Synthesis, cytotoxic activity, ADMET and molecular docking study of quinoline-based hybrid compounds of 1,5-benzothiazepines

Article abstract of DOI:10.1039/d0nj04295a

Some α,β-unsaturated ketones 4a-g of 3-acetyl-4-hydroxyquinolin-2(1H)-one were prepared by its reaction with (hetero)aromatic aldehydes with yields of 61-87% using piperidine as a catalyst. These ketones reacted with o-aminothiophenol in the presence of acetic acid to afford a series of new hybrid compounds, quinoline-benzothiazepine, 6a-g. The yields of benzothiazepines 6a-g were 62-85%. All the synthesized compounds 6a-g were screened for their in vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6d and 6g had the best activity in the series, with IC50 values of 0.25 and 0.27 μg mL-1, respectively, against HepG2, and of 0.26 and 0.28 μM, respectively, against KB cell lines. ADMET properties showed that compounds 6c and 6g possessed drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DA12(F), and DG13(F) in the binding pocket were potential ligand binding hot-spot residues for compounds 6c and 6g. This journal is

Full text of DOI:10.1039/d0nj04295a

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Synthesis, cytotoxic activity, ADMET and molecular docking study
of quinoline-based hybrid compounds of 1,5-benzothiazepines
Received 00th January 20xx,
Accepted 00th January 20xx
Duong Ngoc Toan,a,b* Nguyen Dinh Thanh,b* Mai Xuan Truong,a Duong Nghia Bang,c Mai Thanh
Nga, a Nguyen Thi Thu Huong b
DOI: 10.1039/x0xx00000x
Some α,β-unsaturated ketones 4a-g of 3-acetyl-4-hydroxyquinolin-2(1H)-one were prepared by its reaction with
(hetero)aromatic aldehydes with yields of 61−87% using piperidine as catalyst. These ketones reacted with o-
aminothiophenol in the presence of acetic acid to afford a series of new hybrid compounds, quinoline-benzothiazepine,
6a-g. The yields of benzothiazepines 6a-g were 62−85%. All the synthesized compounds 6a-g were screened for their in
vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.
Compounds 6d and 6g had the best activity in the series, with IC50 values of 0.25 and 0.27 μg/mL, respectively against
HepG2, and of 0.26 and 0.28 μM, respectively, against KB cell lines. ADMET properties showed that compounds 6c and 6g
possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DA12(F), and DG13(F) in
the binding pocket as potential ligand binding hot-spot residues for compounds 6c and 6g.
represented some bioactive benzothiazepine scaffold.
Diltiazem, A,14 was used clinically in USA from 198215, followed
by clentiazem, B,16 for their cardiovascular actions. Other 1,5-
Introduction
Heterocycles containing nitrogen and sulphur as heteroatoms
undoubtedly constitute an important class of highly applicable
bioactive molecules because of their interesting biological
activities and uses as key structural motif for the synthesis of
various products of pharmaceutical interest. Benzothiazepine
is a heterocyclic compound that contains a benzene ring fused
with a seven membered ring having nitrogen and sulphur
atoms. Benzothiazepine derivatives are of three types: 1,4-,
4,1- and 1,5-benzothiazepines1, 2. 1,5-Benzothiazepine is one
of these three possible benzo-condensed derivatives. It is
known that 1,5-benzothiazepine itself has not hitherto been
described in the literature for its pharmacological properties1,
3. However, substituted 1,5-benzothiazepines are of particular
benzothiazepine derivatives were also used clinically for CNS
disorders including thiazesim, C,17 and quetiapine fumarate,
D18. Therefore, their beneficial properties have prompted
several groups to study these compounds. Owing to their
importance from a pharmacological and synthetic point of
view, several approaches have been reported for the synthesis
of 1,5-benzothiazepines. Some 1,5-benzothiazepine derivatives
were synthesized efficiently and environmentally from 2-
aminobenzenethiols with α,β-unsaturated ketones19 in good to
excellent yield under solvent-free microwave irradiations using
sulfuric acid on silica or basic alumina respectively as solid
supports20, under microwave irradiation via Mannich
condensation21, from chalcones and o-aminothiophenol in the
presence of 10 mol% catalyst of ammonium cerium(IV) nitrate
under ultrasonic irradiation13, via a one-pot thia-Michael-
cyclization sequence by the reaction of various o-
aminothiophenols with chalcones in ionic liquid media, such as
1-octyl-3-methyl imidazolium thiocyanate ([omim]SCN) at 60
°C and 1-octyl-3-methyl imidazolium chloride ([omim]Cl)
medium in room temperature22, in PEG-400 catalyzed by acetic
acid23. Another pathway to 1,5-benzothiazepine derivatives
was the reaction of ω-bromoacetophenones and aromatic
aldehydes21, chalcone analogues of dehydroacetic acid24, 2-
interest for lead discovery because they have been found
2
active against different families of targets1,
.
1,5-
Benzothiazepines play
a unique role in drug discovery
programs, as they display a wide spectrum of biological
activities such as antibacterial4, antifungal5, antiviral6,
anticancer7, antihypertensive8 activities, and so on. 1,5-
Benzothiazepine derivatives are also used as calcium channel
10
modulators9, either inhibitors for adenosine kinase
cholinesterase11, antagonists12, vasodilators13, etc. Fig.
,
1
a. Faculty of Chemistry, TNU University of Education (Thai Nguyen University), 20
Luong Ngoc Quyen, Thai Nguyen, Viet Nam.
aminophenyldisulfide
with
itaconic
anhydride
and
dimethylitacone25, α,β-unsaturated ketones with bis(2-
b. Faculty of Chemistry, VNU University of Science (Vietnam National University, Ha
Noi), 19 Le Thanh Tong, Hoan Kiem, Ha Noi, Viet Nam
nitrophenyl)disulphide in the presence of TiClO4/Sm26,
nitrodisulphides and α,β-unsaturated ketones by SmI2
photochemical reaction of 2-phenylbenzothiazole with ethoxy
acetylene/ethoxy propyne28, microwave activated reaction
between 3-(4ʹ-fluoro-2ʹ-methylbenzoyl)-2-propenoic acid with
27
c. Faculty of Chemistry, TNU University of Science (Thai Nguyen University), Tan
Thinh Ward, Thai Nguyen City, Thai Nguyen, Viet Nam.
Electronic Supplementary Information (ESI) available: Synthetic procedures and
,
NMR characterization details for…...See DOI: 10.1039/x0xx00000x
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2-aminothiolphenol29, etc. The most convenient method for aminophenols (as dinucleophiles) with α,β-unsaturated
the synthesis of these compounds involves the treatment of 2- ketones.
6
7
8
O
O
S
N
9
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O
O
S
N
S
N
S
N
Cl
N
O
O
O
O
OH
OH
N
O
O
O
O
.
D
OH
N
N
N
A
B
C
Figure 1. Some bioactive benzothiazepine derivatives.
We have been interested in 1,5-benzodiazepines and 1,5- were prepared by Claisen-Schmidt reaction of 3-
benzothiazepine derivatives for a few years, and recently, have acetylquinolone with some appropriate aromatic and
3
prepared a series of 1,5-benzothiazepines30. Inspired by the heteroaromatic aldehydes 4a-g (Scheme 1). The reaction was
manifold applications of 1,5-benzothiazepine nuclei and in carried out by heating under reflux in absolute ethanol as
continuation of our interest in the synthesis and biological solvent for 25−50 h. Piperidine was used as catalyst for this
evaluation studies of heterocyclic compounds containing process. The molar ratios of 3 and aldehydes 4a-g were 1:1.
nitrogen and sulphur as heteroatoms, we report herein the Initially, the starting materials were dissolved completely in
synthesis, characterization, cytotoxic activities of some novel reaction solvent, then the product was separated as yellow-
benzothiazepines having quinoline ring.
colour precipitates during the reaction. Products were
obtained with yields of 61−87%.
IR spectra of these α,β-unsaturated ketones 5a-g had
characteristic absorption bands of trans-vinyl group in range of
998−967 cm−1. Absorption band appeared at 1680−1634 cm−1
belonged carbonyl group of lactam function. Their 1H NMR
spectra indicated the presence of this trans-vinyl group
through two signals at δ = 8.59−8.41 ppm and δ = 7.95−7.87
ppm for protons H-2ʹ and H-3ʹ, respectively. These signals had
the roof effects that showed the coupling constants J =
15.5−16 Hz. These values indicated that the resulting alkene
had trans configuration. In compounds 5a-g the phenolic
hydroxyl group on position 4 of quinolone ring had no
chemical shift downfield in DMSO-d6 solvent, possibly due to
hydrogen-bonding formation of this group to oxygen atom of
carbonyl ketone (Fig. 2)33. In their IR spectra, weak and narrow
absorption bands presented in region at 3462−3150 cm−1 that
showed this intramolecular hydrogen bonding between this
Results and discussion
Based on above-mentioned literature methods, we have
chosen the synthetic pathway of target 1,5-benzothiazepines
from α,β-unsaturated ketones of 3-acetyl-4-hydroxy-1-
methylquinolin-2(1H)-one (3). This initial material was
prepared from N-methylaniline. First, pyronoquinoline 2,
hydroxy-6-methyl-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione,
was prepared by using Kappe’s and Stadlbauer’s procedures31,
32
by reaction N-methylaniline with diethyl malonate. In
Stadlbauer’s procedure diphenyl ether was used as solvent,
but Kappe’s procedure used excess diethyl malonate and this
diester played the reagent and solvent roles. The former gave
higher yield of pyronoquinoline 2. The ring opening of 2 by
sodium hydroxide in glycerol and subsequent spontaneous
decarboxylation gave 3-acetyl-4-hydroxy-1-methylquinolin-
2(1H)-one (3). α,β-Unsaturated ketones 5a-g, substituted (E)-4-
hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-2(1H)-ones,
1
hydroxyl group and carbonyl oxygen atom. H NMR spectrum
of compound 5f had signal at δ = 9.81 ppm that belonged 4ʹʹ-
hydroxyl group on benzene ring.
