Synthesis, in vitro, and in silico studies of newly functionalized quinazolinone analogs for the identification of potent α-glucosidase inhibitors

Article abstract of DOI:10.1007/s13738-021-02159-2

Functionalized quinazolinone derivatives 1–30 were synthesized by two-step reaction. First, anthranilic acid was treated with substituted phenyl isothiocyanate to synthesize 3-aryl-2-thioxo-2,3-dihydroquinazolinone derivatives 1–8 which in turn reacted with different bromoacetophenone derivatives to obtain fully functionalized quinazolinone derivatives 9–30. Both reactions were catalyzed by triethylamine. All the products were characterized by EI-, HREI-MS, ¹H-, and ¹³CNMR spectroscopic techniques. All compounds were subjected to their in vitro α-glucosidase inhibitory activity. Results showed that except compound 1–3, 5, 7, and 22, all compounds were found potent and showed many folds increased α-glucosidase enzyme inhibition as compared to standard acarbose (IC₅₀ = 750.0 ± 10.0?μM). Compound 13 (IC₅₀ = 85.0 ± 0.5?μM) was recognized as the most potent analog of the whole series, with ninefold enhanced inhibitory potential than the standard acarbose. Compounds 1–9, 11, 12, 22, and 26 were structurally known compounds, while remaining all are new. Kinetic study on compound 13 showed that the compound is following a competitive-type inhibition mechanism. Furthermore, in silico studies have also been performed to better rationalize the interactions between synthetic compound and active site of the enzyme. Graphic abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s13738-021-02159-2

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-021-02159-2
ORIGINAL PAPER
Synthesis, in vitro, and in silico studies of newly functionalized
quinazolinone analogs for the identifcation of potent α‑glucosidase
inhibitors
Hayat Wali1 · Ayaz Anwar2 · Shahbaz Shamim1 · Khalid Mohammed Khan1,3 · Mohammad Mahdavi4 · Uzma Salar5 ·
Bagher Larijani4 · Shahnaz Perveen6 · Muhammad Taha3 · Mohammad Ali Faramarzi7
Received: 20 September 2020 / Accepted: 2 January 2021
© Iranian Chemical Society 2021
Abstract
Functionalized quinazolinone derivatives 1–30 were synthesized by two-step reaction. First, anthranilic acid was treated
with substituted phenyl isothiocyanate to synthesize 3-aryl-2-thioxo-2,3-dihydroquinazolinone derivatives 1–8 which in
turn reacted with diferent bromoacetophenone derivatives to obtain fully functionalized quinazolinone derivatives 9–30.
Both reactions were catalyzed by triethylamine. All the products were characterized by EI-, HREI-MS, 1H-, and 13CNMR
spectroscopic techniques. All compounds were subjected to their in vitro α-glucosidase inhibitory activity. Results showed
that except compound 1–3, 5, 7, and 22, all compounds were found potent and showed many folds increased α-glucosidase
enzyme inhibition as compared to standard acarbose (IC50 =750.0 10.0 µM). Compound 13 (IC50 =85.0 0.5 µM) was
recognized as the most potent analog of the whole series, with ninefold enhanced inhibitory potential than the standard acar-
bose. Compounds 1–9, 11, 12, 22, and 26 were structurally known compounds, while remaining all are new. Kinetic study on
compound 13 showed that the compound is following a competitive-type inhibition mechanism. Furthermore, in silico studies
have also been performed to better rationalize the interactions between synthetic compound and active site of the enzyme.
Supplementary Information The online version contains
supplementary material available at https://doi.org/10.1007/s1373
8-021-02159-2.
4
* Khalid Mohammed Khan
Endocrinology and Metabolism Research Institute, Tehran
khalid.khan@iccs.edu; drkhalidhej@gmail.com
University of Medical Sciences, Tehran, Iran
5
6
7
Dr. Panjwani Center for Molecular Medicine and Drug
Research, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi 75270, Pakistan
1
H. E. J. Research Institute of Chemistry, International Center
for Chemical and Biological Sciences, University of Karachi,
Karachi 75270, Pakistan
PCSIR Laboratories Complex, Karachi,
Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280,
Pakistan
2
Department of Biological Sciences, School of Science
and Technology, Sunway University, Subang Jaya,
47500 Selangor, Malaysia
Department of Pharmaceutical Biotechnology, Faculty
of Pharmacy, Tehran University of Medical Sciences, Tehran,
Iran
3
Department of Clinical Pharmacy, Institute for Research
and Medical Consultations (IRMC), Imam Abdulrahman
Bin Faisal University, P.O. Box 1982, Dammam 31441,
Saudi Arabia
Vol.:(0123456789)
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Graphic abstract
Keywords Quinazolinone · Synthesis · α-Glucosidase · Diabetes mellitus type II · In vitro · Kinetics · In silico
metabolism with multiple etiologies, resulting from failure
in insulin secretion (type I diabetes), insulin dysfunction
(type II diabetes), or both [1–5]. Type II diabetes accounts
for about 80–90% of all cases of diabetes, and it is a wide-
spread, chronic, multifactor, and metabolic disorder [1, 6].
α-Glucosidase and α-amylase are hydrolases, well known to
Introduction
Diabetes is the 6th leading cause of global mortality, and
the most recent WHO (2018) report suggests that over 4.22
billion world population have been afected from diabetes.
Diabetes is an ailment of carbohydrate, fat, and protein
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degrade polysaccharides such as starch, maltose, and sucrose
into simple monosaccharides. α-Glucosidase (EC3.2.1.20)
enzyme is a glycosyl hydrolase-31 located in small intestinal
cells. It hydrolyzes 1,4 α-glycosidic bond of oligosaccha-
rides and generates α-D glucose which is absorbable into the
blood stream through the intestinal walls. [7]. There are two
proposed mechanisms for hydrolysis: One is nucleophilic
displacement, and the second is oxocarbenium ion interme-
diate [8]. Hyperactivity of α-glucosidase leads the rapid con-
version of carbohydrates into glucose molecules which get
absorb in blood stream and ultimately lead to postprandial
hyperglycemia [9]. Post-prandial hyperglycemia is primary
indication for type II diabetes mellitus [10, 11]. Conversion
of carbohydrate into glucose can be suspended by inhibition
of α-glucosidase enzyme which is one of the therapeutic
ways to control and manage type II diabetes [12–14]. Some
classes of compounds such as sulfonylureas, biguanides
(metformin), meglitinides, and thiazolidinediones are used
as oral drugs to treat type II diabetes but associated with
several side efects [15, 16]. Utilizing commercially avail-
able therapies, only 36% of type II diabetes mellitus patients
achieve glycemic control [17]. Therefore, new treatments for
this chronic disorder are desperately needed [18] which can
utilize safely and efectively to treat this disease.
compounds are carbonyl group at position 4, nitrogen atom
at position 1, π system as well as their relative distances
[31]. Many of the biologically active quinazolinones have
substitution of oxygen or sulfur at C-2 [23].
In the near past, biological assessment of quinazolinones
has gained huge interest and proven promise with the discov-
ery of potent anticancer, antiviral, and antiparasitic agents
[32–34]. Since many years, our research team is engaged in
identifcation of several classes of heterocyclic compounds
including 1,4 dihydropyridine, indazole, quinazolinone, ben-
zotriazole, and coumarin as potential leads to α-glucosidase
inhibitory activity [35–42]. We discovered 2-arylquinazolin-
4(3H)-ones as new class of α-glucosidase inhibitors [39].
In this scenario, we urged to further explore this class for
their α-glucosidase inhibitory potential (Fig. 1). For that
purpose, we synthesized fully functionalized quinazolinone
moieties by substituting ring nitrogen as well as sulfur with
aryl and diferent phenacyl rings in order to evaluate their
α-glucosidase inhibitory activity through in vitro and in
silico studies.
