Novel quinazolin–sulfonamid derivatives: synthesis, characterization, biological evaluation, and molecular docking studies

Article abstract of DOI:10.1080/07391102.2020.1847193

In the design of novel drugs, the formation of hybrid molecules via the combination of several pharmacophores can give rise to compounds with interesting biochemical profiles. A series of novel quinazolin–sulfonamid derivatives (9a–m) were synthesized, characterized and evaluated for their in vitro antidiabetic, anticholinergics, and antiepileptic activity. These synthesized novel quinazolin–sulfonamid derivatives (9a–m) were found to be effective inhibitor molecules for the α-glycosidase, human carbonic anhydrase I and II (hCA I and hCA II), butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzyme, with Ki values in the range of 100.62 ± 13.68–327.94 ± 58.21 nM for α-glycosidase, 1.03 ± 0.11–14.87 ± 2.63 nM for hCA I, 1.83 ± 0.24–15.86 ± 2.57 nM for hCA II, 30.12 ± 3.81–102.16 ± 13.87 nM for BChE, and 26.16 ± 3.63–88.52 ± 20.11 nM for AChE, respectively. In the last step, molecular docking calculations were made to compare biological activities of molecules against enzymes which are achethylcholinesterase, butyrylcholinesterase and α-glycosidase. Communicated by Ramaswamy H. Sarma.

Full text of DOI:10.1080/07391102.2020.1847193

Journal of Biomolecular Structure and Dynamics
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
Novel quinazolin–sulfonamid derivatives:
synthesis, characterization, biological evaluation,
and molecular docking studies
Nima Sepehri , Maryam Mohammadi-Khanaposhtani , Nafise Asemanipoor ,
Samanesadat Hosseini , Mahmood Biglar , Bagher Larijani , Mohammad
Mahdavi , Haleh Hamedifar , Parham Taslimi , Nastaran Sadeghian , Mostafa
Norizadehtazehkand & Ilhami Gulcin
To cite this article: Nima Sepehri , Maryam Mohammadi-Khanaposhtani , Nafise Asemanipoor ,
Samanesadat Hosseini , Mahmood Biglar , Bagher Larijani , Mohammad Mahdavi , Haleh
Hamedifar , Parham Taslimi , Nastaran Sadeghian , Mostafa Norizadehtazehkand & Ilhami Gulcin
(2020): Novel quinazolin–sulfonamid derivatives: synthesis, characterization, biological evaluation,
and molecular docking studies, Journal of Biomolecular Structure and Dynamics
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JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2020.1847193
Novel quinazolin–sulfonamid derivatives: synthesis, characterization, biological
evaluation, and molecular docking studies
Nima Sepehria, Maryam Mohammadi-Khanaposhtanib, Nafise Asemanipoorc, Samanesadat Hosseinid, Mahmood
Biglarc, Bagher Larijanic, Mohammad Mahdavic, Haleh Hamedifare, Parham Taslimif , Nastaran Sadeghiang,
Mostafa Norizadehtazehkandh and Ilhami Gulcing
b
aNano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research
c
Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Endocrinology and Metabolism Research Center,
d
Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Shahid Beheshti University of
e
Medical Sciences, Tehran, Iran; CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran;
g
fDepartment of Biotechnology, Faculty of Science, Bartin University, Bartin, Turkey; Department of Chemistry, Faculty of Science, Ataturk
h
University, Erzurum, Turkey; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Zonguldak Bulent Ecevit University,
Zonguldak, Turkey
Communicated by Ramaswamy H. Sarma
ABSTRACT
ARTICLE HISTORY
Received 7 June 2020
Accepted 2 November 2020
In the design of novel drugs, the formation of hybrid molecules via the combination of several phar-
macophores can give rise to compounds with interesting biochemical profiles. A series of novel quina-
zolin–sulfonamid derivatives (9a–m) were synthesized, characterized and evaluated for their in vitro
antidiabetic, anticholinergics, and antiepileptic activity. These synthesized novel quinazolin–sulfonamid
derivatives (9a–m) were found to be effective inhibitor molecules for the a-glycosidase, human car-
bonic anhydrase I and II (hCA I and hCA II), butyrylcholinesterase (BChE) and acetylcholinesterase
(AChE) enzyme, with Ki values in the range of 100.62 13.68–327.94 58.21 nM for a-glycosidase,
1.03 0.11–14.87 2.63 nM for hCA I, 1.83 0.24–15.86 2.57 nM for hCA II, 30.12 3.81–102.16
13.87 nM for BChE, and 26.16 3.63–88.52 20.11 nM for AChE, respectively. In the last step, molecu-
lar docking calculations were made to compare biological activities of molecules against enzymes
which are achethylcholinesterase, butyrylcholinesterase and a-glycosidase.
KEYWORDS
Quinazolin; sulfonamide;
enzyme inhibition;
molecular docking
Introduction
The pathophysiology of Alzheimer’s disease (AD) is related
to the depletion of the neurotransmitter acetylcholine (ACh)
due to acetylcholiesterase (AChE) activity. This enzyme cata-
lyzes hydrolysis of neurotransmitter ACh. Butyrylcholinesterase
(BChE, E.C.3.1.1.8) created inside liver tissue, consider as a
backup for the AChE. Also, BChE had a crucial role in the cho-
linergic mechanism, and its inhibition improved the cognitive
functions (Bayrak et al., 2017; Behc¸et et al., 2018; Bic¸er et al.,
2019; Bilgic¸li et al., 2019; Boztas et al., 2019). Both cholinergic
enzymes share some structural similarities, containing the
presence of a catalytic center. The searches of new cholinester-
ases (AChE and BChE) inhibitors sound a key mechanism to
familiarize novel drug candidates against related dementias
and AD (Bradford, 1976; Burmaoglu et al., 2018, 2019).