2 | J. Name., 2012, 00, 1-3
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O
OH
O
OH
O
1'
ArCHO
3'
5
8
4
COCH3
4a
8a
3
6
7
4a-g
(i)
OH
Ar
(ii)
2'
2CH2(COOC2H5)2
+
2
(iii)
N
O
NH
N
O
N
O
CH3
CH3
CH3
CH3
5a-g
2
3
1
SH
(iv)
2''
6''
3''
5''
R
4''
NH2
1''
Ar =
7'
8'
6'
9'
4a-f, 5a-f, and 6a-f: R = 3''-ClC6H4 (a), 3''-MeC6H4 (b), 4''-MeOC6H4 (c),
4''-BrC6H4 (d), 4''-Me2NC6H4 (e), 4''-OH-3''-MeOC6H3 (f)
5'a
9'a
5'
OH
N
S
1'
Hc
5
4
4'
3'
4a
8a
4''
5''
3''
2''
6
3
2'
Hb
Ar
7
Ha
S
1''
N
2
O
8
4g,5g,6g: 2-thienyl
CH3
6a-g
Tautomerism of compounds 6a-g:
OH
N
O
O
HN
O
O
N
S
S
S
Ar
Ar
Ar
N
N
N
OH
CH3
CH3
CH3
most favoured
Scheme 1. Synthetic pathway for 1,5-benzothiazepines. Reaction conditions: (i) Diphenyl ether, 5 h, under reflux; (ii) 40% NaOH in water, glycerol, under reflux for 1h;
(iii) Piperidine, abs. EtOH, under reflux for 25−50 h; (iv) Glacial acetic acid, abs. EtOH, under reflux for 5−7 h.
after about 3−4 h, the product precipitate began to appear.
The ring-closure condensation process occurred over 5−7 h
with obtained product yields of 65−82%. Structurally, the
H
O
O
O
formation of benzothiazepines 6a-g from α,β-unsaturated
ketones 5a-g of 3-acetyl-4-hydroxy-1-methylquinolin-2(1H)-
one 3 could be confirmed by spectral data (IR, NMR, and MS).
In IR spectra of these compounds, characteristic absorption
band for out-of-plane bending vibration of C−H of trans-alkene
group in α,β-unsaturated ketones 5a-g in the region at
998−967 cm−1 disappeared. Hydroxyl group on position 4 of
quinoline-2-one ring had chemical shift at δ = 14.78−14.76
ppm. This is the difference when compared to the case of α,β-
unsaturated ketones above, in which the phenolic hydroxyl
group on position 4 of quinolone ring had no chemical shift
downfield in DMSO-d6 solvent, and could be used as evidence
to show that benzothiazepine ring was formed in the reaction
Ar
N
CH3
Figure 2. The hydro-bonding formation in compounds 5a-g.
Next, substituted benzothiazepines 6a-g were synthesized by
ring-closure condensation reaction of obtained substituted
α,β-unsaturated ketones 5a-g with o-aminothiophenol.
Reaction was carried out under reflux in absolute ethanol
(Scheme 1) via Michael addition. At the beginning of the
reaction, the initial materials were dissolved in solvent, and
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of α,β-unsaturated ketones 5a-g with 2-aminophenol. In 1H
NMR spectra of these benzothiazepines, the disappearance of
signals at δ = 8.59−8.41 ppm and δ = 7.95−7.87 ppm for
protons H-2ʹ and H-3ʹ, respectively, also suggested that the
benzothiazepine ring was formed.
Table 1. Cytotoxic activity against KB and HepG2 cancer cell line in IC50 of compounds
6a-g
IC50 (M)
Compds.
Ar
6a
6b
6c
6d
6e
6f
6g
3′′-ClC6H4
3′′-MeC6H4
80.0
8.0
0.25
>128
>128
0.8
45.71
32.0
0.26
>128
32.0
2.10
0.28
0.36
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
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43
44
45
46
47
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49
50
51
52
53
54
55
56
57
58
59
60
4′′-MeOC6H4
4′′-BrC6H4
4′′-Me2NC6H4
4′′-OH-3′′-MeOC6H3
2′′-Thienyl
Cytotoxic activity
All the synthesized of 3-(2-amino-6-arylpyrimidin-4-yl)-4-
hydroxy-1-methylquinolin-2(1H)-ones 6a-g were screened for
their in vitro anticancer activity against two representatives:
human squamous cell carcinoma (KB) and hepatocellular
carcinoma (HepG2) cell lines. Ellipticine was used as reference.
Evaluated results for 6a-g were given in Table 1 and Figs. 3 and
4. In general, it has been observed that almost all tested
compounds showed remarkable activity against the tested
cancer cell lines, KB and HepG2, in comparison with the IC50
values of the reference compound (ellipticine). The results in
Table 1 showed that almost all novel molecule exhibited
anticancer activity against the tested KB cell line at wide range
of concentrations. With the exception of compounds 6d and
6e that displayed negligible inhibitory effect on the KB
carcinoma cell line (IC50 >128 μM), the remaining compounds
had a good inhibitory effect. The order of the inhibitory effect
of these compounds was 6c ~ 6g > 6f > 6b > 6a > 6d,6e of
which compounds 6c and 6g had the best activity in the series,
with IC50 values equal to 0.25 and 0.27 μg/mL, respectively,
when compared to IC50 value with 0.28 μM of a positive
reference drug ellipticine. Compound 6f had significant
inhibitory activity with IC50 of 0.8 μM.
For cancer cell line HepG2, compounds 6a-g exhibited weak or
insignificant activity, and two compounds 6c and 6g showed
the highest activity in this sequence, with IC50 values equal to
0.26 and 0.28 μM (Table 1), respectively, when compared to
the IC50 value of ellipticine (with IC50 = 0.36 μM). Compound 6f
exhibited medium activity with IC50 value of 2.10 μM. The
remaining compounds in the series had a negligible activity for
liver cancer cell lines HepG2. The order of inhibitory activity
was as follows: 6c ~ 6g > 6f > 6b > 6e > 6a >6d.
0.27
0.28
Ellipticine
% Inhibition against cancer cell line KB
100
90
80
70
60
50
40
30
20
10
0
6a
6b
6c
6d
6e
6f
6g
128 μg/mL
32 μg/mL
8 μg/mL
2 μg/mL
0.5 μg/mL
Figure 3. Dose-dependent cell growth inhibition percentages against KB cell line by the
synthesized compounds 6a-g.
% Inhibition against cancer cell line HepG2
100
90
80
70
60
50
40
30
20
10
0
6a
6b
6c
6d
6e
6f
6g
128 μg/mL
32 μg/mL
8 μg/mL
2 μg/mL
0.5 μg/mL
Figure 4. Dose-dependent cell growth inhibition percentages against HepG2 cell line by
the synthesized compounds 6a-g.
ADMET studies
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A variety of key ADMET (Absorption, Distribution, Metabolism, evaluating bioavailability of
a
compound after oral
Excretion and Toxicity) properties had been calculated in silico administration Lipinski’s rule of five and Veber’s filter. The first
to estimate the drug-likeness of the compounds (Table 2)34. one assumed that compounds having LogPo/w (octanol/water
The predictions were carried out for synthesized compounds partition coefficient) lower than 5 (with values of 3.95−4.98),
6a-g were screened using PreADMET online software35 (for molecular weight (MW) below 500, less than 10 H-bond
HIA, Caco2) and SwissADME online softwares36 (for TPSA, n- acceptors (n-ON), and less than 5 H-bond donors (n-OHNH)
ROTB, n-ON, n-OHNH, LogP, Lipinski's violations and Veber’s were more likely to show favourable bioavailability37. The
violation). From Table 2, it could be observed that all the Veber rule extended the range of parameters by rotatable
synthesized compounds have shown promising human bonds (preferably n-ROTB <10) and topological polar surface
intestinal percentage absorption (HIA = 95.71−98.59%). These area with values of 79.89−109.35 (preferably TPSA ≤ 140 Å2)38.