Results and discussion
Quinazolinone scafold and their derivatives are pharma-
cologically important and dynamic group of molecules. Dif-
ferent positions of carbonyl group on quinazolinone result in
two structural isomeric forms [19]. Quinazolinone alkaloid
was frst isolated from the Chinese plant aseru [20]. One of
the frst synthesized quinazolinone was methaqualone which
was initially used as antimalarial drug, and later, it was used
against insomnia [21]. A more satisfactory synthetic scheme
was developed by Gabriel in 1903 [22]. The pharmacologi-
cal importance of quinazolinone alkaloids those are isolated
from microorganisms, animals, plants, as well as having syn-
thetic origins is well documented [23–25]. Quinazolinone
derivatives have a range of bioactivities such as anticancer,
sedative, antihyperlipidemic, antihypertensive, and antiviral
[22, 23, 26–28]. They have identifed as dihydrofolate reduc-
tase (DHFR) [28, 29] and phosphodiesterase (PDEs) inhibi-
tors [30]. The main pharmacophoric groups in quinazolinone
Chemistry
A series of functionalized quinazolinones 1–30 were syn-
thesized by two-step reaction scheme. In the first step,
anthranilic acid was treated with substituted phenyl isothio-
cyanate in the presence of catalyst trimethylamine (TEA)
in ethanol to 3-aryl substituted quinazolinones 1–8. Then,
3-aryl substituted quinazolinones 1–8 were reacted with
diferent bromoacetophenone derivatives in ethanol. Again
trimethylamine (TEA) was used as catalyst to obtain the
desired quinazolinone derivatives 9–30 (Scheme 1). Reac-
tion progress was checked by TLC analysis (ethyl acetate/
hexanes, 3:7 for 1–8 and 100% DCM for 9–30). Formation
of the expected products (1–30) was confrmed by EI-MS,
1
HREI-MS, H- and 13C-NMR spectroscopic techniques.
Compounds 1–8, 9, 11, 12, 22, and 26 were structurally
reported [43–45], while rest of the derivatives are new.
Fig. 1 Rationale behind the
study
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Scheme 1 General synthetic
strategy for the synthesis of
compounds 1–8 and 9–30
the active site of enzyme. However, replacing the p-nitro
with p-ethoxy as in case of compound 4 slightly decreases
the inhibitory activity which gives a perception that groups
at para position might interact efectively with the active
site of enzyme as compared to the other positions. In con-
trast to para substituted compounds 4, 6, and p-methoxy
substituted analog 3 was found to be inactive. Compounds
2 and 7 having o-methoxy and o-fuoro were also found to
be inactive (Fig. 2).
In vitro α‑glucosidase inhibitory activity
All synthetic compounds 1–30 were subjected to in vitro
α-glucosidase inhibitory activity. Results in terms of
IC50 values showed that except compounds 1–3, 5, 7,
and 22, all analogs (IC50 = 85.0 0.5–676.2 9.6 µM)
were found potent when compared to standard acar-
bose (IC50 = 750.0 10.0 µM). Interestingly, analog 13
(IC50 = 85.0 0.5 µM) was recognized as ninefold more
potent than standard acarbose (Table 1).
Fully functionalized compounds 9–30 with substi-
tuted aryl (b) and benzoyl (c) rings belong to category
“B.” In this category, except compound 22, all com-
pounds displayed potent α-glucosidase inhibitory activ-
ity (IC50 = 85.0 0.5–676.2 9.6 µM). It is important to
note the p-nitro substitution was present on benzoyl ring
of compounds 10–19. Among these analogs, compound
13 (IC50 = 85.0 0.5 µM) bearing m-bromo substituted
aryl ring showed ninefold enhanced inhibitory activity as
compared to the standard acarbose. This analog was also
recognized as the most potent analog of the whole library.
It seems that m-bromo group along with p-nitro substitu-
tion is playing a crucial role in the inhibitory activity. The
second most active compound 18 (IC50 = 90.7 0.6 µM)
having p-nitro group on aryl ring showed eightfold more
potency than the standard. Comparison of its activity
with its precursor/intermediate 6 (IC50 = 191.1 2.5 µM)
revealed that incorporation of p-nitro-substituted ben-
zoyl ring brought twofold enhanced inhibitory potential.
Switching the position of nitro from para to meta on aryl
ring in case of compound 19 (IC50 = 100.0 0.9 µM)
exhibited a slight decreased activity. Nevertheless, the
compounds were recognized as multi-folds potent than its
inactive precursor 5. Similarly, switching the position of
nitro from para to meta on benzoyl ring leads to a sharp
decline in the activity, as observed in the case of analog
20 (IC50 = 163.2 1.7 µM). Seemingly, para position
Structure–activity relationship (SAR)
All synthetic quinazolinones 1–30 showed varying degree
of inhibitory potential against α-glucosidase enzyme which
could be defensible based on variations in substitution pat-
tern on phenyl rings, electronic and steric factors. Thus, for
simplifying SAR, compounds were divided in two categories
“A” and “B.” Compounds 1–8 are included in category “A,”
while remaining compounds 9–30 are listed as category “B.”
Category “A” comprised of intermediates 1–8 show-
ing signifcant to weak inhibitory potential in the range of
IC50 values of 191.1 2.5–377.2 4.2 µM. Among these
intermediates, compounds 4 (IC50 = 312.4 3.2 µM), 6
(IC50 = 191.1 2.5 µM), and 8 (IC50 = 377.2 4.2 µM)
showed potent inhibitory potential as compared to the stand-
ard acarbose (IC50 =750.0 10.0 µM), while remaining were
found to be inactive with IC50 values greater than 750 µM.
Unsubstituted compound 1 was found to be weakly active,
while most potent intermediate 6 possesses p-nitro substitu-
tion at aryl ring which shows that nitro substitution is play-
ing vital role in the inhibitory potential. Switching the nitro
from para to meta makes the compound 5 inactive. This
inactivity suggests that para position is more favorable for
nitro group to actively participates in the α-glucosidase inhi-
bition which might be by making important interactions with
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Table 1 In vitro α-glucosidase
inhibitory activity of
quinazolinone analogs 1–30
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Table 1 (continued)
aSEM standard error mean
bNA not active
cAcarbose standard inhibitor of α-glucosidase enzyme
nitro substitution interacts with the active site at its best.
Activity of compound 13 can be compared with analog 16
(IC50 = 232.5 3.5 µM) which has trifuoromethyl substi-
tution at aryl ring instead of bromo, and almost threefold
decreased activity was observed. Switching the position
of trifuoromethyl from meta to para further lowered the
inhibition strength as observed in case of compound 17
(IC50 = 305.6 3.1 µM). In contrast to that switching, the
position of trifuoromethyl from meta to ortho and nitro
(on benzoyl ring) from para to meta in compound 23
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Fig. 2 α-Glucosidase inhibi-
tory activity comparison of
compounds 1–8
Fig. 3 α-Glucosidase inhibitory activity comparison of compounds 13, 16–20, and 23
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(IC50 = 219.6 2.9 µM) increased the inhibitory potential
(Fig. 3).
having o-chloro instead of o-methoxy, showing increased
potential. Interestingly, addition of another chloro at meta
position of aryl ring of compound 14 (IC50 =186.7 2.2 µM)
further lifted up the inhibitory strength. However, moving
the nitro substitution on benzoyl ring from para to meta
in case of compound 21 (IC50 =676.2 9.6 µM) brought a
sharp decline in the inhibitory strength (Fig. 4).
Another compound 12 (IC50 =143.2 1.2 µM) is distinc-
tively similar to second most potent compound 18 but has
p-ethoxy instead of p-nitro on aryl ring and showed less
inhibitory strength. This comparison afrms that ethoxy is
less susceptible than nitro group particularly at para posi-
tion, to interact with the active site of enzyme. Switch-
ing the nitro group from para to meta in compound 22
(IC50 =750<µM) also brought a sharp decline in the inhibi-
tory strength. Activity comparison of compounds 12 with
11 (IC50 =183.5 2.1 µM) revealed that p-ethoxy is com-
paratively better than p-methoxy substitution which might
be due to good electron donating ability which increases the
electron density on aryl ring, so that it can better interact
with enzyme. Switching the methoxy from para to ortho
further lowers the inhibitory strength, as observed in case
of compound 10 (IC50 =307.0 3.2 µM) which gives a per-
ception that methoxy at ortho position is not interacted bet-
ter than para position. Inhibitory activity of analog 10 can
be compared with compound 15 (IC50 = 232.5 3.5 µM)
Compound 25 (IC50 =163.2 1.7 µM) bearing p-chloro
and p-trifuoromethyl on benzoyl and aryl rings, respec-
tively, was found to be fvefold more potent than the standard
acarbose. Replacing p-trifuoromethyl with p-ethoxy on aryl
ring in case of compound 26 (IC50 =150.6 1.4 µM) gives
a slight decline in the inhibitory potential, while replacing
the p-chloro with p-methyl on benzoyl ring in compound
27 (IC50 = 344.5 3.7 µM) leads a decline in the inhibi-
tory potential which gives a perception that electron-with-
drawing groups at para positions of aryl and benzoyl rings
stimulates the inhibitory strength. Moreover, activity com-
parison of compounds 25 with 24 (IC50 =338.7 3.6 µM)
revealed that replacement of p-trifuoromethyl with m-bromo
brought more than twofold decline in the inhibitory strength.