Quinazolinone and quinazoline compounds constitute a sig-
nificant class of biologically active derivatives. These two het-
erocycle cores exist in various natural product molecules and
have proven to possess pharmacological properties such as
anticholinesterase, anticancer, antidiabetic, anticonvulsant,
antihypertensive, anti-HIV, anti-inflammatory, antimicrobial,
antimalarial, antitumor, antitubercular, cellular phosphoryl-
ation inhibition, dihydrofolate reductase inhibition, and kin-
ase inhibitory activities. Sulfonamide and quinazoline
moieties have been recorded as classes of cancer chemother-
apeutic factors with an important therapeutic effect against
ꢀ
solid tumors (Akıncıoglu et al., 2017; Aksu et al., 2016, 2018).
Indeed, quinazoline compounds, as a significant pharmaco-
phore, have emerged as a versatile format for inhibition of a
various range of receptor tyrosine kinase and some meta-
bolic enzymes. The most extensively studied of these is the
epidermal growth factor receptor, with the small-molecule
inhibitor gefitinib being the first quinazoline compound to
be recorded for the therapy of non-small cell lung cancer
(Aktas¸ et al., 2017, 2019; Atmaca et al., 2019).
Diabetes mellitus (DM) was known as a popular metabolic
degenerative disorder is characterized by a high amount of
blood glucose. Antidiabetic therapies determine that deter-
mining the amount of blood sugar is effective for diabetes.
a-Glycosidases are found on the brushy surface of the small
intestine and accountable for the breakdown of carbohydrate
polymers (Caglayan et al., 2019; Dastan et al., 2017; Ellman
et al., 1961; Erdemir et al., 2019).
CONTACT Parham Taslimi
ptaslimi@bartin.edu.tr
Faculty of Science, Bartin University, 74100, Bartin, Turkey; Mohammad Mahdavi
momahdavi@sina.tums.ac.ir
Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
N. SEPEHRI ET AL.
Scheme 1. Synthesis procedure for quinazolin–sulfonamid derivatives 9a–m.
The human carbonic anhydrases (hCAs) are belong to the 2,3-dihydroquinazolin-4(1–)-one derivatives 5a–m. On the
other hand, reaction between 4-aminobenzenesulfonamide 6
and chloroacetyl chloride 7 in DMF at room temperature led
to produce 2-chloro-N-(4-sulfamoylphenyl)acetamide 8.
Finally, 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives
a-subfamily of CA and divided into 16 diverse isoforms that
have different catalytic activity, amino acid sequence, kinetic
properties, cellular and tissue distribution, subcellular local-
ization, biochemical properties, sensitivity to inhibitors and
activators. These CA isoenzymes are grouped as cytoplasmic
CAs I, II, III, VII, and XIII, membrane bounded CAs IV, IX, XII,
XIV, and XV, mitochondrial CA V , secretorial CA VI. Finally,
CAs VIII, X and XI are CA-related proteins (CARPs), which
have not performed CO2 hydration activity and physiological
function (Garibov et al., 2016; Gokcen et al., 2017; Gul et al.,
2019; Gulc¸in et al., 2017; Gulc¸in & Taslimi, 2018).
In the light of this information, the aim of this study was
to investigate the inhibition impacts of novel quinazolin–sul-
fonamid derivatives (9a–m) on hCA I, and hCA II isoenzymes
and AChE, BChE, and a-glycosidase enzymes. Also, their
inhibition profiles were compared to acetazolamide as a clin-
ical used inhibitor.
5a–m and 2-chloro-N-(4-sulfamoylphenyl)acetamide
8
reacted in the presence of K2CO3 in DMF at 60 ꢀC to give
desired compounds 9a–m.