values showed that these compounds had good human The Egan rule considered good bioavailability for compounds
intestinal absorption. The most active compounds 6c and 6g with TPSA ≤ 132 Å2 and −1 < LogP < 639. These compounds had
showed 96.90% and 96.92% absorption, respectively. The middle cell permeability with Caco2 values in ranges of
designed structures were tested for compliance with rules 24.51−49.87 mm/s.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
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Table 2. Physicochemical properties, lipophilicity and drug-likeness of compounds 6a-g
Entry
6a
6b
6c
6d
6e
6f
Ar
3′′-ClC6H4
MW[a]
446.95
426.53
442.53
491.40
455.57
458.53
418.53
TPSA[b]
79.89
79.89
89.12
79.89
83.13
109.35
108.13
n-ROTB[c]
n-ON[d]
n-OHNH[e]
LogP[f]
4.94
4.66
4.41
4.98
4.35
3.95
4.41
L.V. [g]
V.V. [h]
Caco2[i]
49.87
31.03
29.33
37.73
30.31
24.51
34.01
%HIA[j]
97.37
97.17
96.90
97.59
97.17
95.71
96.92
2
2
3
2
3
3
2
3
3
4
3
3
5
3
1
1
1
1
1
2
1
1
1
0
1
0
0
0
0
0
0
0
0
0
0
3′′-MeC6H4
4′′-MeOC6H4
4′′-BrC6H4
4′′-Me2NC6H4
4′′-OH-3′′-MeOC6H3
2′′-Thienyl
6g
Note. [a] MW: molecular weight (<500, expressed as Dalton); [b] TPSA: topological polar surface area (Å2); [c] n-ROTB: number of rotatable bonds; [d] n-ON: number of
hydrogen bond acceptors (≤10); [e] n-OHNH: number of hydrogen bond donors (≤5); [f] LogP: logarithm of partition coefficient (<5) of compound between n-octanol
and water 37; [g] L.V.: Lipinski's violations 37; [h] V.V.: Veber’s violation 38; [i] Caco-2: Caco-2 cell permeability (PCaco-2 (nm/s), <4: low, 4−70: middle, >70: high); [j] HIA:
human intestinal absorption (0−20=poor, 20−70=moderate, 70−100=good).
of 2.6 Å with intercalated drug mitoxantrone, and consisted of
7 chains: A, B, C, D, E, and F, two molecules of mitoxantrone
had complexed with these chains. Two of the most active
Molecular Modelling
Molecular docking simulations were performed in order to
better understand the molecular basis for the inhibition of
topoisomerases by ellipticine (reference drug) and compounds
(ligands, herein) 6a-g against above- mentioned cancer cell
lines. Based on the results obtained from the enzymatic
assays, molecular modelling studies were performed as a step
toward understanding the interaction mode of these
compounds as inhibitors. It is known that ellipticine (5,11-
benzothiazepine compounds (6c and 6g), one moderately
active compound (6f), and one of the least active compound
(6d) were chosen for docking examination. The favourably
docked molecules were ranked according to the XP Glide
Score. Obtained docking results (glide score, in kcal/mol) were
represented in Table 3. The order of glide scores was 6c > 6g >
6f > 6d, which indicated that ligands 6c and 6g were docked
nicely fitted into the active site. The active pocked was formed
from chains A, D, F.
dimethyl-6H-pyrido[4,3-b]carbazole,
an
alkaloid
from
extracted from trees of the species Ochrosia elliptica and
Rauvolfia sandwicensis 40) is a potent antineoplastic agent
exhibiting multimodal mechanism of action. This compound
inhibited the enzyme topoisomerase II via intercalative binding
to DNA. The prevalent mechanisms of ellipticine antitumor,
mutagenic and cytotoxic activities were suggested to be
intercalation into DNA and inhibition of DNA topoisomerase II
activity41, 42. Human topoisomerase IIβ in complex with DNA
and mitoxantrone was a targeting anticancer drug, and so we
have chosen it for docking study43, 44. This enzyme was
retrieved with PDB code 4G0V. The structure has a resolution
Table 3. Molecular docking analysis of protein target 6QXG with ligands 6c,6f and 6g
Ligands
6c
6d
Ar
Glide score[a]
−7.964
4-MeOC6H4
4-BrC6H4
−7.555
6f
6g
4-OH-3-MeOC6H3
2-Thienyl
−7.876
−7.948
Ellipticine
−8.102
[a] In kcal/mol.
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Figure 5. Docked (superimposed) poses showed ellipticine (magenta), 6c (red), (6d, orange), 6f (blue), and 6g (green), all binding at the same position on molecular pocket of
human topoisomerase IIβ in complex with DNA (4G0V) and showing common interactions with residues GNL A:778, ARG A:503, DA F:12, DG F:13.
Superimposed poses in Fig. 5 showed that four ligands 6c hydroxyquinolin-2(1H)-one moiety (Fig. 6). Additionally, ligand
(red), (6d, orange), 6f (blue), and 6g (green), all bound at the 6g had more π-π stacking interactions than ligand 6c. This one
same position that the reference ellipticine (magenta) did on could explain the obtained higher glide score value of this
molecular pocket of human topoisomerase IIβ in complex with ligand (Table 3).
DNA. Ligands 6c (with 4-methoxyphenyl group), 6f (4-hydroxy-
3-methoxyphenyl group), and 6g (with 2-thienyl group) gave
better glide scores when compared with other five compounds
Experimental
for the target protein, with binding score of −7.964, −7.876,
and −7.948 kcal/mol, respectively. These values could be
compared with the one of ellipticine (−8.102 kcal/mol). The
worst active ligand 6d with 5-bromophenyl group had glide
Melting points were determined by open capillary method on
STUART SMP3 instrument (BIBBY STERILIN, UK) and are
uncorrected. IR spectra (KBr disc) were recorded on an Impact
410 FT-IR Spectrometer (Nicolet, USA). 1H and 13C NMR spectra
score of −7.555 kcal/mol.
were recorded on Bruker Avance Spectrometer AV500 (Bruker,
The important intermolecular protein-ligand interactions of
Germany) at 500 MHz and 125 MHz, respectively, using DMSO-
compounds 6c and 6g are depicted in Fig. 6 (top). The lowest
d6 as solvent and TMS as an internal standard. ESI-mass
spectra were recorded on LTQ Orbitrap XLTM (Thermo Fisher
energies pose the highest active compounds 6c and 6g
obtained by Glide 8.1 software are reported in Fig. 6 (bottom),
Scientific Co., USA) and ESI-MSD-Trap-SL (Agilent Technologies,
similar to the docking position of ellipticine (Fig. 6, middle).
Inc., USA) mass spectrometers) mass spectrometers. All
Ellipticine itself had some active interactions with the residues
reactions were monitored by thin layer chromatography,
carried out on silica gel 60 WF254S aluminium sheets (Merck,
in active site, such as π-cation (ARG503 on chain A), π-π
stacking (DA12 and DG13 on chain F; DC8 on chain C; DT9, on
Germany) and was visualized with UV light. Chemical reagents
chain D). There was not any hydrogen bonding interaction of
in high purity were purchased from the Merck Chemical
this drug with the residues in active site. The ligands 6c, 6d, 6f,
Company (in Viet Nam). All materials were of reagent grade for
and 6g had common interactions with the residues ARG503
organic
synthesis.
4-Hydroxy-6-methyl-2H-pyrano[3,2-
(on chain A), GLN778(on chain A), DA12 (on chain F), and DG13
(on chain F). There were some intermolecular residue
interactions with compounds 6c and 6g, some interactions
were the same ones in case of ellipticine: π-cation (ARG503 on
chain A), π-π stacking (DA12 and DG13 on chain F). Another
ligand-amino acid interactions of residue GLN778 on chain A of
enzyme 4G0V took place in these ligands. This interaction was
hydrogen bonding of GLN778 with C=O (lactam) group of 4-
c]quinoline-2,5(6H)-dione (2, pyronoquinoline) was prepared
from N-methylaniline according to known method32. 3-Acetyl-
4-hydroxy-1-methylquinolin-2(1H)-one was prepared by
modified procedure according to literatures45, in which
glycerol was used instead ethylene glycol, as follows.
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Figure 6. Residues involved in intermolecular interactions of ligands 6c (top left), 6g (top right), and ellipticine (middle left) in active pocked of human topoisomerase IIβ in complex
with DNA (4G0V). The molecular 4G0V interactions of 6c and 6g (bottom) were depicted as dashed lines (orange hydrogen bonds, green π/ stacking).
–
–
π
mol, 32.1 mL) was added. Reaction mixture was boiled within
1 hour. The obtained solution was cooled in ice bath and
poured into cold water (642 mL), and neutralized the solution
by concentrated HCl until the precipitate completely separated
(to acidic medium, pH 3). The separated precipitates were
filtered, washed with water to pH 7, dried at temperature of
80°C, and crystallized from 96% ethanol. Yield: 12.51 g (56%).