Fig. 4 α-Glucosidase inhibitory activity comparison of compounds 10–12, 14, 15, 21, and 22
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Journal of the Iranian Chemical Society
Similarly, activity of compound 24 can be compared with
compound 30 (IC50 =172.4 1.9 µM) which has p-methyl
instead of p-chloro on benzoyl ring and showed doubled
inhibitory potential. Replacing m-bromo with m-trifuoro-
methyl on aryl ring in compound 28 (IC50 =176.4 1.9 µM)
demonstrated almost same inhibitory strength. Incorpora-
tion of o,m-dichloro groups on aryl ring in compound 29
(IC50 = 605.3 9.1 µM) showed threefold less inhibitory
activity as compared to compounds 28 and 30. One excep-
tion was found in compound 9 (IC50 =167.0 1.8 µM) which
has ethyl acetate instead of benzoyl ring and displayed potent
inhibitory strength comparable to many potent analogs. Its
good activity might be due to hydrogen bond accepting
property of ester group which may play a crucial role in the
inhibitory strength (Fig. 5).
slight decrease in inhibitory activity. However, still all
compounds were found to be many folds better inhibitors of
α-glucosidase enzyme as compared to the standard acarbose.
In order to predict the mode of inhibition, kinetic studies
were conducted, while to rationalize the binding interactions
of the potent compounds with the active site, in silico study
was conducted.
Kinetic study of α‑glucosidase enzyme inhibition
Compound 13 with lowest IC50 value is the most active,
and its inhibition mode against α-glucosidase activity was
analyzed with changed concentrations of substrate (p-nitro-
phenyl α-D-glucopyranoside) (2–10 mM) in the absence
and presence of compound 13 at diferent concentrations
0, 25, 55, and 85 µM. To fnd out the type of inhibition,
a Lineweaver–Burk plot was generated and the value of
Michaelis–Menten constant Km was deduced from plot
between reciprocal of the substrate concentration 1/(S) and
reciprocal of enzyme rate 1/V over diferent inhibitor con-
centrations. Experimental inhibitor constant Ki value was
raised by secondary plots of the inhibitor concentration I
versus Km.
In brief, limited SAR suggests that almost all substitu-
tional variations including electronic factor, size, and posi-
tion of substitutions on aryl and benzoyl rings are playing
vital role in the determination of inhibitory activity. How-
ever, electron-withdrawing nitro and bromine groups favors
the inhibitory strength of compounds especially when pre-
sent at para and meta positions, respectively. Switching the
position of nitro group on aryl and benzoyl rings causes
Fig. 5 α-Glucosidase inhibitory activity comparison of compounds 9 and 24–30
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According to Fig. 6a, the Line Weaver–Burk plot
showed that the Km gradually increased, and Vmax
remained unchanged with increasing inhibitor concen-
tration indicating a competitive inhibition. The results
show compound 13 bind to active site on the enzyme and
compete with the substrate for binding to the active site.
Furthermore, plot of the Km versus different concentra-
tions of inhibitor gave an estimate of the inhibition con-
stant, Ki of 84 µM (Fig. 6b).
Docking study
To evaluate the interaction modes, binding energies, and
amino acid interactions of the most active compounds,
docking study was performed into modeled α-glucosidase
using Auto Dock Tools (version 1.5.6) [43–46]. 3D struc-
ture of the standard inhibitor acarbose is shown in Fig. 7a.
Superimposed of the most potent compound 13 on acarbose
revealed that this new compound ftted well in the active site
(Fig. 7b). The detailed interaction mode of acarbose revealed
that this inhibitor interacted with active site residues Gln322,
Fig. 6 Kinetic analysis of α-glucosidase inhibition by compound 13. a Lineweaver–Burk plot in the absence and presence of diferent concentra-
tions of compound 13. b The secondary plot between Km and various concentrations of compound 13
Fig. 7 a Acarbose in the active site of modeled α-glucosidase. b Acarbose (cyan) and the most potent compound 13 (pink) superimposed in the
modeled α-glucosidase active site pocket
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Thr301, His279, Arg312, Thr307, Glu304, Ser308, and
Asn241 (Fig. 8a). The value of the binding free energy of
acarbose is − 4.04 kcal/mol. Interaction mode of the most
potent compound 13 is shown in Fig. 8b. It can be seen
quinazolinone ring formed a π-cation and a π–π interactions
with His279 and a hydrogen bond with Asn241. 3-Bromo-
phenyl ring attached to quinazolinone core interacted with
Glu304 via a π-anion interaction and Arg312 via a hydro-
phobic interaction. Furthermore, phenyl ring of 4-nitrophe-
nyl moiety interacted with Val305 through a hydrophobic
interaction.
interactions with active site residues Thr307, Glu304, and
Pro309 through quinazolinone core. 4-Nitrophenyl ring
attached to this core formed a hydrogen bond and a π–π
interaction with His239 via nitro group and phenyl ring
and a π-cation interaction with His279 via phenyl ring.
Binding energies of compounds 18 and 6 were − 7.83 and
− 6.49 kcal/mol.
Conclusion
Calculation of the binding energy of compound 13
(− 8.11 kcal/mol) predicted that this compound attached
to active site easily than the standard drug. Quinazolinone
ring of the second most potent compound 18 established
a hydrogen bond with Gln322 and two hydrophobic inter-
actions with Val305 and Pro309 (Fig. 9a). 4-Nitrophenyl
ring attached to 3-position of quinazolinone ring formed
a hydrophobic linkage with Thr301. Other 4-nitrophenyl
ring of compound 18 interacted with Glu304 and Arg312
through a π-anion interaction and a hydrophobic interac-
tion, respectively. Furthermore, this compound formed van
der Waals interaction with Gly306, His279, His239, and
Phe311. Binding energy of this compound was − 7.83 kcal/
mol. Removing group attached to sulfur of compound 18,
as in compound 6 led to a moderate decrease in the inhibi-
tory activity.
Thirty functionalized quinazolinone derivatives were syn-
thesized and investigated for their α-glucosidase inhibitory
potential by in vitro, kinetics, and in silico studies. Com-
pound 13 along with many other analogs was identifed as
most potent analogs of the series. Limited SAR suggested
that along with many structural features, electron-withdraw-
ing nitro and bromine groups favor the inhibitory potential
especially when present at para and meta positions. Kinetic
study of compound 13 has been carried out to determine
the type of enzyme inhibition. Lineweaver–Burk plot
showed that the Km gradually increased, and Vmax remained
unchanged with increasing inhibitor concentration indicating
a competitive inhibition. In silico studies revealed a number
of indispensable interactions between compound and active
site of the α-glucosidase enzyme. This study has recognized
a number of potent molecules that may serve as leads to
future research in the identifcation of antidiabetic agents.
It can be seen in Fig. 9b, compound 6 established a
hydrogen bond, a π–anion interaction, and two hydrophobic
Fig. 8 a Interaction mode of acarbose. b Most potent compound 13 in the active site pocket
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Fig. 9 a Interaction mode of the second potent compound 18. b Compound 6 in the active site pocket
Reaction progress was checked periodically by TLC analy-
sis. On completion, precipitates were appeared in the reac-
tion fask which were collected via fltration and washed
with distilled water and then hexane to remove trace impu-
rities. Crude products were crystallized from ethanol to
obtained purifed products.
Future perspective
Our future plan is to incorporate important heterocyclic scaf-
folds that were reported to potentiate the pharmacological
activity of the main moiety such as thiazole, thiazine, tria-
zine, triazole, and tetrazine in order to identify novel and
potent antidiabetic agents.
General synthetic procedure for the synthesis
of compounds (8–30)
Experimental
Quinazolinone derivative (1 mmol) and phenacyl bromide
derivative (1 mmol) were taken in ethanol (10 ml) into a
100-ml round-bottomed fask. Few drops of triethylamine
were added and refuxed for 2 h. Product formation was
monitored by TLC analysis. Product appeared in the form
of precipitates which were fltered, washed with distilled
water and then hexane, dried in vacuo, and crystallized from
ethanol to get purifed product.
Materials and methods
Chemicals and reagents were purchased from Sigma-
Aldrich, USA. Thin layer chromatography was performed
on pre-coated silica gel aluminum plates (GF-25, Merck,
Germany). Ultraviolet light of 254 and 365 nm wavelengths
was used to visualize the chromatograms. H- and 13C-
1
NMR experiments were performed on Bruker 300, 400, and
500 MHz NMR spectrometers. Mass spectra were recorded
on JEOL JMS 600H and Finnigan MAT-311A mass spec-
trometers. Melting points were noted on Stuart® SMP10
apparatus and are uncorrected.