2.2. Enzymes results
Carbonic anhydrase inhibitors (CAIs) show numerous bioac-
tivities associated to many diseases such as glaucoma, obes-
ity, cancer, epilepsy and osteoporosis. Due to these
important physiological functions, numerous studies have
been carried out on CAs and CAIs. Both CA I, and CA II are
the most studied and examined isoenzymes (Gulc¸in et al.,
2018; Hassanzadeh et al., 2019; Hayakawa et al., 1999). CA I
is expressed in erythrocytes and the gastrointestinal tract on
the other hand, CA II is expressed in almost all tissues mainly
including eye, erythrocytes, gastrointestinal tract, bone osteo-
clasts, kidney, brain, testis, and lung. CA II isoenzyme is a sin-
gle chain protein including 295 amino acids with nearly
29 kDa molecular weight (Hisamoto et al., 2006; Huseynova
et al., 2019). Both CA I, and CA II involved in important meta-
bolic functions such as gas exchange, and ion transport
(Huseynova et al., 2018; Is¸ık et al., 2017). The results pre-
sented in Table 1 record that novel quinazolin–sulfonamid
derivatives (9a–m) had effective inhibition against hCA I iso-
2. Results and discussion
2.1. Chemistry
Synthesis procedure for the preparation of quinazolin–sulfo-
namid derivatives 9a–m was depicted in Scheme 1. It was
started of reaction between 2H-benzo[d][1,3]oxazine-2,4(1H)-
dione 1 and various amines 2a–m in water at room tempera-
ture. Then, the obtained 2-aminobenzamide derivatives
3a–m reacted with disulfide carbon 4 in the presence of
KOH in ethanol at reflux condition and produced 2-thioxo- form. The hCA
I
isoform was inhibited by novel

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
3
quinazolin–sulfonamid derivatives (9a–m) in nanomolar lev-
els, the Ki of which obtained between 1.03 0.11 and
14.87 2.63 nM. Indeed, acetazolamide (AZA), as a broad-spe-
cificity CA inhibitor showed Ki value of 20.52 3.17 nM
against hCA I. Among the inhibitors , the 9i and 9k were
obtained to be the excellent hCA I inhibitor with Ki of
1.03 0.11 and 2.55 0.32 nM, respectively. The hCA I inhib-
ition effects of novel quinazolin–sulfonamid derivatives
(9a–m) were found to be the greater than AZA. For hCA I,
IC50 values of AZA as positive control and some novel quina-
zolin–sulfonamid derivatives (9a–m); the following order: 9i
(0.93 nM, r2: 0.9687) < 9k (2.11 nM, r2: 0.9482) < 9e (4.86 nM,
r2: 0.9830) < 9j (5.16 nM, r2: 0.9623) < AZA (18.21 nM, r2:
0.9675). Against the hCA II isoform, the novel quinazolin–sul-
fonamid derivatives (9a–m) demonstrated Kis varying from
1.83 0.24 to 15.86 2.57 nM (Table 1). These novel quinazo-
lin–sulfonamid derivatives (9a–m) were observed to have
high inhibition effects toward hCA II. Additionally, AZA
showed Ki of 23.77 4.01 nM against hCA II. The 9i and 9k
had shown the most inhibition effect with Ki values of
1.83 0.24 and 3.63 0.91 nM, respectively. For hCA II, IC50
values of AZA and some novel quinazolin–sulfonamid deriva-
tives (9a–m); the following order: 9i (1.32 nM, r2: 0.9793) <
9k (3.11 nM, r2: 0.9562) < 9e (5.97 nM, r2: 0.9699) < 9 g
(6.82 nM, r2: 0.9717) < AZA (21.20 nM, r2: 0.9863).
AChE and BChE inhibition properties of novel quinazolin–-
sulfonamid derivatives (9a–m) were determined according to
the Ellman’s procedure (1961) as previously described. Novel
quinazolin–sulfonamid derivatives (9a–m) are the potent
derivatives with IC50 values in ranging between 35.97 and
100.73 nM for AChE (Table 1) and 40.32 and 125.04 nM for
BChE, whereas, TAC had IC50 value of 137.21 nM against
AChE (r2: 0.9833) and 163.21 nM against BChE (r2: 0.9809). All
studied compounds demonstrated powerful inhibition
against cholinergic enzyme of AChE, but 9f showed the best
inhibition effect against AChE (IC50: 35.97 nM; r2: 0.9683)
(Table 1). It is well known that sulfonamid compounds pos-
sess a wide spectrum of pharmacological activities mainly
acting as anticancer agents. On the other hand, when the
inhibition results for BChE were examined, it was clearly
observed that 9f was the best inhibitor with IC50 value of
40.32 nM, which 4.65 times greater than tacrine (IC50:
163.21 nM; r2: 0.9809). All of novel quinazolin–sulfonamid
derivatives (9a–m) had significantly higher AChE inhibitory
activity than tacrine as control molecule. Furthermore, the Ki
values of novel quinazolin–sulfonamid derivatives (9a–m)
and tacrine are summarized in Table 1. As can be observed
from the results recorded in Table 1, novel quinazolin–sulfo-
namid derivatives (9a–m) effectively inhibited AChE, with Ki
values in the range of 26.16 3.63 to 88.52 20.11 nM. Thus,
all of these novel compounds had almost similar inhibition
profiles. The most active 9f and 9a showed Ki values of
26.16 3.63 and 30.74 5.96 nM. For AChE, IC50 values of
TAC and some novel quinazolin–sulfonamid derivatives
(9a–m) the following order: 9f (35.97 nM, r2: 0.9683) < 9a
(40.93 nM, r2: 0.9490) < 9j (43.54 nM, r2: 0.9306) < TAC
(137.21 nM, r2: 0.9833). AChEIs like donepezil are approved
by the Drug Administration and United States Food for the

4
N. SEPEHRI ET AL.
Figure 1. Interaction pose of compound 9i in the active sites of hCA I (a) and hCA II (b).
treatment of AD, and have clinical trial data supporting their
As can be seen in Table 1, compound 9i was the most potent
compound against hCA I and hCA II and therefore was evaluated
in the active site of these isoenzymes. Acetazolamide as a stand-
ard inhibitor against hCA I and hCA II isoenzymes can be estab-
lished interactions with His200 and Zn301 in the active site of
hCA I and Asn67, Thr199, and Zn265 in the hCA II active site
(Nasab et al., 2018). As can be seen in Figure 1a, compound 9i in
addition two weak interaction with His200 and Zn301 also can
be formed two hydrogen bonds with Thr199, three sulfur inter-
actions with His94, His96, and Trp209, and a hydrophobic inter-
action via phenylsulfonamide moiety and hydrophobic
interactions with Pro201, Pro202, and Trp5 via 4-chlorophenyl
group. On the other hand, as can be seen in Figure 1b, com-
pound 9i established two hydrogen bonds with Thr199, a hydro-
gen bond with Asn67, and a covalent bond with Zn265 in the
hCA II active site. Furthermore, this compound interacted with
residues His94 (p–p), Asn62 (H-bond), Gln92 (H-bond), Glu106
(salt bridge), and Trp209 (p-sulfur). Other interactions of com-
pound 9i with active site of hCA II were observed in Figure 1b.