Synthesis of 3-acetyl-4-hydroxy-1-methylquinolin-
2(1H)-one (3)
This compound was prepared by modified procedure45. To
suspension of pyronoquinoline 2 (0.103 mol, 25 g) in glycerol
(321 mL) a 40% aqueous solution of sodium hydroxide (0.515
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M.p. 141−142°C, ref.32: 141−142.5°C. IR (KBr, ν, cm−1): 3468 yellow crystals. M.p.: 178−179°C (96% ethanol/DMF 5:1 by
(νOH), 1650 (νC=O lactam), 1620 (νC=O conj. acetyl). H NMR (500 MHz, volume); Rf = 0.81 (n-hexane/ethyl acetate = 5:3 by volume). IR
DMSO-d6), δ (ppm): 2.71 (3H, s, 3-COCH3), 3.54 (s, 3H, N-CH3), (KBr), ν (cm−1): 3103, 2971, 2933, 2838, 1643, 1599, 1532,
1
1
7.31 (t, J = 8.0 Hz, 1H, H-6), 7.50 (d, J = 8.0 Hz, 1H, H-5), 7.79 1504, 980. H NMR (500 MHz, DMSO-d6), δ (ppm): 8.51 (d, J =
(td, J = 8.0, 1.5 Hz, 1H, H-7), 8.06 (dd, J = 8.0, 1.5 Hz, 1H, H-8).
15.5 Hz, 1H, H-2ʹ), 8.13 (d, J = 8.0 Hz, 1H, H-5), 7.93 (d, J = 15.5
Hz, 1H, H-3ʹ), 7.81 (t, J = 8.0 Hz, 1H, H-7), 7.72 (d, 2H, J = 8.5 Hz,
H-3ʹʹ, H-5ʹʹ), 7.55 (d, J = 8.0 Hz, 1H, H-8), 7.33 (t, J = 8.0 Hz, 1H,
H-6), 7.06 (d, 2H, J = 8.5 Hz, H-2ʹʹ, H-6ʹʹ), 3.83 (s, 3H, 4ʹʹ-OCH3),
3.59 (s, 3H, N-CH3). ESI-MS (+): calcd. for C20H17NO4, M=335.1
Da, found: m/z 335.9 [M]+.
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General procedure for synthesis of (E)-4-hydroxy-
3-(3-(aryl/hetaryl)acryloyl)-1-methylquinolin-
2(1H)-ones (5a-g)
(E)-4-Hydroxy-3-(3-(4-bromophenyl)acryloyl)-1-methylquinolin-
2(1H)-one (5d)
To a mixture of 3-acetyl-4-hydroxy-N-methyl-2(1H)-quinolone
(3, 5 mmol) and appropriate (un)substituted benzaldehydes
4a-f or thiophene-2-carboxaldehyde 4g (5 mmol) in absolute
ethanol (25 mL) was added piperidine (1 mol%, 0.1 mL). The
reaction mixture was heated under reflux for 25−50 h. After
reaction, solvent was led to evaporate to half a volume.
Separated solid product was filtered, washed with a little of
96% ethanol (2×2 mL), recrystallized from appropriate solvents
to afford the titled compounds 5a-g.
From 3 (5 mmol, 1085 mg) and 4d (R =4ʹ-Br, 5 mmol, 925 mg),
under reflux for 25 h. Yield: 1632 mg (80%) of 5d as pale-yellow
crystals. M.p.: 200−201°C (96% ethanol/DMF 5:1 by volume); Rf =
0.68 (n-hexane/ethyl acetate = 5:3 by volume). IR (KBr), ν (cm−1):
1
3088, 3045, 2925, 1680, 1616, 1535, 979, 756. H NMR (500 MHz,
DMSO-d6), δ (ppm): 8.58 (d, J = 16.0 Hz, 1H, H-3ʹ), 8.12 (dd, J = 8.0,
1.0 Hz, 1H, H-5), 7.86 (d, J = 16.0 Hz, 1H, H-2ʹ), 7.81 (td, J = 8.0, 1.5
Hz, 1H, H-7), 7.72-7.67 (m, 4H, H-2ʹʹ, H-3ʹʹ, H-5ʹʹ, H-6ʹʹ), 7.55 (d, J =
8.5 Hz, 1H, H-8), 7.33 (t, J = 8.5 Hz, 1H, H-6), 3.58 (s, 3H, N-CH3). ESI-
MS (-): calcd. for C19H1479BrNO3, M-H=382.0 Da, found: m/z 381.9
[M-H]+.
(E)-4-Hydroxy-3-(3-(3-chlorophenyl)acryloyl)-1-methylquinolin-
2(1H)-one (5a)
From 3 (5 mmol, 1085 mg) and 3a (Ar=3ʹʹ-ClC6H4, 5 mmol, 702 mg),
under reflux for 35 h. Yield: 1324 mg (78%) of 5a as pale-yellow
crystals. M.p.: 168−169°C (96% ethanol/DMF 5:1 by volume); Rf =
0.70 (n-hexane/ethyl acetate = 5:3 by volume). IR (KBr), ν (cm−1):
3102, 1650, 1623, 1596, 1542, 983. 1H NMR (500 MHz, DMSO-d6), δ
(ppm): 8.57 (d, J = 16.0 Hz, 1H, H-3ʹ), 8.17 (dd, J = 8.0 and 1.5 Hz,
1H, H-5), 7.87 (d, J = 16.0 Hz, 1H, H-2ʹ), 7.81 (td, J = 8.0 and 1.5 Hz,
1H, H-7), 7.76 (s, 1H, H-2ʹʹ), 7.71−7.69 (m, 1H, H-6ʹʹ), 7.56 (d, J = 8.0
Hz, 1H, H-8), 7.52−7.51 (m, 2H, H-4ʹʹ, H-5ʹʹ), 7.34 (t, J = 8.0 Hz, 1H, H-
6), 3.62 (s, 3H, N-CH3). ESI-MS (+): calcd. for C19H1435ClNO3, M=339.1
Da, found: m/z 399.9 [M]+.
(E)-4-Hydroxy-3-(3-(4-(N,N-dimethylamino)phenyl)acryloyl)-1-
methylquinolin-2(1H)-one (5e)
From 3 (5 mmol, 1085 mg) and 4e (Ar=4ʹʹ-Me2NC6H4, 5 mmol,
820 mg), under reflux for 42 h. Yield: 1061 mg (61%) of 5e as
red brown crystals. M.p.: 220−221°C (96% ethanol/DMF 5:2 by
volume); Rf = 0.78 (n-hexane/ethyl acetate = 5:3 by volume). IR
(KBr), ν (cm−1): 3110, 2910, 2807, 2538, 1636, 1595, 1504, 979,
1
762. H NMR (500 MHz, DMSO-d6), δ (ppm): 8.43 (d, J = 15.5
Hz, 1H, H-3ʹ), 8.10 (d, J = 8.0 Hz, 1H, H-5), 7.94 (d, J = 15.5 Hz,
1H, H-2ʹ), 7.75 (t, J = 8.0 Hz, 1H, H-7), 7.58 (s, 2H, J = 8.5 Hz, H-
3ʹʹ, H-5ʹʹ), 7.50 (d, J = 8.0 Hz, 1H, H-8), 7.28 (t, J = 8.0 Hz, 1H, H-
6), 6.77 (d, 2H, J = 8.5 Hz, H-2ʹʹ, H-6ʹʹ), 3.56 (s, 3H, N-CH3), 3.02
(E)-4-Hydroxy-3-(3-(3-methylphenyl)acryloyl)-1-methylquinolin-
2(1H)-one (5b)
From 3 (5 mmol, 1085 mg) and 4b (Ar=3ʹʹ-MeC6H4, 5 mmol, [s, 6H, 4ʹ-N(CH3)2].
600 mg), under reflux for 32 h. Yield: 1308 mg (87%) of 5b as
yellow crystals. M.p.: 172−173°C (96% ethanol); Rf = 0.82 (n-
hexane/ethyl acetate = 5:3 by volume). IR (KBr), ν (cm−1): 3110,
(E)-4-Hydroxy-3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-1-
methylquinolin-2(1H)-one (5f)
1
3034, 2917, 2849, 1633, 1625, 980, 870, 797, 750. H NMR From 3 (5 mmol, 1085 mg) and 4f (Ar=4ʹʹ-OH-3ʹʹ-MeOC6H3, 5
(500 MHz, DMSO-d6), δ (ppm): 8.57 (d, J = 16.0 Hz, 1H, H-3ʹ), mmol, 706 mg), under reflux for 38 h. Yield: 1440 mg (82%) of
8.13 (d, J = 8.0 Hz, 1H, H-5), 7.88 (d, J = 16.0 Hz, 1H, H-2ʹ), 7.80 5f as yellow crystals. M.p.: 232−233°C (96% ethanol/DMF 5:1
(t, J = 8.0 Hz, 1H, H-7), 7.53−7.51 (m, 3H, H-8, H-2ʹʹ, H-6ʹʹ), 7.38- by volume); Rf = 0.81 (n-hexane/ethyl acetate = 5:3 by
7.29 (m, 3H, H-6, H-4ʹʹ, H-5ʹʹ), 3.58 (s, 3H, N-CH3), 2.36 (s, 3H, volume). IR (KBr), ν (cm−1): 3365, 3116, 3010, 2962, 2838,
1
3ʹʹ-CH3).