3‑Phenyl‑2‑thioxo‑2,3‑dihydroquinazolin‑4(1H)‑one
(1) [43]
White solid; Yield: 89%; M.P.: 290–292 °C; Rf = 0.73
1
(70% EtOAc/Hexane); H-NMR (300 MHz, DMSO-d6):
General synthetic procedure for the synthesis
of compounds (1–8)
δH 13.01 (s, 1H, NH), 7.96 (dd, J5,6 =7.8 Hz, J5,7 =1.2 Hz,
1H, H-5), 7.80 (dt, J7(6,8) =8.4 Hz, J7,5 =1.5 Hz, 1H, H-7),
7.49 (ovp, 4H, H-8, H-3′, H-4′, H-5′), 7.36 (t, J6,5 =8.1 Hz,
J6,7 = 6.9 Hz, 1H, H-6), 7.27 (d, J2′,3′ = J6′,5′ = 6.9 Hz, 2H,
H-2′, H-6′); EI-MS: m/z (rel. abundance%)=254 [M]+ (66),
253 (100), 119 (21), 90 (15).
Phenyl isothiocyanate derivative (1 mmol) and anthranilic
acid (1 mmol) were added in absolute ethanol (10 ml) into
a 100-ml round-bottomed fask. Few drops of triethylamine
were added in the reaction mixture and refuxed for 2–3 h.
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13.14 (s, 1H, NH), 8.35 (d, J5′,6′ =J3′,2′ =10.2 Hz, 2H, H-3′,
H-5′), 7.96 (d, J5,6 =7.8 Hz, 1H, H-5), 7.80 (t, J7,6 =7.2 Hz,
J7,8 = 6.9 Hz, 1H, H-7), 7.65 (d, J2′,3′ = J6′,5′ = 10.3 Hz,
2H, H-2′, H-6′), 7.45 (d, J8,7 = 8.1 Hz, 1H, H-8), 7.36 (t,
J6,5 =7.5 Hz, J6,7 =7.2 Hz, 1H, H-6); EI-MS m/z (rel. abun-
dance%)=298 [M]+ (100), 299 (95), 119 (22), 252 (21).
3‑(2‑Methoxyphenyl)‑2‑thioxo‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (2) [44]
White solid; Yield: 79%; M.P.: 255–257 °C; Rf =0.70 (70%
EtOAc/Hexane); 1H-NMR (300 MHz, DMSO-d6): δH 13.01 (s,
1H, NH), 7.95 (dd, J5,7 =1.2 Hz, J5,6 =9.0 Hz, 1H, H-5), 7.81
(dt, J7(6,8) =9.0 Hz, J7,5=3.0 Hz, 1H, H-7), 7.45 (ovp, 3H, H-6,
H-8, H-6′), 7.22 (ovp, 2H, H-4′, H-3′), 7.05 (t, J5′(4′,6′)=9.0 Hz,
1H, H-5′); EI-MS: m/z (rel. abundance%)=284[M]+ (10), 253
(100), 236 (17), 254 (16), 221 (15).
3‑(2‑Fluorophenyl)‑2‑thioxo‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (7) CAS#23892‑21‑9
White solid; Yield: 70%; M.P.: 224–227 °C; Rf = 0.64
(70% EtOAc/Hexane); 1H-NMR (300 MHz, DMSO-d6): δH
13.20 (s, 1H, NH), 7.98 (d, J5,6 = 9.0 Hz, 1H, H-5), 7.84
(dt, J7(6,8) =9.0 Hz, J7,5 =3.0 Hz, 1H, H-7), 7.47 (ovp, 6H,
3‑(4‑Methoxyphenyl)‑2‑thioxo‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (3) [43]
′
′
′
′
H-6, H-8, H-3 , H-4 , H-5 , H-6 ); EI-MS: m/z (rel. abun-
White solid; Yield; 70%; M.P.: 240–242 °C; Rf = 0.66
(70% EtOAc/Hexane); 1H-NMR (300 MHz, DMSO-d6): δH
12.97 (s, 1H, NH), 7.94 (d, J5,6 =7.2 Hz, 1H, H-5), 7.78 (t,
J7,6 =7.2 Hz, J7,8 =8.1 Hz, 1H, H-7), 7.44 (d, J8,7 =8.4 Hz,
1H, H-8), 7.35 (t, J6,7 = J6,5 = 7.5 Hz, 1H, H-6), 7.17 (d,
J2′,3′ =J6′,5′ =8.7, 2H, H-2′, H-6′), 7.00 (d, J3′,2′ =J5′,6′ =8.7,
2H, H-3′, H-5′), 3.80 (s, 3H, OCH3); EI-MS: m/z (rel. abun-
dance%)=284 [M]+ (100), 283 (94), 252 (13), 162 (30).
dance%)=272 [M]+ (92), 253 (100), 119 (24), 163 (10).
3‑(3‑Chlorophenyl)‑2‑thioxo‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (8) [44]
White solid; Yield: 70%; M.P.: 231–233 °C; Rf = 0.67
(70% EtOAc/Hexane); 1H-NMR (300 MHz, DMSO-d6): δH
13.06 (s, 1H, NH), 7.95 (d, J5,6 =7.2 Hz, 1H, H-5), 7.79 (t,
J7(6,8) = 7.2 Hz, 1H, H-7), 7.53 (ovp, 4H, H-8, H-2′, H-5′,
H-6′), 7.36 (t, J6,5 =7.8 Hz, J6,7 =7.2 Hz, 1H, H-6), 7.29 (m,
1H, H-4′); EI-MS: m/z (rel. abundance%)=288 [M]+ (80),
290 [M+2] (25), 287 (100), 162 (8), 119 (9).
3‑(4‑Ethoxyphenyl)‑2‑thioxo‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (4) [44]
White solid; Yield: 70%; M.P.: 296–297 °C; Rf = 0.69
(70% EtOAc/Hexane); 1H-NMR (300 MHz, DMSO-d6): δH
12.95 (s, 1H, NH), 7.94 (dd, J5,7 =1.2 Hz, J5,6 =7.8 Hz, 1H,
H-5), 7.78 (dt, J7,5 =1.5 Hz, J7,6 =J7,8 =7.8 Hz, 1H, H-7),
7.43 (d, J8,7 = 8.1 Hz, 1H, H-8), 7.32 (dt, J6(5,7) = 7.8 Hz,
J6,8 = 0.6 Hz, 1H, H-6), 7.14 (d, J2′,3′ = J6′,5′ = 9.0 Hz, 2H,
H-2′, H-6′), 6.97 (d, 2H, J3,2 =J5,6 =8.7, H-3′, H-5′), 4.05 (q,
JCH2,CH3 =7.2 Hz, 2H, OCH2), 1.34 (t, 3H, JCH3,CH2 =6.9 Hz,
CH3); EI-MS m/z (rel abundance%)=298 [M]+ (100), 162
(46), 119 (19).
Ethyl‑2‑((3‑(4‑ethoxyphenyl)‑4‑oxo‑3,4‑dihydroquinazo‑
lin‑2‑yl) thio) acetate (9) CAS#28831‑42‑7
White solid; Yield: 70%; M.P.: 240–243 °C; Rf = 0.51
(100% DCM); 1H-NMR (300 MHz, DMSO-d6): δH 8.07 (d,
J5,6 =7.8 Hz, H-5), 7.84 (dt, J7(6,8) =8.4 Hz, J7,5 =1.5, 1H,
H-7), 7.49 (ovp, 2H, H-8, H-6), 7.35 (d, J2′,3′ =J6′,5′ =9.0 Hz,
2H, H-2′, H-6′), 7.09 (d, J3′,2′ = J5′,6′ = 8.7 Hz, 2H, H-3′,
H-5′), 4.15 (ovp, 4H, 2OCH2), 3.94 (s, 2H, S-CH2), 1.39 (t,
J CH3,CH2 =6.9 Hz, 3H, CH3), 1.22 (t, JCH3,CH2 =7.2 Hz, 3H,
CH3); EI-MS: m/z (rel. abundance%)=384 [M]+ (100), 339
(33), 265 (70), 207 (98).