Among the synthesized compounds, the most potent
inhibitor against a-glucosidase was compound 9h. As can be
seen in Figure 2a, standard inhibitor acarbose established
hydrogen bonds with residues Gln322, Thr301, Arg312,
Thr307, Glu304, Ser308, and Asn241 and a hydrophobic inter-
action with His279. Furthermore, this drug formed weak car-
bon hydrogen bonds with Phe157, Val305, Glu304, and
His239. On the other hand, two unfavorable interactions with
Thr307 and Arg312 also observed in interaction mode of
acarbose. Compound 9 h established four hydrogen bonds
with residues Glu304, Phe157, Arg312, and His279. This com-
pound also created two weak carbon hydrogen bonds with
His239 and Gly306 (Figure 3(b)). Sulfur atom attached to
utilize in Parkinson’s disease and vascular dementia (Jafari
et al., 2011; Khodarahmi et al., 2012; Kocyigit et al.,
2018, 2019).
Inhibition of a-glucosidases by inhibitors tends to slow
the breakdown and release of sugar molecules into the
bloodstream and can be utilized as therapeutic factors in the
therapy of obesity and diabetes. Indeed, some of the inhibi-
tors are utilized in the treatment mainly voglibose, acarbose,
and miglitol compounds (Kocyigit, Budak et al., 2017;
Kocyigit, Tas¸kıran, et al., 2017; Kucukoglu et al., 2019; Kuzu
et al., 2019; Lineweaver & Burk, 1934). Finally, a-glycosidase
was much more inhibited by all tested novel quinazolin–sul-
fonamid derivatives (9a–m) (IC50: 94.16–315.74 nM) (Table 1).
The results showed that all novel quinazolin–sulfonamid
derivatives (9a–m) had effective a-glycosidase inhibition
effects than that of acarbose (IC50: 354.87 nM, r2: 0.9673) as
standard a-glycosidase inhibitor. Also, when the results were
evaluated, 9h was found to be the best inhibitor for a-glyco-
sidase (IC50:94.16 nM; r2: 0.9873). For a-glycosidase, IC50 val-
ues of ACR as positive control and some novel
quinazolin–sulfonamid derivatives (9a–m) the following
order: 9h (94.16 nM, r2: 0.9873) < 9e (109.36 nM, r2: 0.9901)
< 9b (132.71 nM, r2: 0.9377) < ACR (354.87 nM, r2: 0.9673).
2.3. Docking results
Given that our new compounds evaluated against hCA I,
hCA II, a-glucosidase, AChE, and BuChE, docking study of the
most potent compounds against each of these enzymes was
also performed by Autodock Tools (1.5.6).

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
5
Figure 2. (a) Interaction mode of standard inhibitor acarbose and (b) compound 9h in the active site of a-glucosidase.
Figure 3. Interaction modes of compound 9f in the active sites of AChE (a) and BuChE (b).
quinazolin ring interacted with His239 and Phe311. interactions with AChE active site residues Phe288 (acyl
Furthermore, compound 9h two hydrophobic interactions
formed with Pro309 and Arg312.
pocket) and Arg289. Interaction mode of compound 9f in the
active site of BuChE is also showed in Figure 3b. Compound
9f formed interactions with catalytic anionic site residues
Trp82 and Phe329, acyl pocket residue Leu286, and amino
acids Trp231, Trp430, and Ala328 of BuChE active site.
All the synthesized compounds 9a–m demonstrated excel-
lent to good anti-cholinesterase activity against AChE and
BuChE. For example, compound 9f exhibited inhibitory activity
around 20-fold more than standard inhibitor tacrine against
the latter enzymes (Table 1). Docking study of compound 9f
predicted that this compound interacted with catalytic anionic
site residues Trp84, Phe300, and Phe301 and peripheral
3. Conclusions
A series of quinazolin–sulfonamid derivatives (9a–m) with
3(a)) (Okten et al., 2019). Furthermore, compound 9f formed various sulfonamides were synthesized and characterized by
anionic site residue Tyr121 in the active site of AChE (Figure
€

6
N. SEPEHRI ET AL.
different spectroscopic techniques. The inhibitory effects of
some novel quinazolin–sulfonamid derivatives (9a–m) on
hCA I, and II isoenzymes and AChE, BChE and a-glycosidase
enzymes were evaluated together. The novel quinazolin–sul-
fonamid derivatives (9a–m) we used in our study showed
inhibition effects on hCA I, and II isoenzymes and AChE,
BChE and a-glycosidase enzymes activities at low nanomolar
concentrations. We believe that these results may be useful
in the synthesis of new CA isoenzyme inhibitors and in the
development of drugs for the treatment of some diseases.
2-((4-Oxo-3-propyl-3,4-dihydroquinazolin-2-yl)thio)-N-(4-
sulfamoylphenyl)acetamide 9a
Yield: 91%; mp ¼ 198-200. IR (KBr): 3367.0, 3278.5 (NH),
1688.0, 1668 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 0.97 (t,
1
4. Experimental
J ¼ 7.5 Hz, 3H, CH3), 1.73-1.81(m, 2H, CH2), 4.05 (m, 2H, S-
CH2), 4.28 (s, 2H, N-CH2), 7.29 (bs, 2H, NH2), 7.41–7.45 (m, 2H,
Hb, Hd), 7.72–7.81 (m, 5H, Hc, H2, H6, H3, H5), 8.07 (d,
J ¼ 9.6 Hz, 1H, Ha), 10.81 (bs, 1H, NH) ppm. 13C NMR (75 MHz,
DMSO-d6): 11.5, 21.4, 37.2, 46.1, 119.1, 126.1, 126.4, 126.9,
127.2, 135.1, 138.9, 142.3, 147.0, 156.5, 160.8, 166.8 ppm. MS
(70 ev, m/z): 432.09 (Mþ). Anal. calcd. For C19H20N4O4S2: C,
52.76; H, 4.66; N, 12.95. Found: C, 51.76; H, 4.86; N, 12.89.