1634, 1616, 1597, 1505, 998, 747. H NMR (500 MHz, DMSO-
d6), δ (ppm): 9.81 (s, 1H, 4ʹʹ-OH), 8.43 (d, J = 16.0 Hz, 1H, H-3ʹ),
8.07 (d, J = 8.0 Hz, 1H, H-5), 7.88 (d, J = 16.0 Hz, 1H, H-2ʹ), 7.74
(td, J = 8.0, 1.5 Hz, 1H, H-7), 7.47 (d, J = 8.0 Hz, 1H, H-8), 7.28-
(E)-4-Hydroxy-3-(3-(4-methoxyphenyl)acryloyl)-1-methylquinolin-
2(1H)-one (5c)
From 3 (5 mmol, 1085 mg) and 4c (Ar=4ʹʹ-MeOC6H4, 5 mmol, 7.21 (m, 3H, H-6, H-2ʹʹ, H-5ʹʹ), 6.88 (d, 1H, J = 8.0 Hz, H-6ʹʹ),
680 mg), under reflux for 30 h. Yield: 1423 mg (85%) of 5c as 3.85 (s, 3H, 3ʹʹ-OCH3), 3.53 (s, 3H, N-CH3).
8 | J. Name., 2012, 00, 1-3
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(E)-4-Hydroxy-3-(3-(2-thienyl)acryloyl)-1-methylquinolin-2(1H)-
one (5g)
system: n-hexane/acetone 5:2). IR (KBr), ν (cm–1): 3444 (νOH),
2933 (νC−H alkyl), 1627 (νC=O lactam), 1600, 1548, 1479 (νC=C
arene). 1H NMR (500 MHz, DMSO-d6), δ (ppm): 14.78 (s, 1H, 4-
OH), 8.16−8.10 (m, 1H, H-5), 7.69−7.60 (m, 3H, H-7, H-6ʹ, H-8ʹ),
7.53 (d, J = 7.5 Hz, 1H, H-9ʹ), 7.44−7.40 (m, 2H, H-8, H-7ʹ),
7.24−7.08 (m, 5H, H-6, H-2ʹʹ, H-4ʹʹ, H-5ʹʹ, H-6ʹʹ), 5.26 (dd, J =
13.0, 4.5 Hz, 1H, Hc), 4.44 (dd, J = 11.0, 3.0 Hz, 1H, Hb), 3.51 (s,
3H, N-CH3), 2.73-2.67 (m, 1H, Ha), 2.28 (s, 3H, 3′′-CH3); 13C NMR
(125 MHz, DMSO-d6), δ (ppm): 143.4 (C-4), 134.9 (C-6ʹ), 133.6
(C-7), 130.1 (C-8ʹ), 128.0 (C-4ʹʹ), 127.7 (C-5ʹʹ), 127.6 (C-7ʹ),
127.5 (C-3ʹʹ), 127.2 (C-5), 126.3 (C-1ʹʹ), 124.6 (C-9ʹ), 122.7
(C2ʹʹ), 121.0 (C-6), 119.8 (C-4a), 114.2 (C-8), 55.7 (C-2ʹ), 38.4 (C-
3ʹ), 28.4 (N-CH3), 20.56 (3′′-CH3); ESI-MS: calcd. for
C26H22N2O2S, M=426.53 Da, found: m/z 427.0 [M+H]+.
From 3 (5 mmol, 1085 mg) and 4g (Ar =2ʹʹ-thienyl, 5 mmol, 701
mg), under reflux for 50 h. Yield: 1078 mg (70%) of 5g as bright
yellow crystals. M.p.: 211−212°C (96% ethanol); Rf = 0.80 (n-
hexane/ethyl acetate = 5:3 by volume). IR (KBr), ν (cm−1): 3106,
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3086, 1655, 1607, 1597, 1532, 967, 755. H NMR (500 MHz,
DMSO-d6), δ (ppm): 8.41 (d, J = 15.5 Hz, 1H, H-3ʹ), 8.12−8.10
(m, 2H, H-5, H-2ʹ), 7.79−7.78 (m, 2H, H-7, H-5ʹʹ), 7.61 (d, 1H, J =
3.5 Hz, H-3ʹʹ), 7.53 (d, J = 8.0 Hz, 1H, H-8), 7.31 (t, J = 8.0 Hz,
1H, H-6), 7.20 (td, 1H, J = 3.5, 1.0 Hz, H-4ʹʹ), 3.58 (s, 3H, N-CH3).
General procedure for synthesis of 3-(2-
aryl/hetaryl-1,5-benzothiazepin-4-yl)-4-hydroxy-1-
methyl-quinolin-2(1H)-ones (6a-g)
3-(2-(4-Methoxyphenyl)-1,5-benzothiazepin-4-yl)-4-hydroxy-1-
methyl-quinolin-2(1H)-one (6c)
From 5c (Ar=4ʹʹ-MeOC6H4, 1 mmol, 335 mg) under reflux for 5
h. Yield: 318 mg (72%) of 6c as white crystals. M.p.: 213−214°C
(from 96% ethanol/DMF=5:2 in volume), Rf = 0.68 (TLC solvent
system: n-hexane/acetone 5:3). IR (KBr), ν (cm–1): 3415 (νOH),
3061 (νC−H aryl), 2948, 2836 (νC−H alkyl), 1631 (νC=O lactam),
1590, 1550, 1478 (νC=C arene). 1H NMR (500 MHz, DMSO-d6), δ
(ppm): 14.77 (s, 1H, 4-OH), 8.17 (d, 1H, H-5), 7.68-7.66 (m, 2H,
H-7, H-6ʹ), 7.61 (t, J = 7.5 Hz, 1H, H-8ʹ), 7.51 (d, J = 7.5 Hz, 1H,
H-9ʹ), 7.42 (t, J = 7.5 Hz, 2H, H-8, H-7ʹ), 7.27 (d, J = 7.5 Hz, 2H,
H-2ʹʹ, H-6ʹʹ), 7.23 (t, J = 8.0 Hz, 1H, H-6), 6.89 (d, J = 7.5 Hz, 2H,
H-3ʹʹ, H-5ʹʹ), 5.28 (d, 1H, Hc), 4.44-4.36 (m, 1H, Hb), 3.75 (s, 3H,
4′′-OCH3), 3.54 (s, 3H, N-CH3), 2.73-2.71 (m, 1H, Ha); 13C NMR
(125 MHz, DMSO-d6), δ (ppm): 162.5 (C-2 & C-4ʹ), 158.4 (C-4ʹʹ),
139.9 (C-4), 139.5 (C-9aʹ), 135.9 (C-1ʹʹ), 135.0 (C-6ʹ), 133.7 (C-
7), 130.2 (C-8ʹ), 127.8 (C-7ʹ), 127.2 (C-5aʹ), 126.9 (C-2ʹʹ, C-6ʹʹ),
125.9 (C-5), 124.7 (C-9ʹ), 121.2 (C-6), 120.1 (C-4a), 114.4 (C-8),
113.7 (C-3ʹʹ, C-5ʹʹ), 91.5 (C-3), 55.5 (C-2ʹ), 54.9 (4′′-OCH3), 39.4
(C-3ʹ), 28.5 (N-CH3); ESI-MS: calcd. for C26H22N2O3S, M=442.52
Da, found: m/z 441 (100%) [M−H]+.
A reaction mixture of appropriate α,β-(un)saturated ketone
5a-g (1 mmol) and o-aminothiophenol (1 mmol, 125 mg, 0.1
mL) in absolute ethanol (30 mL). Glacial acetic acid (0.05 mL, 5
mol%) was added to this mixture. Obtained reaction mixture
was heated under reflux for 5−7 h. Separated products were
filtered and recrystallized from a mixture of DMF and 96%
ethanol (in appropriate volume rations) to afford the
compounds 6a-g.
3-(2-(3-Chorophenyl)-1,5-benzothiazepin-4-yl)-4-hydroxy-1-
methyl-quinolin-2(1H)-one (6a)
From 5a (Ar=3ʹʹ-ClC6H4, 1 mmol, 339 mg) under reflux for 6 h.
Yield: 299 mg (67%) of 6a as white crystals. M.p.: 222−223°C
(from 96% ethanol/DMF=5:1 in volume), Rf = 0.80 (TLC solvent
system: n-hexane/acetone 5:3). IR (KBr), ν (cm–1): 3428 (νOH),
3061 (νC−H aryl), 2940, 2887 (νC−H alkyl), 1628 (νC=O lactam),
1590, 1550, 1478 (νC=C arene). 1H NMR (500 MHz, DMSO-d6), δ
(ppm): 14.76 (s, 1H, 4-OH), 8.16−8.12 (m, 1H, H-5), 7.69−7.61
(m, 3H, H-7, H-6ʹ, H-8ʹ), 7.53 (d, J = 7.5 Hz, 1H, H-9ʹ), 7.43−7.31
(m, 6H, H-8, H-7ʹ, H-2ʹʹ, H-4ʹʹ, H-5ʹʹ, H-6ʹʹ), 7.23 (t, J = 7.5 Hz,
1H, H-6), 5.33−5.30 (m, 1H, Hc), 4.34−4.32 (m, 1H, Hb), 3.52 (s,
3H, N-CH3), 2.75−2.70 (m, 1H, Ha); 13C NMR (125 MHz, DMSO-
d6), δ (ppm): 145.7 (C-4), 134.8 (C-6ʹ), 134.8 (C-3ʹʹ), 134.0 (C-7),
132.8 (C-2ʹʹ), 130.3 (C-8ʹ), 130.1 (C-6ʹʹ), 127.7 (C-7ʹ), 127.0 (C-
5ʹʹ), 126.7 (C-5), 126.3 (C-1ʹʹ), 125.7 (C-4ʹʹ), 124.7 (C-9ʹ), 124.4
(C-6), 116.9 (C-4a), 114.3 (C-8), 101.0 (C-3), 54.7 (C-2ʹ), 54.9
(OCH3), 38.2 (C-3ʹ), 28.4 (N-CH3); ESI-MS: calcd. for
C25H1935ClN2O2S/C25H1937ClN2O2S, M=446.94/448.94 Da, found:
m/z 447 (100%) [M−H]+ and 449 (32%) [M+2−H]+.
