306.0821, Found 306.0834.
(t, J2,1/2,3 =7.2 Hz, 1H, H-2), 7.11 (s, 1H, CH), 7.06 (t,
J4″,3″/4″,5″ =7.6 Hz, 6.80 (d, J4,3 =8 Hz, 1H, H-4), (d,
J5″,6″ =8.4 Hz, 1H, H-5″), 6.70 (t, J4′,5′/4′,3′ =7.2 Hz, 1H,
H-4′), 6.67 (d, J3″,4″ =7.6 Hz, 1H, H-3″), 6.37 (d, J=2.0 Hz,
1H, NH); EI MS m/z (% rel. abund.): 316 (M+, 87), 224
(100), 223 (91), 195 (52), 180 (46), 167 (26), 120 (31), 77
(26).
2‑(3‑Bromo‑4‑hydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquina‑
zolin‑4(1H)‑one (30) Solid; yield: 79%; 1HNMR (400 MHz,
DMSO-d6): δ 10.31 (s, 1H, OH), 7.71 (d, J1,2 =7.6 Hz, 1H,
H-1), 7.52 (d, J=2 Hz, 1H, CH), 7.45 (d, J2",6" =2 Hz, 1H,
H-2"), 7.33 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz, 2H, H-3′, H-5′),
7.30 (t, J3,2/3,4 =7.6 Hz, 1H, H-3), 7.25 (d, J2′,3′/6′,5′ =7.6 Hz,
2H, H-2′, H-6′), 7.19 (t, J4′,3′/4′,5′ =8 Hz, 1H, H-4′), 7.14
(dd, J6",5" =8 Hz, J6",2" =2 Hz, 1H, H-6"), 6.82 (dd,
J5",6" =8.4 Hz, 1H, H-5"), 6.76 (d, J4,3 =8 Hz, 1H, H-4),
6.71 (t, J2,1/2,3 =7.2 Hz, 1H, H-2), 6.19 (d, J=2 Hz, 1H,
NH); EI MS m/z (% rel. abund.): 394 (M+, 23), 396 (M+2,
15), 302 (100), 276 (5), 223 (41), 195 (8).
2‑(4‑Bromophenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
lin‑4(1H)‑one (34) Solid; yield: 73%; HNMR (400 MHz,
DMSO-d6): δ 7.69 (d, J1,2 =7.6 Hz, 1H, H-1), 7.63 (s,
1H, CH), 7.49 (d, J2″,3″/6″,5″ =8.4 Hz, 2H, H-2″, H-6″),
7.33 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz, 2H, H-3′, H-5′), 7.30 (t,
J3,2/3,4 =8 Hz, 1H, H-3), 7.27 (d, J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′,
H-6′), 7.23 (d, J3″,2″/5″,6″ =8.4 Hz, 2H, H-3″, H-5″), 6.75 (d,
J4,3 =8 Hz, 1H, H-4), 6.71 (t, J2,1/2,3 =7.2 Hz, 1H, H-2), 6.29
(s, 1H, NH); EI MS m/z (% rel. abund.): 378 (M+, 22), 380
(M+2, 20), 286 (100), 223 (76), 179 (11), 152 (9).
2‑(3‑Hydroxy‑4‑methoxyphenyl)‑3‑phenyl‑2,3‑dihydro‑
quinazolin‑4(1H)‑one (31) Solid; yield: 75%; 1H-NMR
(400 MHz, DMSO-d6): δ 8.98 (s, 1H, OH), 7.70 (dd,
J1,2 =8.0 Hz, J1,3 =1.2 Hz, 1H, H-1), 7.50 (d, J=2.4 Hz, 1H,
CH), 7.34(t, J3,2/3,4 =8.0Hz, 1H, H-3), 7.30(t, J3′,2′/3′,4′/5′,4′/5′,6′
=7.6 Hz, 2H, H-3′, H-5′), 7.25 (d, J2′,3′/6′,5′ =7.2 Hz, 2H,
H-2′, H-6′), 7.19 (d, J4′,5′/4′,3′ =7.2 Hz, 1H, H-4′), 6.83 (d,
J6",2" =2.0 Hz, 1H, H-6"), 6.80 (d, J4,3 =8.4 Hz, 1H, H-4),
6.73 (t, J2,1/2,3 =8.0 Hz, 1H, H-2), 6.69 (ovp, 2H, H-2",
H-5"), 6.09 (d, J=2.8 Hz, 1H, NH); EI-MS m/z (% rel.
abund.): 346 (M+, 22), 254 (100), 223 (25), 183 (11), 130
(15), 77 (17).