4.1. General procedure for the synthesis of 2-
aminobenzamide derivatives 3a–m
A
mixture of 2H-benzo[d][1,3]oxazine-2,4(1H)-dione
1
(1 mmol) and various amines 2a–m (1 mmol) in water (10 ml)
was stirred at room temperature for 8 h. Then, the latter mix-
ture was filtrated to give 2-aminobenzamide deriva-
tives 3a–m.
2-((3-Butyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-sul-
famoylphenyl)acetamide 9 b
4.2. General procedure for the synthesis of 2-thioxo-2,3-
dihydroquinazolin-4(1H)-one derivatives 5a–m
2-Aminobenzamide derivatives 3a–m (1 mmol), carbon disul-
fide (1.5 mmol), and KOH (2 mmol) in ethanol (15 mL) was
heated under reflux for 12 h. After completion of the reaction
(checked by TLC), reaction mixture was poured into cold
water and the obtained precipitates were filtered off, washed
with cold water for obtain the pure 2-thioxo-2,3-dihydroqui-
nazolin-4(1H)-one derivatives 5a–m.
Yield: 93%; mp ¼ 215–217; IR (KBr): 3397.0, 3271.49 (NH),
1
1682.0, 1669.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 0.95
(t, J ¼ 7.2 Hz, 3H, CH3), 1.36–1.42 (m, 2H, CH2), 1.69–1.74 (m,
2H, CH2), 4.05–5.10 (m, 2H, N-CH2), 4.29 (s, 2H, S-CH2), 7.42
(bs, 2H, NH2), 7.71–7.83 (m, 7H, Hb, Hc, Hd, H2, H6, H3, H5),
8.06 (d, J ¼ 8.4 Hz, 1H, Ha), 10.95 (bs, 1H, NH) ppm. 13C NMR
(75 MHz, DMSO-d6): 14.0, 20.1, 30.1, 37.3, 44.4, 119.1, 119.2,
126.1, 126.3, 127.2, 135.0, 138.9, 142.3, 147.1, 156.4, 160.8,
162.7, 166.9 ppm. MS (70 ev, m/z): 446.11 (Mþ). Anal. calcd.
For C20H22N4O4S2: C, 53.80; H, 4.97; N, 12.55. Found: C, 53.90;
H, 4.76; N, 11.03.
4.3. Synthesis of 2-chloro-N-(4-
sulfamoylphenyl)acetamide 8
A mixture of 4-aminobenzenesulfonamide 6 (1 mmol) and
chloroacetyl chloride 7 (1.2 mmol) in DMF (10 mL) was stirred
at room temperature for 30 min. Then, the reaction mixture
was diluted with water, poured into cold water, and the
obtained precipitate was filtered off. This precipitates was
washed with water to give pure 2-chloro-N-(4-sulfamoylphe-
nyl)acetamide 8.
2-((3-Isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-
sulfamoylphenyl)acetamide 9c
4.4. General procedure for the synthesis of
quinazolin–sulfonamid derivatives 9a–m
A mixture of 2-thioxo-2,3-dihydroquinazolin-4(1H)-one deriva-
tives 5a–m (1 mmol), 2-chloro-N-(4-sulfamoylphenyl)aceta-
mide 8 (1 mmol) and, potassium carbonate (2 mmol) in DMF
(10 ml) was heated at 60 ꢀC for 4 h. Thereafter, the mixture
reaction was poured in cold water and the residue was fil-
trated and purified using recrystallization from ethanol to
give quinazolin–sulfonamid derivatives 9a–m.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
7
Yield: 89%; mp ¼ 190–192; IR (KBr): 3297.0, 3276.4 (NH),
2-((4-Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)-N-(4-
sulfamoylphenyl)acetamide 9f
1
1687.0, 1669.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 1.61
(d, J ¼ 6.0 Hz, 6H, CH3), 3.99–4.07 (m, 1H, CH), 4.22 (s, 2H, S-
CH2), 7.26 (bs, 2H, NH2), 7.38-7.44 (m, 2H, Hb, Hd), 7.73 (t,
J ¼ 8.1 Hz, 1H, Hc), 7.80 (m, 4H, H2, H6, H3, H5), 8.04 (d,
J ¼ 8.1 Hz, 1H, Ha), 10.79 (bs, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): 19.4, 36.2, 48.1, 119.1, 126.1, 126.4, 127.0, 127.3,
135.1, 138.9, 139.9, 142.3, 147.1, 156.6, 160.8, 166.6. Anal.
calcd. For C19H20N4O4S2: C, 52.76; H, 4.66; N, 12.95. Found: C,
52.63; H, 4.81; N, 13.08.