3-(2-(4-Bromophenyl)-1,5-benzothiazepin-4-yl)-4-hydroxy-1-
methyl-quinolin-2(1H)-one (6d)
From 5d (Ar=4ʹʹ-BrC6H4, 1 mmol, 384 mg) under reflux for 6 h.
Yield: 382 mg (78%) of 6d as white crystals. M.p.: 221−222°C
(from 96% ethanol/DMF=5:1 in volume), Rf = 0.60 (TLC solvent
system: n-hexane/acetone 5:2). IR (KBr), ν (cm–1): 3525, 3320
(νOH), 3189, 3061 (νC−H aryl), 2977, 2858 (νC−H alkyl), 1628 (νC=O
lactam), 1593, 1541, 1463 (νC=C arene). 1H NMR (500 MHz,
DMSO-d6), δ (ppm): 14.76 (s, 1H, 4-OH), 8.18 (d, 1H, H-5),
7.70−7.67 (m, 2H, H-7, H-6ʹ), 7.62 (t, J = 7.5 Hz, 1H, H-8ʹ), 7.55-
7.52 (m, 3H, H-3ʹʹ, H-5ʹʹ, H-9ʹ), 7.44−7.41 (m, 2H, H-7ʹ, H-8),
7.36 (d, J = 8.0 Hz, 2H, H-2ʹʹ, H-6ʹʹ), 7.24 (t, J = 7.5 Hz, 1H, H-6),
5.34 (1H, d, Hc), 4.42 (1H, dd, Hb), 3.56 (s, 3H, N-CH3), 2.75 (1H,
t, Ha); 13C NMR (125 MHz, DMSO-d6), δ (ppm): 172.6 (C-4),
162.3 (C-4ʹʹ), 143.2 (C-2), 141.0 (C-8a), 139.7 (C-9aʹ), 135.4 (C-
1ʹʹ), 134.1 (C-6ʹ), 131.5 (C-3ʹʹ, C-5ʹʹ), 130.8 (C-8ʹ), 128.3 (C-2ʹʹ, C-
3-(2-(3-Methylphenyl)-1,5-benzothiazepin-4-yl)-4-hydroxy-1-
methyl-quinolin-2(1H)-one (6b)
From 5b (Ar=3ʹʹ-MeC6H4, 1 mmol, 319 mg) under reflux for 7 h.
Yield: 349 mg (82%) of 6b as white crystals. M.p.: 208−209°C
(from 96% ethanol/DMF=5:1 in volume), Rf=0.76 (TLC solvent
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6ʹʹ), 127.0 (C-5aʹ), 126.5 (C-7ʹ), 125.3 (C-5), 125.2 (C-9ʹ), 121.6 arene). H NMR (500 MHz, DMSO-d6), δ (ppm): 8.17 (s, 1H, H-
(C-6), 120.5 (C-7), 120.1 (C-4a), 114.8 (C-8), 101.4 (C-3), 55,2 5), 7.70−7.61 (m, 3H, H-7, H-6ʹ, H-8ʹ), 7.52 (dd, J = 8.0, 2.0 Hz,
(C-2ʹ), 39.5 (C-3ʹ), 28.7 (N-CH3); ESI-MS: calcd. for 1H, H-9ʹ), 7.45−7.40 (m, 3H, H-8, H-7ʹ, H-5ʹʹ), 7.24 (td, J = 8.0,
C25H1979BrN2O2S/ C25H1981BrN2O2S, M=490.52/492.52 Da, 1.0 Hz, 1H, H-6), 7.05 (s, 1H, H-3ʹʹ), 6.98 (td, J = 5.0, 3.5 Hz, 1H,
found: m/z 489 (9.7%) [M−H]+ and 491 (9.5%) [M+2−H]+.
H-4ʹʹ), 5.60 (dd, J = 12.0, 4.5 Hz, 1H, Hc), 4.56 (s, 1H, Hb), 3.55
(s, 3H, N-CH3), 2.69−2.63 (m, 1H, Ha); 13C NMR (125 MHz,
DMSO-d6), δ (ppm): 148.5 (C-4), 147.1 (C-2ʹʹ), 139.5 (C-9aʹ),
135.5 (C-6ʹ), 133.8 (C-7), 130.5 (C-8ʹ), 126.4 (C-5ʹʹ), 126.3 (C-5),
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3-(2-(4-(N,N-Dimethylamino)phenyl)-1,5-benzothiazepin-4-yl)-4-
hydroxy-1-methyl-quinolin-2(1H)-one (6e)
From 5e (Ar=4ʹʹ-Me2NC6H4, 1 mmol, 348 mg) under reflux for 7 126.0 (C-5aʹ), 125.9 (C-5), 124.7 (C-9ʹ), 124.6 (C-3ʹʹ), 123.6 (C-
h. Yield: 354 mg (78%) of 6e as red brown crystals. M.p.: 4ʹʹ), 121.2 (C-6), 114.4 (C-8), 90.6 (C-3), 51.4 (C-2ʹ), 39.0 (C-3ʹ),
228−229°C (from 96% ethanol/DMF=5:2 in volume), Rf = 0.81 28.5 (N-CH3); ESI-MS: calcd. for C23H18N2O2S2, M=418.53 Da,
(TLC solvent system: n-hexane/acetone 5:3). IR (KBr), ν (cm–1): found: m/z 419 [M+H]+.
3450 (νOH), 2895, 2794 (νC−H alkyl), 1630 (νC=O lactam), 1610,
1542, 1482 (νC=C arene); 1H NMR (500 MHz, DMSO-d6), δ
(ppm): 14.77 (s, 1H, 4-OH), 8.17-8.11 (m, 1H, H-5), 7.69−7.52
Cytotoxicity assay
(m, 4H, H-7, H-6ʹ, H-8ʹ, H-9ʹ), 7.46−7.41 (m, 2H, H-8, H-7ʹ), 7.23
Dilution series (128, 32, 8, 2, and 0.5 µg/mL of each compound
(1H, t, J = 7.5 Hz, H-6), 7.13 (d, 2H, J = 8.5 Hz, H-3ʹʹ, H-5ʹʹ), 6.66
6a-g) were prepared and used for 3-(4, 5-dimethylthiazol-2-yl)-
(d, 2H, J = 8.5 Hz, 2H, H-2ʹʹ, H-6ʹʹ), 5.25 (dd, 1H, J = 12.0, 4.0 Hz
2, 5-diphenyl tetrazolium bromide (MTT) assay 46. Two cancer
Hc), 4.42−4.28 (m, 1H, Hb), 3.52 (s, 3H, N-CH3), 2.87 [s, 6H,
cell lines were seeded at a density of 3×104 cells/well and
N(CH3)2], 2.73−2.63 (m, 1H, Ha); 13C NMR (125 MHz, DMSO-d6),
treated with a range of concentrations in triplicate in 96-well
δ (ppm): 149.6 (C-4ʹʹ), 139.9 (C-4), 134.9 (C-6ʹ), 133.4 (C-7),
cell culture plates, whereupon cell proliferation was assessed
131.2 (C-1ʹʹ), 129.9 (C-8ʹ), 127.5 (C-7ʹ), 126.2 (C-3ʹʹ, C-5ʹʹ), 125.9
using a standard MTT assay. Specifically, the growth inhibitory
(C-5), 124.5 (C-9ʹ), 121.1 (C-6), 114.2 (C-8), 111.9 (C-2ʹʹ, C-6ʹʹ),
activity of benzothiazepines was determined using MTT, which
56.0 (CH3), 55.9 (C-2ʹ), 38.7 (C-3ʹ), 28.4 (N-CH3).
correlates the cell number with the mitochondrial reduction of
MTT to a blue formazan precipitate. In brief, the cells were
plated in 96-well plates and allowed to attach overnight. The
medium was then replaced with serum-free medium
containing the test compounds and cells were incubated at
37°C for 72 h. The medium was then replaced with fresh
medium containing 1 mg/mL MTT. Following incubation at
37°C for 2−4 h, the wells were aspirated, the dye was
solubilized in DMSO and the absorbance was measured at 540
nm using a Tecan™ GENios® Microplate Reader (Conquer
Scientific, USA). The viability of cells was compared with that
of the control cells. The slope of the absorbance change was
used for calculating the reaction rate. Negative controls were
performed in the absence of enzyme and compound, and
positive controls in the presence of enzyme and 100% DMSO.