2‑Mercapto‑3‑(3‑nitrophenyl) quinazolin‑4(3H)‑one
(5) CAS#107943‑47‑5
Of white solid; Yield: 68%; M.P.: 322–324 °C; Rf = 0.65
(70% EtOAc/Hexane); 1H-NMR (300 MHz, DMSO-d6): δH
8.34 (d, J5,6 =9.0 Hz, 1H, H-5), 8.20 (s, 1H, H-2′), 8.08 (d,
J4′,5′ = 6.0 Hz, 1H, H-4′), 7.79 (ovp, 3H, H-6, H-5′, H-6′),
7.38 (ovp, 2H, H-7, H-8), 4.56 (s, 1H, SH); EI-MS m/z (rel.
abundance%) = 299 [M]+ (83), 298 (100), 252 (78), 267
(61), 253 (21).
3‑(2‑Methoxyphenyl)‑2‑((2‑(4‑nitrophenyl)‑2‑oxoethyl)
thio) quinazolin‑4(3H)‑one (10)
White solid; Yield: 68%; M.P.: 201–202 °C; Rf = 0.39
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH
8.41 (d, J3′′,2′′ = J5′′,6′′ = 6.6 Hz, 2H, H-3′′, H-5′′), 8.31
(d, J2′′,3′′ = J6′′,5′′ = 6.6 Hz, 2H, H-2′′, H-6′′), 8.03 (dd,
J5,7 =1.2 Hz, J5,6 =6.0 Hz, 1H, H-5), 7.72 (dt, J7(6,8) =6.3 Hz,
J7,5 = 1.2 Hz, 1H, H-7), 7.60 (dt, J6(5,7) = 6.3 Hz,
J6,8 =1.2 Hz, 1H, H-6), 7.43 (ovp, 2H, H-8, H-4′), 7.29 (d,
J6′,5′ =5.7 Hz, 1H, H-6′), 7.16 (t, J5′(4′,6′) =5.7 Hz, 1H, H-5′),
7.05 (d, J3′,4′ =6.0 Hz, 1H, H-3′), 4.80 (d, JHa,Hb =12.6 Hz,
3‑(4‑Nitrophenyl)‑2‑thioxo‑2,3‑dihydroquinazo‑
lin‑4(1H)‑one (6) [45]
Of white solid; Yield: 70%; M.P.: 316–317 °C; Rf = 0.61
(70% EtOAc/Hexane); 1H-NMR (300 MHz, DMSO-d6): δH
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Journal of the Iranian Chemical Society
1H, S-CHa), 4.68 (d, JHb,Ha = 12.6 Hz, 1H, S-CHb), 3,75
(s, 3H, OCH3); 13C-NMR (125 MHz, DMSO-d6): δC 193.5,
159.9, 157.2, 155.0, 149.9, 146.9, 141.2, 135.0, 131.9,
130.5, 129.6, 129.6, 126.6, 126.1, 126.1, 125.5, 123.9,
123.9, 120.9, 119.1, 112.8, 55.9, 39.1; EI-MS: m/z (rel.
abundance%) = 447 [M]+ (15), 415 (28), 384 (100), 297
(91), 234 (63), 150 (48); HREI-MS Calcd for C23H17N3O5S:
m/z=447.0889, found: 447.0868.
HREI-MS Calcd for C23H14ClF3N2O2S: m/z = 494.9888,
found: 494.9879.
3‑(2,3‑Dichlorophenyl)‑2‑((2‑(4‑nitrophenyl)‑2‑oxoethyl)
thio) quinazolin‑4(3H)‑one (14)
White solid; Yield: 53%; M.P.: 211–214 °C; Rf = 0.29
(100% DCM); 1H-NMR (300 MHz, DMSO-d6): δH
8.39 (d, J3′′,2′′ = J5′′,6′′ = 8.8 Hz, 2H, H-3′′, H-5′′), 8.29
(d, J2′′,3′′ = J6′′,5′′ = 8.8 Hz, 2H, H-2′′, H-6′′), 8.04 (d,
J5,6 = 7.6 Hz, 1H, H-5), 7.92 (d, J4′,5′ = 8.0 Hz, 1H, H-4′),
7.75 (ovp, 2H, H-6, H-6′), 7.64 (t, J7(6,8) =8.4 Hz, 1H, H-7),
7.45 (t, J5′(4′,6′) = 7.6 Hz, 1H, H-5′), 7.08 (d, J8,7 = 8.4 Hz.
1H, H-8), 4.84 (d, JHa,Hb = 16.8 Hz, 1H, S-CHa), 4.77 (d,
JHb,Ha =16.8 Hz, 1H, S-CHb); 13C-NMR (125 MHz, DMSO-
d6): δC 193.0, 159.6, 155.5, 150.0, 146.8, 141.1, 137.2,
135.5, 132.8, 132.6, 131.2, 130.6, 129.7, 129.7, 129.3,
126.7, 126.5, 125.7, 123.9. 123.9, 118.9, 39.2; EI-MS: m/z
(rel. abundance%) = 485 [M]+ (9), 487 [M + 2] (6), 489
[M + 4] (2), 450 (100), 452 (41) 418 (13), 335 (36), 287
(35), 150 (37); HREI-MS Calcd for C23H14ClF3N2O2S:
m/z=485.0004, found: 484.9983.
3‑(4‑Methoxyphenyl)‑2‑((2‑(4‑nitrophenyl)‑2‑oxoethyl)
thio) quinazolin‑4(3H)‑one (11) CAS#760195‑87‑7
Of white solid; Yield: 70%; M.P.: 209–212 °C; Rf = 0.43
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH
8.42 (d, J3′′,2′′ = J5′′,6′′ = 6.3 Hz, 2H, H-3′′, H-5′′), 8.31 (d,
J2′′,3′′ =J6′′,5′′ =6.0 Hz, 2H, H-2′′, H-6′′), 8.03 (d, J5,6 =5.7 Hz,
1H, H-5), 7.70 (t, J7(6,8) =5.7 Hz, 1H, H-7), 7.42 (ovp, 3H,
H-2′, H-6′), 7.14 (d, J3′,2′ = J5′,6′ = 6.3 Hz, 2H, H-3′, H-5′),
7.03 (d, J8,7 =6.0 Hz, 1H, H-8), 4.72 (s, 1H, S-CH2), 3.85 (s,
3H, OCH3); EI-MS: m/z (rel. abundance%)=447 [M]+ (30),
415 (83), 297 (92), 285 (68), 265 (100), 251 (60), 150 (45).
3‑(4‑Ethoxyphenyl)‑2‑((2‑(4‑nitrophenyl)‑2‑oxoethyl) thio)
quinazolin‑4(3H)‑one (12) CAS#768287‑72‑5
3‑(2‑Chlorophenyl)‑2‑((2‑(4‑nitrophenyl)‑2‑oxoethyl) thio)
quinazolin‑4(3H)‑one (15)
Of white solid; Yield: 70%; M.P.: 246–249 °C; Rf = 0.45
(100% Dichloromethane); 1H-NMR (400 MHz, DMSO-d6):
δH 8.42 (d, J3′′,2′′ =J5′′,6′′ =6.6 Hz, 2H, H-3′′, H-5′′), 8.31 (d,
J2′′,3′′ =J6′′,5′′ =6.6 Hz, 2H, H-2′′, H-6′′), 8.03 (d, J5,6 =6.0 Hz,
1H, H-5), 7.70 (t, J7(6,8) = 5.7 Hz, 1H, H-7), 7.42 (t,
J6(5,7) =6.0 Hz, 1H, H-6), 7.37 (d, J2′,3′ =J6′,5′ =6.6 Hz, 2H,
H-2′, H-6′), 7.11 (d, J3′,2′ = J5′,6′ = 6.3 Hz, 2H, H-3′, H-5′),
7.02 (d, J8,7 =6.3 Hz, 1H, H-8), 4.72 (s, 2H, S-CH2), 4.15
(q, JCH2,CH3 =6.8 Hz, 2H, OCH2), 1.39 (t, JCH3,CH2 =5.4 Hz,
3H, CH3); EI-MS: m/z (rel. abundance%)=461 [M]+ (33),
429 (93), 400 (27), 298 (64), 279 (84).