Yield: 83%; mp ¼ 227-229; IR (KBr) 3397.1, 3271.28 (NH),
1
1681.2, 1665.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 4.26
2-((3-Cyclopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-
(4-sulfamoylphenyl)acetamide 9d
(s, 2H, CH2), 7.30-7.37 (m, 3H, H4, NH2), 7.47–7.53 (m, 4H, H2,
H6, H3, H5), 7.54–7.63 (m, 2H, Hb, Hd), 7.79–7.97 (m, 5H, Hc,
H20, H30, H50, H60), 8.13 (d, J ¼ 8.4 Hz, 1H, Ha), 10.79 (bs, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): 37.8, 47.5, 115.1, 119.2,
120.0, 126.5, 126.6, 127.1, 127.3, 129.1, 130.5, 135.4, 139.0,
142.4, 147.6, 156.9, 157.4, 161.1, 161.2, 166.9. Anal. calcd. For
C22H18N4O4S2: C, 56.64; H, 3.89; N, 12.01. Found: C, 56.72; H,
3.94; N, 12.11.
2-((4-Oxo-3-(p-tolyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-
sulfamoylphenyl)acetamide 9 g
Yield: 87%; mp ¼ 222-224; IR (KBr) 3396.0, 3271.2 (NH),
1
1682.0, 1646.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 0.99
(t, J ¼ 7.2 Hz, 2H, CH2), 1.72-1.80 (m, 2H, CH2), 4.02–4.07 (m,
1H, CH), 4.28 (s, 2H, S-CH2), 7.37 (bs, 2H, NH2), 7.38–7.44 (m,
2H, Hb, Hd), 7.76 (t, 1H, J ¼ 8.3 Hz, Hc), 7.82 (bs, 4H, H2, H6,
H3, H5), 8.07 (d, J ¼ 8.4 Hz, 1H, Ha), 10.82 (bs, 1H, NH). 13C
NMR (75 MHz, DMSO-d6): 11.6, 21.5, 37.3, 46.1, 119.1, 119.2,
126.1, 126.4, 126.9, 127.2, 135.1, 138.9, 142.4, 145.8, 147.1,
156.5, 160.8, 162.8, 166.9, 167.3. Anal. calcd. For
C19H18N4O4S2: C, 53.01; H, 4.21; N, 13.01. Found: C, 53.13; H,
4.17; N, 13.16.
Yield: 82%; mp ¼ 244–246; IR (KBr): 3397.0, 3271.49 (NH),
1
1682.0, 1666.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 3.88
(s, 3H, CH3), 4.14 (s, 2H, CH2), 7.15 (d, J ¼ 8.7 Hz, 2H, H3, H5),
7.31(bs, 2H, NH2), 7.43 (d, J ¼ 8.3 Hz, 2H, H2, H6), 7.49–7.55
(m, 2H, Hb, Hd), 7.81(m, 5H, Hc, H20, H30, H50, H60), 8.09 (d,
J ¼ 7.8 Hz, 1H, Ha), 10.75 (bs, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): 21.36, 37.8, 55.9, 115.1, 119.1, 120.0, 126.3, 126.4,
127.1, 127.2, 128.6, 130.5, 131.1, 135.3, 138.9, 142.3, 147.5,
157.6, 158.0, 160.6, 161.3, 167.0. Anal. calcd. For
C23H20N4O4S2: C, 57.49; H, 4.20; N, 11.66. Found: C, 56.28; H,
4.31; N, 11.52.
2-((3-Allyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-sul-
famoylphenyl)acetamide 9e
2-((3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-
yl)thio)-N-(4-sulfamoylphenyl)acetamide 9 h
Yield: 85%; mp ¼ 234–236; IR (KBr) 3397.0, 3271.4(NH),
1
1714, 1688 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 4.27 (s,
2H, CH2), 4.76 (d, J ¼ 5.1 Hz, 2H, N-CH2), 5.16–5.28 (m, 2H,
¼CH2), 5.9–6.0 (m, 1H, CH), 7.30 (bs, 2H, NH2), 7.41–7.46 (m,
2H, Hb, Hd), 7.74–7.81 (m, 5H, Hc, H2, H6, H3, H5) , 8.07 (d,
J ¼ 6.9 Hz, 1H, Ha), 10.82 (bs, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): 37.4, 46.4, 118.1, 119.1, 126.1, 126.5, 127.0, 127.2,
131.7, 135.2, 138.9, 142.3, 147.1, 156.7, 160.7, 166.8. Anal.
calcd. For C19H18N4O4S2: C, 53.01; H, 4.21; N, 13.01. Found: C,
52.89; H, 4.32; N, 13.09.

8
N. SEPEHRI ET AL.
Yield: 87%; mp ¼ 256–258; IR (KBr): 3394.0, 3271.6 (NH),
2-((3-(4-Fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-2-
yl)thio)-N-(4-sulfamoylphenyl)acetamide 9k
1
1682.5, 1669.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 3.87
(s, 3H, CH3), 4.13 (s, 2H, S-CH2), 7.14 (d, J ¼ 8.1 Hz, 2H, H3,
H5), 7.41 (s, 2H, NH2), 7.42 (d, J ¼ 9 Hz, 2H, H2, H6), 7.46–7.54
(m, 2H, Hb, Hd), 7.80 (m, 5H, Hc, H20, H60, H30, H50), 8.09 (d,
J ¼ 8.1 Hz, 1H, Ha), 10.77 (bs, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): 37.8, 56.0, 115.1, 119.1, 120.0, 126.3, 126.4, 127.1,
127.2, 128.6, 130.5, 131.1, 135.3, 138.9, 142.3, 147.5, 157.6,
158.0, 160.6, 161.2, 162.7, 166.9. Anal. calcd. For
C23H20N4O5S2: C, 55.63; H, 4.06; N, 11.28. Found: C, 55.52; H,
4.14; N, 11.38.