The percentage of residual activity was calculated as the
difference in absorbance between the time 6 and 2 min,
obtained by the average of two experiments carried out in
triplicate. The obtained rate was related to the rate when the
inhibitor was absent. IC50 values were calculated from linear
extrapolations of reaction rate (as a function of the logarithm
of the concentration). The IC50 values were determined with
increasing concentrations of inhibitor (128, 32, 8, 2, and 0.5
µg/mL) versus % of inhibition, in triplicate in two independent
experiments. The experimental data were analysed with
TableCurve 2D Software (Systat Software, Inc.) and the IC50
values determined by linear regression. It is important to
stress the fact that all compounds are soluble in the assay
mixtures at the described experimental conditions.
3-(2-(4-Hydroxy-3-methoxyphenyl)-1,5-benzothiazepin-4-yl)-4-
hydroxy-1-methyl-quinolin-2(1H)-one (6f)
From 5f (Ar=4ʹʹ-OH-3ʹʹ-MeOC6H3, 1 mmol, 351 mg) under reflux
for 6 h. Yield: 284 mg (62%) of 6f as white crystals. M.p.:
241−242°C (from 96% ethanol/DMF=5:1 in volume), Rf = 0.72
(TLC solvent system: n-hexane/acetone 5:2). IR (KBr), ν (cm–1):
3475 (νOH), 2935, 2837 (νC−H alkyl), 1628 (νC=O lactam), 1595,
1552 (νC=C arene). 1H NMR (500 MHz, DMSO-d6), δ (ppm):
14.77 (s, 1H, C4-OH), 8.99 (s, 1H, C4ʹʹ -OH), 8.17-8.11 (m, 1H,
H-5), 7.70-7.66 (m, 2H, H-7, H-6ʹ), 7.61 (t, J=7.5 Hz, 1H, H-8ʹ),
7.55 (d, J=7.5 Hz, 1H, H-9ʹ), 7.47-7.41 (m, 2H, H-8, H-7ʹ), 7.23
(1H, t, J=7.5 Hz, H-6), 6.90 (m, 1H, H-6ʹʹ), 6.72 (m, 2H, 2H, H-2ʹʹ,
H-3ʹʹ), 5.26-5.22 (m, 1H, Hc), 4.33-4.31 (m, 1H, Hb), 3.71 (s, 3H,
4′′-OCH3), 3.52 (s, 3H, N-CH3), 2.75-2.60 (m, 1H, Ha); 13C NMR
(500 MHz, DMSO-d6), δ (ppm): 180.5 (C-4ʹ), 172.8 (C-4), 162.3
(C-4ʹʹ), 147.4 (C-5ʹʹ), 146.0 (C-2), 141.0 (C-8a), 139.7 (C-9aʹ),
135.4 (C-1ʹʹ), 135.0 (C-6ʹ), 134.0 (C-7), 130.5 (C-8ʹ), 128.1 (C-7ʹ),
127.6 (C-5aʹ), 126.1 (C-5), 125.0 (C-9ʹ), 121.4 (C-6), 120.0 (C-
4a), 118.2 (C-6ʹʹ), 115.1 (C-3ʹʹ), 114.7 (C-8), 110.2 (C-2ʹʹ), 101.4
(C-3), 55.4 (C-2ʹ), 55.9 (OCH3), 39.3 (C-3ʹ), 28.6 (N-CH3).
3-(2-(2-Thienyl)-1,5-benzothiazepin-4-yl)-4-hydroxy-1-methyl-
quinolin-2(1H)-one (6g)
From 5g (Ar=2ʹʹ-thienyl, 1 mmol, 312 mg) under reflux for 7 h.
Yield: 356 mg (85%) of 6g as white crystals. M.p.: 216−217°C
(from 96% ethanol/DMF=5:1 in volume), Rf = 0.81 (TLC solvent
system: n-hexane/acetone 5:2). IR (KBr), ν (cm–1): 3450 (νOH),
3059 (νC−H aryl), 1630 (νC=O lactam), 1600, 1548, 1475 (νC=C
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molecules (559 molecules) and 6 magnesium ions were
removed. Mitoxantrone molecule complexed with chains A, C,
D, F was chosen for Protein Preparation Wizard used OPLS-
2005 force field for structural optimization and minimization
and for Receptor Grid Generation tool of Glide v.8.1. The Glide
HTVS 8.1 algorithm (High-Throughput Virtual Screening Mode)
was employed using a grid box volume of 10ꢀ×ꢀ10ꢀ×ꢀ10ꢀÅ.
Briefly, Glide approximates a systematic search of positions,
orientations and conformations of the ligand in the receptor
binding site using a series of hierarchical filters. Docking
progress used constraints of two H-bond donor on Arg503,
GLU522 and GLU778, one H-bond acceptor on ASN520. Upon
completion of each docking calculation, 32 poses per ligand
were generated and the best docked structure was chosen
using a GlideScore (Gscore) function. A flow chart for
molecular docking calculation using Schrödinger suite was
implemented Supplementary Information file in online version
of this article.
5
6
7
8
In silico physicochemical property calculation and
druglikeness evaluation
PreADMET online software (https://preadmet.bmdrc.kr/)35
and SwissADME online (http://www.swissadme.ch/)36
prediction tools were applied for determination of
physicochemical properties, lipophilicity, water solubility,
pharmacokinetics, drug-likeness and medicinal chemistry
parameters, and also Topological Polar Surface Area (TPSA),
number of rotatable bonds, LogP, violations of Veber's rule38,
and violations of Lipinski's rule of five37.
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Molecular docking
The two-dimensional structures (.mae) of compounds 6a-g
(ligands), were drawn and the structure was analysed by using
2D sketcher and 3D builder of Maestro 11.8 (Schrödinger, LLC,
New York, NY, USA) 47. The three-dimensional structures of
these compounds (ligands) were generated from three-
dimensional structures prepared first using LigPrep 3.6 using
OPLS-2005 force field. The tautomeric isomers for the ligands,
as displayed in Scheme 1, were searched and energy
minimizations were carries out by applying the OPLS 2005
force fields, at pH 7.0 ± 2.0. The Epik v.4.3 methodology was
used when preparing the ligands. Then geometrically
minimized with MacroModel 12.2 followed by conformational
analysis using MMFFs force field. Monte Carlo Multiple
Minimum (MCMM) conformational search was used with 2500
iterations and convergence threshold of 0.05ꢀkJ/mol. Water
was chosen as solvent. Truncated Newton Conjugate Gradient
minimization was used with 2500 iterations and convergence
threshold of 0.05ꢀkJ/mol. Other parameters were used as
default. Crystal structure of human topoisomerase IIβ in
complex with DNA and mitoxantrone (code: 4G0V) was
Conclusions
A series of (E)-4-hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-
2(1H)-ones (5a-g) were prepared from 3-acetyl-4-hydroxy-1-
methylquinolin-2(1H)-one with yields of 61−87%. These α,β-
unsaturated ketones were converted into 3-(2-amino-6-
arylpyrimidin-4-yl)-4-hydroxy-1-methylquinolin-2(1H)-ones
(6a-g) by reaction with o-aminothiophenol in the presence of
piperidine as catalyst. The yields of benzothiazepines 6a-g
were 62−85%. All synthesized compounds 6a-g were evaluated
for in vitro anticancer activity against two cancer cell lines,
human squamous cell carcinoma (KB) and hepatocellular
carcinoma (HepG2). Compounds 6c and 6g exhibited
remarkable inhibitory activity against the tested cancer cell
lines with MIC values of 0.25−0.27 and 0.26−0.28 μM,
respectively. ADMET properties as well as drug-likeness
behaviours showed that of compounds 6c, 6f, and 6g were
evaluated. Docking results indicated that residues GLN778(A),
DA12(F), and DG13(F) in the binding pocket as potential ligand
binding hot-spot residues for compounds 6c and 6g.
retrieved
(https://www.rcsb.org/structure/4G0V). This structure was
solved by X-ray crystallography at 2.6 resolution.
from
the
RCSB
Protein
Data
Bank
Å
Coordinates of the protein-ligand complex were fixed for
errors in atomic representations and optimized using Protein
Preparation Wizard Maestro v. 11.5 (Maestro, v. 11.5:
Schrödinger, LLC, New York, NY, USA). The bond orders were
assigned to residues, hydrogen atoms were added at pH 7.0 ±
2.0. The restrained minimizations were carried out using the
OPLS 2005 force field with an RMSD cut-off value of 0.3 Å for
heavy atom convergences. The molecular docking was
accomplished and analysed via the Glide v. 8.1 docking tool48.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The receptor grid was located in the centre based on the active This research is funded by grant number of B2019-TNA-11.
site of the protein, using the receptor grid generation tool. The
ligands were flexibly docked in grid box using Monte Carlo-
based simulation algorithm and an XP (Extra Precision) method
without any constraints was employed that generated binding
poses based on energy. For preparation of protein, water
References
1. K. A. M. El-Bayouki, Organic Chemistry International, 2013, 2013,
210474.
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ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
View Article Online
DOI: 10.1039/D0NJ04295A
2. D. Saha, G. Jain and A. Sharma, RSC Advances, 2015, 5, 70619- 25. M. M. Baag, M. K. Sahoo, V. G. Puranik and N. P. Argade,
70639. Synthesis, 2007, 2007, 457-463.
3. J. B. Bariwal, K. D. Upadhyay, A. T. Manvar, J. C. Trivedi, J. S. 26. W. Zhong, X. Chen and Y. Zhang, Synthetic Communications,
Singh, K. S. Jain and A. K. Shah, European Journal of Medicinal
Chemistry, 2008, 43, 2279-2290.