Yellow solid; Yield: 70%; M.P.: 187–189 °C; Rf = 0.31
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH
8.41 (d, J3′′,2′′ = J5′′,6′′ = 9.2 Hz, 2H, H-3′′, H-5′′), 8.32 (d,
J2′′,3′′ =J6′′,5′′ =8.8 Hz, 2H, H-2′′, H-6′′), 8.06 (d, J5,6 =8 Hz,
J5,7 = 1.2 Hz, 1H, H-5), 7.79 (ovp, 5H, H-7, H-3′, H-4′,
H-5′, H-6′), 7.46 (t, J6(5,7) = 7.2 Hz, 1H, H-6), 7.10 (d,
J8,7 = 8.0 Hz, 1H, H-8), 4.85 (d, JHa,Hb = 16.8 Hz, 1H,
S-CHa), 4.76 (d, JHb,Ha =16.8 Hz, 1H, S-CHb); 13C-NMR
(125 MHz, DMSO-d6): δC 193.2, 159.7, 155.9, 149.9, 146.8,
141.1, 135.3, 133.1, 132.4, 132.2, 131.6, 130.3, 129.7,
129.7, 128.7, 126.7, 126.3, 125.6, 123.9, 123.9, 118.9, 39.2;
EI-MS: m/z (rel. abundance%)=451 [M]+ (10), 453 [M+2]
(4), 416 (100), 384 (46), 301 (37), 253 (14), 234 (35), 150
(31); HREI-MS Calcd for C22H14ClN3O4S: m/z=451.0394,
found: 451.0384.
3‑(3‑Bromophenyl)‑2‑((2‑(4‑nitrophenyl)‑2‑oxoethyl) thio)
quinazolin‑4(3H)‑one (13)
White solid; Yield: 75%; M.P.: 226–228 °C; Rf = 0.34
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH
8.42 (d, J3′′,2′′ = J5′′,6′′ = 6.9 Hz, 2H, H-3′′, H-5′′), 8.31
(d, J2′′,3′′ = J6′′,5′′ = 6.6 Hz. 2H, H-2′′, H-6′′), 8.04 (dd,
J5,6 = 5.7 Hz, J5,7 = 1.0 Hz, 1H, H-5), 7.85 (ovp, 2H, H-8,
H-6′), 7.72 (dt, J7(6,8) =6.3 Hz, J7,5 =1.2 Hz, 1H, H-7), 7.60
(ovp, 2H, H-4′, H-5′), 7.44 (t, J6,7 =6.3 Hz, 1H, H-6), 7.04
(d, J6′,5′ =6.0 Hz, 1H, H-6′), 4.76 (s, 2H, S-CH2); 13C-NMR
(125 MHz, DMSO-d6): δC 193.3, 160.4, 156.0, 150.0, 146.8,
141.2, 137.3, 135.0, 133.1, 132.3, 131.4, 129.6, 129.6,
128.8, 126.6, 126.1, 125.5, 123.9, 123.9, 121.7, 119.4, 39.9;
EI-MS: m/z (rel. abundance%)=495 [M]+ (30), 497 [M+2]
(32), 464 (36), 347 (100), 333 (61), 234 (65), 150 (53);
2‑((2‑(4‑Nitrophenyl)‑2‑oxoethyl)
thio)‑3‑(3‑(trifuoromethyl) phenyl) quinazolin‑4(3H)‑one
(16)
Of white solid; Yield: 70%; M.P.: 210–212 °C; Rf = 0.42
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH
8.42 (d, J3′′,2′′ = J5′′,6′′ = 8.8 Hz, 2H, H-3′′, H-5′′), 8.31
(d, J2′′,3′′ = J6′′,5′′ = 8.8 Hz, 2H, H-2′′, H-6′′), 8.04 (ovp,
3H, H-5, H-2′, H-4′), 7.87 (ovp, 2H, H-5′, H-6′), 7.73
(dt, J7(6,8) = 8.4 Hz, J7,5 = 1.2 Hz, 1H, H-7), 7.45 (dt,
J6(5,7) =8.0 Hz, J6,8 =0.8 Hz, 1H, H-6), 7.06 (d, J8,7 =8.0 Hz,
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Journal of the Iranian Chemical Society
H-8), 4.82 (d, JHa,Hb = 16.8 Hz, 1H, S-CHa), 4.76 (d,
JHb,Ha = 16.8 Hz, 1H, S-CHb); 13C-NMR (125 MHz,
DMSO-d6): δC 193.2, 160.5, 155.8, 150.0, 146.8, 141.1,
136.7, 135.0, 133.9, 130.9, 130.4, 130.1, 129.6, 129.6,
126.9, 126.7, 126.6, 126.1, 125.5, 123.9, 123.9, 119.4, 39.5;
EI-MS: m/z (rel. abundance%)= 485 [M]+ (41), 452 (28),
335 (100), 323 (19), 289 (28), 150 (36); HREI-MS Calcd for
C23H14ClF3N3O4S: m/z=485.0657, found: 485.0670.
H-3′′, H-5′′), 8.32 (d, J2′′,3′′ =J6′′,5′′ =8.8 Hz, 2H, H-2′′, H-6′′),
8.07 (ovp, 2H, H-4′, H-6′), 7.95 (t, J7,6 =J7,8 =8.0 Hz, 1H,
H-7), 7.75 (dt, J6,5 =J6,7 =8.8 Hz, J6,8 =1.6 Hz, 1H, H-6),
7.46 (t, J5′,4′ =J5′,6′ =7.4 Hz, 1H, H-5′), 7.08 ( J8,7 =8.4 Hz,
1H, H-8), 4.84 (d, JHa,Hb = 12.6 Hz, 1H, S-CHa), 4.76 (d,
JHb,Ha =12.6 Hz, 1H, S-CHb); 13C-NMR (125 MHz, DMSO-
d6): δC 194.1, 160.2, 159.3, 152.3, 148.1, 148.9, 141.5,
134.2, 133.6, 133.4, 129.9, 129.7, 129.7, 127.3, 126.7,
126.5, 123.8, 123.8, 121.4, 120.8, 119.5, 39.5; EI-MS: m/z
(rel. abundance%) = 462 [M]+ (28), 429 (33), 312 (100),
280 (14), 266 (23), 233 (16), 150 (71); HREI-MS Calcd for
C22H14N4O6S: m/z=462.2313, found: 462.2301.
2‑((2‑(4‑Nitrophenyl)‑2‑oxoethyl)
thio‑3‑(4‑(trifuoromethyl) phenyl quinazolin‑4(3H)‑one
(17)
White solid; Yield: 70%; M.P.: 208–209 °C; Rf = 0.38
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH
8.42 (d, J3′′,2′′ = J5′′,6′′ = 8.8 Hz, 2H, H-3′′, H-5′′), 8.31 (d,
J2′′,3′′ = J6′′,5′′ = 8.8 Hz, 2H, H-2′′, H-6′′), 8.05 (ovp, 3H,
H-5, H-3′, H-5′), 7.81 (d, J2′,3′ = J6′,5′ = 8.0 Hz, 2H, H-2′,
H-6′), 7.74 (dt, J7(6, 8) =8.4 Hz, J7,5 =1.2 Hz, H-7), 7.45 (t,
J6(5,7) =7.2 Hz, 1H, H-6), 7.06 (d, J8,7 =8.0 Hz, 1H, H-8),
4.77 (s, 2H, S-CH2); 13C-NMR (125 MHz, DMSO-d6):
δC 193.2, 160.4, 155.6, 150.0, 146.8, 141.1, 139.6, 135.1,
132.1, 130.7, 130.7, 130.3, 130.3, 129.6, 129.6, 126.8,
126.6, 126.2, 125.5, 123.9, 123.9, 119.3, 39.7; EI-MS: m/z
(rel. abundance%) = 485 [M]+ (51), 452 (30), 335 (100),
321 (27), 303 (28), 289 (31), 150 (57), 119 (15); HREI-MS
Calcd for C23H14F3N3O4S: m/z=485.0657, found: 485.0669.
3‑(4‑Nitrophenyl)‑2‑((2‑(3‑nitrophenyl)‑2‑oxoethyl) thio)
quinazolin‑4(3H)‑one (20)
White solid; Yield: 70%; M.P.: 289–290 °C; Rf = 0.35
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH
8.77 (s, 1H, H-2′′), 8.55 (ovp, 2H, H-4′′, H-6′′), 8.47 (d,
J3′,2′ =J5′,6′ =8.8 Hz, 2H, H-3′, H-5′), 8.05 (d, J5,6 =7.2 Hz,
1H, H-5), 7.93 (ovp, 3H, H-2′, H-6′, H-5′′), 7.73 (t,
J7(6,8) =7.2 Hz, 1H, H-7), 7.46 (t, J6(5,7) =7.6 Hz, 1H, H-6),
7.08 (d, J8,7 =8.0 Hz, 1H, H-8), 4.83 (s, 2H, S-CH2); 13C-
NMR (125 MHz, DMSO-d6): δC 192.6, 160.4, 155.3, 148.3,
148.0, 146.8, 141.5, 137.6, 135.1, 134.5, 131.3, 131.3,
130.7, 127.7, 126.6, 126.2, 125.5, 124.8, 124.8, 122.6,
119.4, 39.2; EI-MS: m/z (rel. abundance%) = 462 [M]+
(8), 430 (42), 401 (19), 312 (36), 298 (54), 280 (26), 150
(100), 119 (23); HREI-MS Calcd for C23H14ClF3N2O2S:
m/z=462.0634, found: 462.0620.