Yield: 86%; mp ¼ 240–242; IR (KBr) 33996.0, 3271.2 (NH),
1684.0, 1661.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 4.26
1
2-((3-(4-Chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-
yl)thio)-N-(4-sulfamoylphenyl)acetamide 9i
(s, 2H, CH2), 5.36 (s, 2H, CH2), 7.17–7.23 (m, 2H, H3, H5),
7.39–7.43 (m, 4H, Hb, Hd, H2, H6), 7.77–7.81 (m, 5H, Hc, H20,
H60, H30, H50), 7.97 (s, 2H, NH2), 8.11 (d, J ¼ 8.1 Hz, 1H, Ha).
13C NMR (75 MHz, DMSO-d6): 37.5, 46.9, 115.7, 116.0, 119.1,
119.2, 126.1, 126.6, 127.1, 127.2, 129.6, 129.7, 132.2, 132.3,
135.4, 139.1, 142.3, 147.1, 156.8, 160.3, 161.2, 162.7, 163.5,
166.7. Anal. calcd. For C23H19FN4O4S2: C, 55.41; H, 3.84; N,
11.24. Found: C, 55.31; H, 3.92; N, 11.39.
2-((3-(4-Methoxyphenethyl)-4-oxo-3,4-dihydroquinazolin-2-
yl)thio)-N-(4-sulfamoylphenyl)acetamide 9l
Yield: 83%; mp ¼ 203–205; IR (KBr) 3318.2, 3161.1 (NH),
1
1688.5, 1662.3 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 4.16
(s, 2H, CH2), 7.30 (s, 2H, NH2), 7.48 (t, J ¼ 8.1 Hz, 1H, Hb), 7.54
(d, J ¼ 7.9 Hz, 1H, Hd), 7.60 (d, 2H, J ¼ 8.7 Hz, H3, H5), 7.70 (d,
J ¼ 8.7 Hz, 2H, H2,H6), 7.80-7.83 (m, 5H, Hc, H20, H60, H30,
H50), 8.09 (d, J ¼ 8.1 Hz, 1H, Ha), 10.75 (bs, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): 37.8, 119.1, 119.9, 126.3, 126.6, 127.1,
127.2, 130.1, 131.9, 135.1, 135.2, 138.9, 142.3, 147.5, 156.9,
161.0, 166.8. Anal. calcd. For C22H17ClN4O4S2: C, 52.74; H,
3.42; N, 11.18. Found: C, 52.83; H, 3.34; N, 11.25.
Yield: 85%; mp ¼ 233–235; IR (KBr) 3395.0, 3171.49 (NH),
1685.0, 1656.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 3.04
1
2-((4-Oxo-3-(pyridin-3-ylmethyl)-3,4-dihydroquinazolin-2-
yl)thio)-N-(4-sulfamoylphenyl)acetamide 9j
(t, J ¼ 7.8 Hz, 2H, CH2) , 3.77 (s, 3H, CH3), 4.25 (s, 2H, S-CH2),
4.29 (t, J ¼ 7.3 Hz, 2H, N-CH2), 6.86–6.98 (m, 4H, H3, H5, H2,
H6), 7.17-7.26 (m, 2H, Hb, Hd), 7.41 (bs, 2H, NH2), 7.73–7.82
(m, 5H, Hc, H20, H30, H50, H60), 8.09 (d, J ¼ 7.8 Hz, 1H, Ha),
10.80 (bs, 1H, NH). 13C NMR (75 MHz, DMSO-d6): 28.1, 37.4,
44.7, 55.6, 111.1, 119.1, 119.2, 120.8, 126.1, 126.3, 126.9,
127.2, 128.7, 130.6, 135.1, 138.9, 142.3, 147.1, 156.7, 157.9,
160.8, 166.9. Anal. calcd. For C25H24N4O5S2: C, 57.24; H, 4.61;
N, 10.68. Found: C, 57.19; H, 4.73; N, 10.54.
Yield: 82%; mp ¼ 210–212; IR (KBr) 3397.5, 3271.69 (NH),
2-((3-(3,4-Dimethoxyphenethyl)-4-oxo-3,4-dihydroquinazo-
lin-2-yl)thio)-N-(4-sulfamoylphenyl)acetamide 9 m
1
1688.0, 1663.0 (CO) cmꢁ1. H NMR (300 MHz, DMSO-d6): 4.28
(s, 2H, S-CH2), 5.40 (s, 2H, N-CH2), 7.33 (bs, 2H, NH2),
7.37–7.42 (m, 1H, H5), 7.45-7.47 (m, 2H, Hb, Hc), 7.75-7.82 (m,
6H, Hd, H6, H20, H60, H30, H50), 8.10 (d, J ¼ 8.4 Hz, 1H, Ha),
8.52 (d, J ¼ 4.8 Hz, 1H, H4), 8.66 (s, 1H, H2), 10.83 (bs, 1H,
NH). 13C NMR (125 MHz, DMSO-d6) 37.5, 45.5, 119.1, 119.2,
124.1, 126.2, 126.6, 127.1, 127.3, 131.9, 135.4, 138.9, 142.3,
147.1, 149.1, 149.2, 156.5, 161.3, 162.8, 166.7. Anal. calcd. For
C22H19N5O4S2: C, C, 54.87; H, 3.98; N, 14.54. Found: C, 54.85;
H, 3.88; N, 14.58.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
9
Yield: 81%, mp ¼ 249–251; IR (KBr) 3331.09, 3254.34, compound 9 h as most potent compound against a-glucosi-
3105.4 (NH), 1663.8, 1645.4 (CO) cmꢁ1 1H NMR (300 MHz, dase (modeled enzyme) were performed by Autodock Tools
.