2‑(3,4‑Dihydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (35) Solid; yield: 80%; H-NMR (400 MHz,
1
DMSO-d6): δ 8.90 (s, 2H, OH), 7.70 (d, J1,2 =7.6 Hz, 1H,
H-1), 7.44 (d, J=2.0 Hz, CH), 7.32 (t, J3′,2′/3′,4′/5′,4′/5′,6′=7.6 H
z, 2H, H-3′, H-5′), 7.27 (t, J3,2/3,4 =8.0 Hz, 1H, H-3), 7.23 (d,
J2′,3′/6′,5′=7.2 Hz, 2H, H-2′, H-6′), 7.16 (t, J4′,5′/4′,3′=7.2 Hz, 1H,
H-4′), 6.78 (s, 1H, H-6″), 6.71 (d, J4,3 =8.4 Hz, 1H, H-4), 6.68
(t, J2,1/2,3 =7.6 Hz, 1H, H-2), 6.58 (s, 2H, H-5″, H-2″), 6.04 (d,
J=2.4 Hz, 1H, H-NH), 13C-NMR (100 MHz, DMSO-d6): δ
162.2, 146.6, 145.3, 144.9, 140.9, 133.6, 131.7, 128.5, 127.9,
126.3, 125.9, 117.8, 117.2, 115.2, 115.1, 114.7, 114.0; EI-MS
m/z (% rel. abund.): 332 (M+, 63), 240 (100), 223 (27), 212
(16), 120 (21); HR-EIMS Calcd for C20H16N2O3: 332.1161,
found=332.1149.
2‑(3‑Hydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
lin‑4(1H)‑one (32) Solid; yield: 70%; H-NMR (400 MHz,
DMSO-d6): δ 9.43 (s, 1H, OH), 7.71 (d, J1,2 =7.6 Hz, 1H,
H-1), 7.58 (d, J=2.8 Hz, CH), 7.35 (t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 H
z, 2H, H-3′, H-5′), 7.26 (d, J2′,3′/6′,5′ =7.2 Hz, 2H, H-2′, H-6′),
7.23 (t, J3,2/3,4 =8.0 Hz, 1H, H-3), 7.18 (t, J2,1/2,3 =7.6 Hz,
1H, H-2), 7.06 (t, J5",4"/5",6" =7.6 Hz, 1H, H-5"), 6.78 (s,
1H, H-2"), 6.76 (d, J6",5" =8.0 Hz, 1H, H-6"), 6.72 (d,
J4,3 =8.0 Hz, 1H, H-4), 6.69 (t, J4′,3′/4′,5′ =7.6 Hz, 1H, H-4′),
6.61 (dd, J4",2" =1.6 Hz, J4",5" =7.6 Hz, 1H, H-4"), 6.14 (d,
J=2.4 Hz, 1H, NH); EI MS m/z (% rel. abund.): 316 (M+,
27), 223 (100), 196 (12), 77 (17).
2‑(2,5‑Dihydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
lin‑4(1H)‑one (36) Solid; yield: 72%; H-NMR (400 MHz,
DMSO-d6): δ 7.81 (dd, J1,2 =8.0 Hz, J1,3 =1.2 Hz, 1H, H-1),
7.32 (t, J3′,2′/3′,4′/5′,4′/5,6′=7.2 Hz, 2H, H-3′, H-5′), 7.26 (d,
J2′,3′/6′,5′=7.2 Hz, 2H, H-2′, H-6′), 7.29 (t, J3,2/3,4 =8.0 Hz,
1H, H-3), 7.19 (d, J4′,5′/4′,3′=7.2 Hz, 1H, H-4′), 6.79 (d,
J6″,4″=2.8 Hz, 1H, H-6″), 6.75 (t, J2,1/2,3 =7.6 Hz, 1H, H-2),
6.70 (d, J3″,4″=8.4 Hz, 1H, H-3″), 6.60 (d, J4,3 =8.8 Hz, 1H,
H-4), 6.52 (dd, J4″,3″=8.8 Hz, J4″,6″=2.8 Hz, 1H, H-4″), 6.33
(s, 1H, CH); EI-MS m/z (% rel. abund.): 332 (M+, 100), 239
(51), 211 (55), 120 (21), 77 (30).