3‑(4‑Nitrophenyl)‑2‑((2‑(4‑nitrophenyl)‑2‑oxoethyl)
thioquinazolin‑4(3H)‑one (18)
White solid; Yield: 69%; M.P.: 210–212 °C; Rf = 0.26
3‑(2‑Chlorophenyl)‑2‑((2‑(3‑nitrophenyl)‑2‑oxoethyl) thio)
quinazolin‑4(3H)‑one (21)
1
(100% DCM); H-NMR (400 MHz, DMSO-d6): δH 8.47
(ovp, 4H, H-2, H-3, H-5, H-6), 8.32 (d, J3′,2′ =J5′,6′ =8.8 Hz,
2H, H-3′, H-5′), 8.05 (d, J5, 6 = 7.6 Hz, 1H, H-5), 7.89 (d,
J2′,3′ =J6′,5′ =8.8 Hz, 2H, H-2′, H-6′), 7.74 (t, J7(6,8) =8.0 Hz,
1H, H-7), 7.46 (t, J6(5,7) = 7.6 Hz, 1H, H-6), 7.08 (d,
J8,7 = 8.0 Hz, 1H, H-8), 4.80 (s, 2H, S-CH2); 13C-NMR
(125 MHz, DMSO-d6): δC 193.1, 160.4, 155.2, 150.0, 148.3,
146.8, 141.5, 141.1, 135.1, 131.3, 131.3, 129.6, 129.6,
126.6, 126.3, 125.6, 124.8, 124.8, 123.9, 123.9, 119.3, 39.5;
EI-MS: m/z (rel. abundance%) = 462 [M]+ (2), 430 (16),
298 (92), 252 (20), 178 (46), 150 (100), 119 (48); HREI-
MS Calcd for C23H14ClF3N2O2S: m/z = 462.0634, found:
462.0620.
Of white solid; Yield: 68%; M.P.: 174–176 °C; Rf = 0.37
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH 8.77 (s,
1H, H-2′′), 8.54 (ovp, 2H, H-4′′, H-6′′), 8.06 (d, J5,6 =8.0 Hz,
1H, H-5), 7.92 (t, J5′′(4′′,6′′) =8.0 Hz, 1H, H-5′′), 7.79 (ovp,
3H, H-7, H-3′, H-6′), 7.68 (ovp, 2H, H-5′, H-4′), 7.46 (t,
J6(5,7) =8.0 Hz, 1H, H-6), 7.11 (d, J8,7 =8.0 Hz, H-8); 13C-
NMR (125 MHz, DMSO-d6): δC 192.7, 159.7, 155.9, 148.0,
146.8, 137.6, 135.3, 134.5, 133.1, 132.4, 132.2, 131.6,
130.6, 130.3, 128.7, 127.6, 126.7, 126.3, 125.6, 122.6,
118.9, 38.8; EI-MS: m/z (rel. abundance%)=451 [M]+ (17),
453 [M+2] (6), 384 (57), 301(78), 253 (70), 150 (96), 132
(33); HREI-MS Calcd for C22H14ClN3O4S: m/z=451.0394,
found: 451.0385.
3‑(3‑Nitrophenyl)‑2‑((2‑(4‑nitrophenyl)‑2‑oxoethyl) thio)
quinazolin‑4(3H)‑one (19)
3‑(4‑Ethoxyphenyl)‑2‑((2‑(3‑nitrophenyl)‑2‑oxoethyl) thio)
White solid; Yield: 72%; M.P.: 224–226 °C; Rf = 0.33
quinazolin‑4(3H)‑one (22) CAS#767994‑98‑9
1
(100% DCM); H-NMR (400 MHz, DMSO-d6): δH 8.57
(t, J2′(4′,6′) = 2.0 Hz, 1H, H-2′), 8.48 (dd, J5,6 = 8.0 Hz,
J5,7 =1.2 Hz, 1H, H-5), 8.42 (d, J3′′,2′′ =J5′′,6′′ =8.8 Hz, 2H,
White solid; Yield: 70%; M.P.: 179.0–182.5 °C; Rf =0.46
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH 8.77 (s,
1 3

Journal of the Iranian Chemical Society
1H, H-2′′), 8,54 (m, 2H, H-4′′, H-6′′), 8.03 (d, J5,6 =7.6 Hz,
1H, H-5), 7.92 (t, J5(4,6) = 8.0 Hz, 1H, H-5′′), 7.70 (dt,
J7(5,8) =8.4 Hz, J7,5 =1.2 Hz, 1H, H-7), 7.42 (ovp, 3H, H-6,
H-2′, H-6′), 7.11 (d, J3′,2′=J5′,6′=8.8 Hz, 2H, H-3′, H-5′), 7.02
(d, J8,7 =8.0 Hz, 1H, H-8), 4.75 (s, 2H, CH2), 4.15 (quartet,
JCH2,CH3 =7.2 Hz, 2H, OCH2), 1.39 (t, JCH3,CH2 =6.8 Hz, 3H,
CH3); EI-MS: m/z (rel. abundance%)=461 [M]+ (37), 429
(41), 311 (100), 299 (44), 284 (30), 279 (38), 265 (24), 150
(31), 119 (16).
2‑((2‑(4‑Chlorophenyl)‑2‑oxoethyl)
thio)‑3‑(4‑(trifuoromethyl) phenyl) quinazolin‑4(3H)‑one
(25)
White solid; Yield: 85%; M.P.: 221–222 °C; Rf = 0.41
1
(100% DCM); H-NMR (300 MHz, DMSO-d6): δH 8.11
(d, J2′′,3′′ = J6′′,5′′ = 8.8 Hz, 2H, H-2′′, H-6′′), 8.05 (d,
J5,6 = 6.8 Hz, 1H, H-5), 8.02 (d, J3′′,2′′ = J5′′,6′′ = 8.4 Hz,
2H, H-3′′, H-5′′), 7.80 (d, J3′,2′ = J5′,6′ = 8.4 Hz, 2H, H-3′,
H-5′), 7.76 (dt, J7(6,8) = 8.4 Hz, J7,5 = 1.2 Hz, 1H, H-7),
7.68 (d, J2′,3′ = J6′,5′ = 8.4 Hz, 2H, H-2′, H-6′), 7.45 (t,
J6(5,7) = 7.6 Hz, 1H, H-6), 7.12 (d, J8,7 = 8.0 Hz, 1H, H-8),
4.73 (s, 2H, S-CH2); 13C-NMR (125 MHz, DMSO-d6):
δC 192.6, 160.4, 155.7, 146.8, 139.6, 138.3, 135.0, 135.0,
130.6, 130.6, 130.4, 130.4, 130.1, 130.1, 128.9, 128.9,
126.8, 126.7, 126.5, 126.1, 125.6, 119.4, 39.2; EI-MS:
m/z (rel. abundance%) = 474 [M+] (61), 476 [M + 2] (26),
335 (82), 321 (38), 303 (31), 289 (25), 139 (100); HREI-
MS Calcd for C23H14ClF3N2O2S: m/z = 474.0417, found:
474.0406.
2‑((2‑(3‑Nitrophenyl)‑2‑oxoethyl)
thio)‑3‑(2‑(trifuoromethyl) phenyl) quinazolin‑4(3H)‑one
(23)
Of white solid; Yield: 60%; M.P.: 189–191 °C; Rf =0.44
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH 8.77 (t,
J2′′(6′′,4′′) =2.0 Hz, 1H, H-2′′), 8.54 (ovp, 2H, H-4′′, H-6′′),
8.05 (ovp, 6H, H-5, H-3′, H-4′, H-5′, H-6′, H-5′′), 7.75 (dt,
J7(6,8)=8.4 Hz, J7,5=1.6 Hz, 1H, H-7), 7.46 (dt, J6(5,7)=8.0 Hz,
J6,8 =0.8 Hz, 1H, H-6), 7.11 (d, J8,7 =8.0 Hz, 1H, H-8), 4.86
(d, JHa,Hb =16.4 Hz, 1H, S-CHa), 4.80 (d, JHb,Ha =16.8 Hz,
1H, S-Hb); 13C-NMR (125 MHz, DMSO-d6): δC 192.6, 160.5,
156.1, 147.9, 146.7, 137.6, 135.3, 134.5, 134.3, 133.0, 132.5,
131.4, 130.6, 127.8, 127.6, 127.3, 127.0, 126.6, 126.4, 125.6,
122.6, 118.9, 39.1; EI-MS: m/z (rel. abundance%) = 485
[M]+ (36), 452 (34), 335 (100), 289 (18), 253 (17), 150 (26);
HREI-MS Calcd for C23H14F3N3O4S: m/z=485.0657, found:
485.0632.