DMSO-d6): 2.99 (t, J ¼ 7.8 Hz, 2H, CH2), 3.72 (s, 6H, CH3), 4.30 1.5.6 (Zengin et al., 2018). The 3D structures of compounds
(m, 4H, N-CH2, S-CH2), 6.81–6.91 (m, 3H, H2, H5, H6), 9f, 9h, and 9i were generated by MarvineSketch 5.10.4, and
7.42–7.46 (m, 2H, NH2), 7.73-7.85 (m, 7H, Hb, Hc, Hd, H20, then their pdbqt formats were provided by Autodock Tools.
H30, H50, H60), 8.07 (d, J ¼ 7.8 Hz, 1H, Ha). 13C NMR (75 MHz, By this software, the pdbqt structures of AChE, BuChE, hCA I,
DMSO-d6): 37.4, 43.1, 45.1, 55.8, 55.9, 112.4, 112.8, 119.1,
119.2, 121.0, 126.1, 126.4, 126.9, 127.3, 130.5, 135.1, 138.9,
142.4, 147.1, 148.1, 149.2, 156.3, 160.7, 162.7, 166.9. Anal.
calcd. For C26H26N4O6S2: C, 56.30; H, 4.73; N, 10.10. Found: C,
56.41; H, 4.76; N, 10.59.
hCA II, modeled a-glucosidase were also prepared and
Autodock Tools parameters for this enzymes were set as fol-
lows: (1) AChE: grid box size: 40 ꢂ 40 ꢂ 40 Å, the center of
grid box: x ¼ 2.023, y ¼ 63.295, z ¼ 67.062, (2) BuChE: grid
box size: 56 ꢂ 56 ꢂ 56 Å, the center of grid box: x ¼ 137.985,
y ¼ 122.725, z ¼ 38.78, (3) hCA I: grid box size: 40 ꢂ 40 ꢂ 40 Å,
the center of grid box: x ¼ 1.8085, y ¼ 72.66, z ¼ 55.3515, (4)
hCA II: grid box size: 60 ꢂ 60 ꢂ 60 Å, the center of grid box: x
¼ ꢁ3.8315, y ¼ 3.9065, z ¼ 15.043, and (5) modeled a-glucosi-
dase: grid box size: 40 ꢂ 40 ꢂ 40 Å, the center of grid box:
x ¼ 12.5825, y ¼ ꢁ7.8955, z ¼ 12.519. Each autodocked sys-
tem was performed by 50 runs of the AUTODOCK
Lamarckian genetic algorithm. Finally, the best pose was con-
sidered each compound analyzed by Discovery Studio 2019
Client (Accelrys, Inc., San Diego, CA).
4.5. Enzymes studies
In the present work, hCA I, and II isoenzymes were purified
by Sepharose-4B-L-Tyrosine-sulfanilamide affinity column
chromatography, CA isoenzymes activity was determined
according to the spectrophotometric method of Verpoorte
et al. (1967) as described in our previous studies in details
€
(Ozgun et al., 2019; Oztaskın et al., 2015, 2017, 2019;
Rajasekaran & Gopalkrishna, 2012). p-Nitrophenylacetate (p-
NPA) was used as substrate for the enzymatic reaction. One
CA enzyme unit is adopted the amount of CA, which had
absorbance difference at 348 nm over a 3 min at 25 ꢀC (Rezai
et al., 2018; Sujayev et al., 2016). For determination of inhib-
ition kinetics of novel quinazolin–sulfonamid derivatives
(9a–m), an activity (%) and [sulfonamid] graph was drowned.
From these graphs, half maximal inhibitor concentrations
(IC50) for novel quinazolin–sulfonamid derivatives (9a–m)
were determined. Also, for Kis, three different concentrations
novel quinazolin–sulfonamid derivatives (9a–m) were used in
this paper. Then, Lineweaver and Burk (1934) graphs were
drawn according to these measurements. Kis of novel quina-
zolin–sulfonamid derivatives (9a–m) were determined from
Lineweaver–Burk graphs as previously described (Taslimi &
Gulc¸in, 2018; Taslimi, Akıncıoglu, et al., 2017; Taslimi,
Caglayan, et al., 2017; Taslimi et al., 2018; Taslimi & Gulc¸in,
2017). Quantity of protein during the purification processing,
Bradford’s (Taslimi et al., 2019) technique was utilized, which
bovine serum albumin used as the standard protein. Sodium
dodecyl sulfate–polyacrylamide gel electrophoresis was
employed for visualzing of image of isoenzymes (Taslimi
et al., 2017, 2018). The inhibitory effect of novel quinazolin–-
sulfonamid derivatives (9a–m) on AChE and BChE activities
was performed according to spectrophotometric method of
Ellman et al. (1961) as described previously (Tugrak et al.,
2018; Turan et al., 2016; Turkan et al., 2019a, 2019b; Yamali
et al., 2018). a-Glycosidase inhibition effect of novel quinazo-
lin–sulfonamid derivatives (9a–m) was evaluated according
to the method of Tao et al. (2013) The absorbance o samples
Disclosure statement
The authors report no conflicts of interest.
ORCID
Parham Taslimi
Ilhami Gulcin
http://orcid.org/0000-0002-3171-0633
http://orcid.org/0000-0001-5993-1668
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