2‑(2‑Hydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
lin‑4(1H)‑one (33) Solid; yield: 67%; H-NMR (400 MHz,
2‑(2,3‑Dihydroxyphenyl)‑3‑phenyl‑2,3‑dihydroquinazo‑
1
DMSO-d6): δ 7.73 (d, J1,2 =7.6 Hz, 1H, H-1), 7.30
(t, J3′,2′/3′,4′/5′,6′/5′,4′ =7.6 Hz, 2H, H-3′, H-5′), 7.24 (d,
J6″,5″ =8.4 Hz, 1H, H-6″), 7.22 (t, J3,2/3,4 =8.0 Hz, 1H,
H-3), 7.20 (d, J2′,3′/6′,5′ =7.6 Hz, 2H, H-2′, H-6′), 7.17
lin‑4(1H)‑one (37) Solid; yield: 77%; HNMR (400 MHz,
DMSO-d6): δ 9.48 (s, 1H, OH), 8.82 (s, 1H, OH), 7.72
(d, J1,2 =7.6 Hz, 1H, H-1), 7.32 (t, J3′,2′/3′,4′/5′,6′/5′,4′=8 H
z, 2H, H-3′, H-5′), 7.23 (t, J3,2/3,4 =8 Hz, 1H, H-3), 7.21 (d,
J2′,3′/6′,5′=7.6 Hz, 2H, H-2′, H-6′), 7.15 (t, J4′,3′/4′,5′=7.2 Hz,
1H, H-4′),7.04 (d, J=2 Hz, 1H, CH), 6.76 (d, J6″,5″=8 Hz,
1 3

Molecular Diversity
1H, H-6″), 6.68 (ovp, 3H, H-4, H-5″, H-4″), 6.51 (t,
J2,1/2,3 =7.2 Hz, 1H, H-2), 6.36 (d, J=2 Hz, 1H, NH); EI MS
m/z (% rel. abund.): 332 (M+, 100), 239 (51), 223 (13), 211
(25), 184 (41), 120 (48).
of α-amylase and α-glucosidase inhibitors (0.0625, 0.125,
0.2, and 0.4 mM) with diferent concentrations of inhibitor
substrate (p-nitrophenylR-D-maltoside (NPM)) such as 0.02,
0.2, 0.4, 0.8, and 1.0 mM. The enzymes were dissolved in
de-ionized water to produce the concentration of 0.2 mg/
mL for each well, and the pH was adjusted to 7.0 by using
PIPES bufer. The reaction mixture was incubated for the
period of 30 min at 25 °C for a one-minute interval, and the
absorbance was measured using the ELISA reader (BioTek
XL-800, USA). The kinetic parameters Vmax, Km, AICc,
and R2 values of all the α-amylase and α-glucosidase inhibi-
tors were determined by graph ftting analysis using Sigma-
Plot enzyme kinetic software 14.0 version [43, 44].
α‑Amylase inhibition assay
The α-amylase inhibitory activity was determined by an assay
modifed from Kwon, Apostolidis and Shetty. A volume of 500
µL of α-amylase solution (0.5 mg/mL) in 0.2 mM phosphate
bufer (pH 6.9) and that of 500 µL of test sample (100, 200,
400, 800, 1000 µg/mL) were incubated for 10 min at 25 ˚C.
After pre-incubation, 1% starch solution (500 μL) in 0.02 M
sodium phosphate bufer (pH 6.9) was added to each tube and
incubated at 25 ˚C for 10 min. One milliliter of dinitrosalicylic
acid color reagent was then added to the reaction mixture, and
the tubes were incubated in boiling water for 5 min and fnally
cooled to room temperature. The solutions were diluted by
adding 10 mL distilled water, and the absorbance was meas-
ured at 540 nm [41]. The percentage inhibition was calculated
as illustrated:
Ligand docking protocols
α‑amylase enzyme
Ligand docking study was conducted by using the Molecu-
lar Operating Environment (MOE) software package [45] to
explore the binding mode of the synthesized compounds in
the active site of the α-amylase enzyme. The structural coor-
dinates of α-amylase (PDB code 3BAJ) [46] were retrieved
from Protein Data Bank (www.rcsb.org). All the solvent mol-
ecules were removed and were protonated, and up to 0.05,
gradient energy minimization is done using the MMFF94s
force feld implemented in MOE. The structural coordinates
of all the compounds were built using the Molecular Builder
Module in MOE. All the compounds were docked, and a
total of ten diferent conformations for each compound were
set. The ligands are fexible during docking so that to obtain
the protein–ligand complex of minimum energy. The ligands
were ranked by the scores from the GBVI/WSA binding free
energy calculation, which is the score of the last stage. The
GBVI/WSA is a scoring function which estimates the free
energy of binding of the ligand from a given pose. For all
scoring functions, lower scores indicate more favorable
poses. The unit for all scoring functions is kcal/mol. Finally,
the predicted ligand–protein complexes were analyzed for
molecular interactions using PyMol v 1.7.