2‑((2‑(4‑Chlorophenyl)‑2‑oxoethyl) thio)‑3‑(4‑ethoxyphe‑
nyl) quinazolin‑4(3H)‑one (26) CAS#566902‑45‑2
Of white solid; Yield: 66%; M.P.: 223–225 °C; Rf = 0.47
(100% DCM); 1H-NMR (300 MHz, DMSO-d6): δH 8.10 (d,
J3′′,2′′ =J5′′,6′′ =8.4 Hz, 2H, H-3′′, H-5′′), 8.03 (d, J5,6 =8.0 Hz,
1H, H-5), 7.28 (dt, J7(6,8) =8.4 Hz, J7,5 =1.2 Hz, 1H, H-7),
7.67 (d, J2′′,3′′ = J6′′,5′′ = 8.4 Hz, 2H, H-2′′, H-6′′), 7.42 (t,
J6(5,7) = 8.0 Hz, 1H, H-6), 7.37 (d, J2′,3′ = J6′,5′ = 8.8 Hz,
2H, H-2′, H-6′), 7.11 (ovp, 3H, H-8, H-3′, H-5′), 4.68 (s,
2H, S-CH2), 4.14 (q, JCH2,CH3 = 7.2 Hz, 2H, OCH2), 1.39
(t, JCH3,CH2 = 6.8 Hz, 3H, CH3); EI-MS: m/z (rel. abun-
dance%)=450 [M+] (36), 452 [M+2] (13), 311 (100), 288
(36), 265 (28), 138 (88), 119 (22).
3‑(3‑Bromophenyl)‑2‑((2‑(4‑chlorophenyl)‑2‑oxoethyl) thio)
quinazolin‑4(3H)‑one (24)
White solid; Yield: 75%; M.P.: 204–206 °C; Rf = 0.36
(100% DCM); 1H-NMR (400 MHz, DMSO-d6): δH 8.10 (d,
J2′′,3′′ =J6′′,5′′ =6.8 Hz, 2H, H-2′′, H-6′′), 8.04 (dd, J5,6=8.0 Hz,
J5,7=1.2 Hz, 1H, H-5), 7.84 (t, J2′,6′=J2′,4′=2.0 Hz, 1H, H-2′),
7.82 (m, 1H, H-4′), 7.74 (dt, J7(6,8) =7.2 Hz, J7,5 =1.6 Hz, 1H,
H-7), 7.68 (d, J3′′,2′′ =J5′′,6′′ =8.8 Hz, 2H, H-3′′, H-5′′), 7.59
(ovp, 2H, H-6′, H-5′), 7.44 (dt, J6(5,7) =8.0 Hz, J6,8 =1.2 Hz,
1H, H-6), 7.11 (d, J8,7 = 8.0 Hz, 1H, H-8), 4.73 (s, 1H,
S-CH2); 13C-NMR (125 MHz, DMSO-d6): δC 192.8, 160.5,
156.0, 146.8, 138.4, 137.3, 135.0, 134.9, 133.0, 132.3, 131.4,
130.2, 130.2, 128.9, 128.9, 128.8, 126.6, 126.1, 125.5, 121.7,
119.4, 38.9; EI-MS: m/z (rel. abundance%)=484 [M]+ (11),
486 [M+2] (16), 488 [M+4] (4), 405 (17), 345 (32), 168
(13), 139 (100); HREI-MS Calcd for C22H14BrClN2O2S:
m/z=483.9648, found: 483.9641.
2‑((2‑Oxo‑2‑(p‑tolyl) ethyl) thio)‑3‑(4‑(trifuoromethyl)
phenyl) quinazolin‑4(3H)‑one (27)
White solid; Yield: 75%; M.P.: 230–232 °C; Rf = 0.51
1
(100% DCM); H-NMR (400 MHz, DMSO-d6): δH 8.05
(dd, J5,6 = 8.0 Hz, J5,7 = 1.2 Hz, 1H, H-5), 8.03 (ovp, 4H,
H-2′′, H-3′′, H-5′′, H-6′′), 7.80 (d, J2,3 = J6,5 = 8.4 Hz, 2H,
H-2′, H-6′), 7.75 (dt, J7(6,8) =8.4 Hz, J7,5 =1.6 Hz, 1H, H-7),
7.45 (t, J6(5,7) = 8.0 Hz, J6,8 = 0.8 Hz, 1H, H-6), 7.40 (d,
J3′′,2′′ =J5′′,6′′ =8.0 Hz, 2H, H-3′′, H-5′′), 7.17 (d, J8,7 =8.0 Hz,
1H, H-8), 4.74 (s, 2H, S-CH2), 2.41 (s, 3H, CH3); 13C-NMR
(125 MHz, DMSO-d6): δC 194.1, 160.6, 159.3, 146.9, 142.8,
136.0, 133.4, 132.4, 132.1, 129.7, 129.7, 128.8, 128.8,
128.1, 128.1, 127.3 126.7, 126.4, 125.3, 125.3, 124.2, 120.8.
38.8, 22.7; EI-MS: m/z (rel. abundance%)=454 [M+] (11),
1 3

Journal of the Iranian Chemical Society
421 (19), 303 (9), 289 (6), 148 (15), 119 (100); HREI-MS
JHb,Ha =12.3 Hz, 1H, S-CHb), 2.40 (s, 1H, CH3); 13C-NMR
(125 MHz, DMSO-d6): δC 192.9, 160.5, 156.1, 146.9, 143.9,
137.3, 134.9, 133.8, 133.0, 132.3, 131.4, 129.3, 129.3, 128.8,
128.4, 128.4, 126.6, 126.0, 125.7, 121.7, 119.0, 39.0, 21.2;
EI-MS: m/z (rel. abundance%)=464 [M+] (10), 466 [M+2]
(11), 431 (14), 433 (13), 385 (12), 119 (100); HREI-MS:
Calcd for C23H17BrN2O2S: m/z 464.0194, found: 464.0189.
Calcd for C24H17N2F3O2S: m/z=454.3132, found: 454.3116.
2‑((2‑Oxo‑2‑(p‑tolyl) ethyl) thio)‑3‑(3‑(trifuoromethyl)
phenyl) quinazolin‑4(3H)‑one (28)
White solid; Yield: 62%; M.P.: 213–214 °C; Rf = 0.53
1
(100% DCM); H-NMR (400 MHz, DMSO-d6): δH 8.05
Acknowledgements The authors are thankful to the Pakistan Academy
of Sciences, Pakistan, for providing fnancial support to Project No.
(5-9/PAS/440).
(d, J2′′,3′′ = J6′′,5′′ = 8.0 Hz, 2H, H-2′′, H-6′′), 7,98 (ovp,
3H, H-5, H-2′, H-4′), 7.87 (dd, J3′′,2′′ = J5′′,6′′ = 5.2 Hz,
J3′′,5′′ = J5′′,3′′ = 1.2 Hz, 2H, H-3′′, H-5′′), 7.75 (dt,
J7(6,8) = 8.4 Hz, J7,5 = 1.2 Hz, 1H, H-7), 7.45 (ovp, 3H,
H-6, H-5′, H-6′), 7.17 (d, J8,7 =8.0 Hz, 1H, H-8), 4.78 (d,
JHa,Hb = 16.8 Hz, 1H, S-CHa), 4.72 (d, JHb,Ha = 16.4 Hz,
1H, S-CHb); 13C-NMR (125 MHz, DMSO-d6): δC 192.9,
160.6, 156.0, 146.9, 143.9, 136.7, 134.9, 133.9, 133.7,
130.9, 130.4, 129.3, 129.3, 128.4, 128.4, 126.9, 126.7,
126.5, 126.0, 125.6, 124.7, 119.4, 39.4, 21.2; EI-MS: m/z
(rel. abundance%)=454 [M+] (47), 421 (72), 321 (23), 303
(19), 289 (15), 145 (14), 119 (100); HREI-MS Calcd for
C24H17N2F3O2S: m/z=454.0963, found: 454.0975.
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1
(100% DCM); H-NMR (300 MHz, DMSO-d6): δH 8.04
(d, J5,6 = 6.8 Hz, 1H, H-5), 7.96 (d, J2′′,3′′ = J6′′,5′′ = 8.4 Hz,
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