4. B. V. Kendre, M. G. Landge and S. R. Bhusare, Arabian Journal of
Chemistry, 2019, 12, 2091-2097.
5. A. Dandia, R. Singh and S. Khaturia, Journal of Fluorine Chemistry,
2007, 128, 524-529.
6. C. Mallikarjunaswamy, L. Mallesha, D. G. Bhadregowda and O.
Pinto, Arabian Journal of Chemistry, 2017, 10, S484-S490.
7. M. R. Gudisela, N. Srinivasu, C. Mulakayala, P. Bommu, M. V. B.
2000, 30, 4451-4460.
27. X. Chen, W. Zhong and Y. Zhang, Journal of Chemical Research,
2000, 2000, 386-387.
28. M. Sindler-Kulyk and D. C. Neckers, The Journal of Organic
Chemistry, 1982, 47, 4914-4919.
29. A. Dandia, M. Sati and A. Loupy, Green Chemistry, 2002, 4, 599-
602.
30. T. Duong Ngoc, T. Nguyen Dinh, T. Mai Xuan and T. Nguyen
Minh, Current Organic Synthesis, 2020, 17, 404-410.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rao and N. Mulakayala, Bioorganic & Medicinal Chemistry 31. K. Faber and T. Kappe, Journal of Heterocyclic Chemistry, 1984,
Letters, 2017, 27, 4140-4145. 21, 1881-1883.
8. H. Inoue, M. Konda, T. Hashiyama, H. Otsuka, K. Takahashi, M. 32. P. Roschger and W. Stadlbauer, Liebigs Annalen der Chemie,
Gaino, T. Date, K. Aoe and M. Takeda, Journal of Medicinal
Chemistry, 1991, 34, 675-687.
9. K. Noboru, M. Ryuko, H. Yoshihito and S. Ken, Current Clinical
Pharmacology, 2009, 4, 126-131.
10. S. Butini, S. Gemma, M. Brindisi, G. Borrelli, A. Lossani, A. M.
Ponte, A. Torti, G. Maga, L. Marinelli, V. La Pietra, I. Fiorini, S.
1990, 1990, 821-823.
33. M. M. Abdou, Arabian Journal of Chemistry, 2017, 10, S3324-
S3337.
34. D. Lagorce, C. Reynes, A. C. Camproux, M. A. Miteva, O.
Sperandio and B. O. Villoutreix, ADMET for Medicinal
Chemists. John Wiley & Sons, Inc, 2011, 29-124.
Lamponi, G. Campiani, D. M. Zisterer, S.-M. Nathwani, S. 35. S. K. Lee, S. H. Park, I. H. Lee and K. T. No.
Sartini, C. La Motta, F. Da Settimo, E. Novellino and F. Focher, 36. A. Daina, O. Michielin and V. Zoete, Scientific Reports, 2017, 7,
Journal of Medicinal Chemistry, 2011, 54, 1401-1420.
11. Z. Ul-Haq, W. Khan, S. Kalsoom and F. L. Ansari, Theoretical 37. C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney,
Biology and Medical Modelling, 2010, 7, 22. Advanced drug delivery reviews, 1997, 23, 3-25.
12. T. Suzuki, M. Ohashi, O. Takaiti and S. Harigaya, Arzneimittel- 38. D. F. Veber, S. R. Johnson, H. Y. Cheng, B. R. Smith, K. W. Ward
42717.
Forschung, 1994, 44, 3-6.
and K. D. Kopple, Journal of Medicinal Chemistry, 2002, 45,
2615-2623.
39. W. J. Egan, K. M. Merz and J. J. Baldwin, Journal of Medicinal
Chemistry, 2000, 43, 3867-3877.
13. A. V. Chate, R. S. Joshi, P. G. Mandhane and C. H. Gill, Journal of
the Korean Chemical Society, 2011, 55, 776-780.
14. M. Chaffman and R. N. Brogden, Drugs, 1985, 29, 387-454.
15.
Diltiazem
Hydrochloride, 40. S. Goodwin, A. F. Smith and E. C. Horning, Journal of the
American Chemical Society, 1959, 81, 1903-1908.
41. C. Auclair, Archives of Biochemistry and Biophysics, 1987, 259, 1-
16. H. Narita, M. Gaino, T. Suzuki, H. Kurosawa, H. Inoue and T.
Nagao, Chemical & Pharmaceutical Bulletin, 1990, 38, 407- 42. M. Stiborová, J. Poljaková, E. Martínková, L. Bořek-Dohalská, T.
https://www.drugs.com/monograph/diltiazem-
hydrochloride.html).
14.
410.
Eckschlager, R. Kizek and E. Frei, Interdiscip Toxicol, 2011, 4,
98-105.
17. H. M. Geyer, N. Watzman and J. P. Buckley, Journal of
Pharmaceutical Sciences, 1970, 59, 964-968.
18. A. C. Young, K. C. Kleinschmidt and P. M. Wax, Journal of
Medical Toxicology, 2009, 5, 24-26.
19. A. Acharya, R. Kamble, S. Patil, S. Hese, O. Yemul, S. Patil, S.
Halale and B. Dawane, Chemical Papers, 2014, 68, 719.
20. T. S. Saleh, N. M. Abd El-Rahman and R. S. A. Assaker, Green
Chemistry Letters and Reviews, 2012, 5, 315-320.
21. T. R. Ravikumar Naik, H. S. Bhojya Naik, M. Raghavendra, P. J.
43. S. Salerno, V. La Pietra, M. Hyeraci, S. Taliani, M. Robello, E.
Barresi, C. Milite, F. Simorini, A. N. García-Argáez, L. Marinelli,
E. Novellino, F. Da Settimo, A. M. Marini and L. Dalla Via,
European Journal of Medicinal Chemistry, 2019, 165, 46-58.
44. C.-C. Wu, Y.-C. Li, Y.-R. Wang, T.-K. Li and N.-L. Chan, Nucleic
Acids Research, 2013, 41, 10630-10640.
45. P. Roschger, W. Fiala and W. Stadlbauer, Journal of Heterocyclic
Chemistry, 1992, 29, 225-231.
Bindu and K. M. Mahadevan, Journal of Sulfur Chemistry, 46. D. A. Scudiero, R. H. Shoemaker, K. D. Paull, A. Monks, S.
2007, 28, 589-595.
22. A. Sharifi, F. Hosseini, N. Ghonouei, M. S. Abaee, M. Mirzaei, A.
Tierney, T. H. Nofziger, M. J. Currens, D. Seniff and M. R. Boyd,
Cancer Research, 1988, 48, 4827-4833.
W. Mesbah and K. Harms, Journal of Sulfur Chemistry, 2015, 47. Schrödinger, suite 2018-1, Schrödinger, Inc., New York, 2018.
36, 257-269. http://www.schrodinger.com.
23. A. P. Acharya, R. D. Kamble, S. D. Patil, S. V. Hese, O. S. Yemul, S. 48. T. A. Halgren, R. B. Murphy, R. A. Friesner, H. S. Beard, L. L. Frye,
G. Patil, S. N. Halale and B. S. Dawane, Chemical Papers, 2014,
68, 719-724.
24. O. Prakash, A. Kumar, A. Sadana, R. Prakash, S. P. Singh, R. M.
Claramunt, D. Sanz, I. Alkorta and J. Elguero, Tetrahedron,
2005, 61, 6642-6651.
W. T. Pollard and J. L. Banks, Journal of Medicinal Chemistry,
2004, 47, 1750−1759.
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DOI: 10.1039/D0NJ042
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New Journal of Chemistry
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Synthesis, cytotoxic activity, ADMET and molecular docking
study of quinoline-based hybrid compounds of 1,5-
benzothiazepines
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Duong Ngoc Toan,a,b* Nguyen Dinh Thanh,b* Mai Xuan Truong,a Duong Nghia Bang,c Mai Thanh Nga,
a Nguyen Thi Thu Huong b
Some α,β-unsaturated ketones 4a-g of 3-acetyl-4-hydroxyquinolin-2(1H)-one were prepared by its reaction with
(hetero)aromatic aldehydes with yields of 61−87% using piperidine as catalyst. These ketones reacted with o-
aminothiophenol in the presence of acetic acid to afford a series of new hybrid compounds, quinoline-benzothiazepine,
6a-g. The yields of benzothiazepines 6a-g were 62−85%. All the synthesized compounds 6a-g were screened for their in
vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.
Compounds 6d and 6g had the best activity in the series, with IC50 values of 0.25 and 0.27 μg/mL, respectively against
HepG2, and of 0.26 and 0.28 μM, respectively, against KB cell lines. ADMET properties showed that compounds 6c and
6g possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DA12(F), and
DG13(F) in the binding pocket as potential ligand binding hot-spot residues for compounds 6c and 6g.
O
OH
OH
O
O
O
OH
N
S
COCH3
O
Ar
OH
Ar
N
N
NH
N
O
N
O
CH3
CH3
CH3
CH3
CH3
5a-g
6a-g
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1