(
)
% Inhibition = AbsorbanceControl−AbsorbanceSample
∕AbsorbanceControl × 100
α‑Glucosidase inhibition assay
Rat intestinal acetone powder in typical saline (100:1; w/v)
was sonicated appropriately, and the supernatant was used
as a source of basic intestinal α-glucosidase after centrifuga-
tion. In short, 10 mL of test samples of 5 mg/mL in DMSO
solution was reconstituted in 100 mL of 100 mM-phosphate
bufer at pH 6.8 in 96-well micro-plate and incubated with
50 mL of basic intestinal α-glucosidase for fve min before
50 mL substrate (5 mM, p-nitrophenyl-α-D-glucopyranoside
prepared in the same buffer) was added; p-nitro-phenol
released was measured at 405 nm spectrophotometrically
(SpectraMax plus384, Molecular Devices Corporation, Sun-
nyvale, CA, USA) 5 min after incubation with the substrate.
Individual blanks for test samples were prepared to accurate
background absorbance where the substrate was changed
with 50 mL of buffer. Control sample contained 10 mL
DMSO besides test samples. Percentage of enzyme inhibi-
tion was measured as (1B/A)100 where [A] represents the
absorbance of control exclusive of test samples and [B]corre-
sponding to absorbance in the presence of test samples [42].
α‑glucosidase enzyme
Ligand docking approach was performed using MOE-dock
module implemented in MOE software package [47] to dock
all the synthesized derivatives against the α-glucosidase
enzyme. Due to the unavailability of the crystallographic
structure of the corresponding enzyme, we used the homol-
ogy modeling structural coordinates described by Carreiro
et al. [47] for the α-glucosidase enzyme. Next, the homology
model was subjected for 3D protonation and energy mini-
mization up to 0.05 gradient using the MMFF94s force feld
implemented in MOE software. The 3D structures for all the
α‑Amylase and α‑glucosidase inhibition kinetic
assay
To determine the mechanism of enzyme inhibition, kinetic
studies were performed by using a varying concentration
1 3

Molecular Diversity
3. Chelladurai GRM, Chinnachamy C (2018) α-Amylase and
α-glucosidase inhibitory efects of aqueous stem extract of Sala-
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https://doi.org/10.1590/s2175-97902018000117151
derivatives were built by using the Molecular Builder Mod-
ule in MOE. During the small-molecular docking approach,
all the derivatives were set to fexible during docking, so that
to obtain minimal energy complex. Later, the docked com-
plexes were ranked based on the docking scores (S). Finally,
the predicted ligand–protein complexes were analyzed for
molecular interactions using PyMol v 1.7.
4. Dall T, Mann SE, Zhang Y, Martin J, Chen Y (2008) Economic
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Molecular dynamics simulation
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The compound 4 was parameterized with the generalized
Amber force feld, GAFF. The coordinates of both the targets
taken from the RCSB database as the PDB codes mentioned
in the docking part. The Generalized Amber forcefield
atom types were assigned using Antechamber [48], and the
parameter fles were prepared with AMBER’s tleap module.
All-atom MD simulations and analyses were conducted in
AMBER version 2018 [49]. The LEaP module was used
to add hydrogen atoms to the crystal structures. Next, the
counter ions were added to maintain the system neutrality.
All the systems were solvated in a truncated octahedral box
of the TIP3P water model with a cut-of 10 Å bufer. The
particle mesh Ewald (PME) method [50] was used to treat
long-range electrostatic interactions, and f14SB forcefeld
was used for all MD simulations. The CUDA version of
PMEMD was used to accelerate all MD simulations. The
steepest descent method was used to minimize the solvated
systems for 20,000 steps, then 400 ps heating, and 200 ps
equilibration in the NVT ensemble. The temperature and
pressure were coupled with a time constant of 1.0 ps, iso-
tropic position scaling, and a relaxation time of 2.0 ps,
according to Langevin’s algorithm [51]. Finally, both the
systems were submitted to AMBER for MD simulation of
total 70 ns. Finally, the post-MD analysis was conducted
using CPPTRAJ module of AMBER.
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Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s11030-021-10196-5.
Acknowledgements One of the authors Dr. Oluwatoyin Babatunde is
thankful to The World Academy of Sciences, Trieste, Italy, for awarding
prestigious Fellowship for year 2018-2019 under TWAS postgraduate
fellowship programme. The authors are thankful to the Pakistan Academy
of Sciences for providing fnancial support to Project No. (5-9/PAS/440).
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