Design, synthesis, and molecular docking study of novel quinoline-based bis-chalcones as potential antitumor agents

Article abstract of DOI:10.1002/ardp.202100094

A novel series of quinoline-based symmetrical and unsymmetrical bis-chalcones was synthesized via a Claisen–Schmidt condensation reaction between 3-formyl-quinoline/quinolone derivatives with acetone or arylidene acetones, respectively, by using KOH/MeOH/H₂O as a reaction medium. Twelve of the obtained compounds were evaluated for their in vitro cytotoxic activity against 60 different human cancer cell lines according to the National Cancer Institute protocol. Among the screened compounds, the symmetrical N-butyl bis-quinolinyl-chalcone 14g and the unsymmetrical quinolinyl-bis-chalcone 17o bearing a 7-chloro-substitution on the N-benzylquinoline moiety and 4-hydroxy-3-methoxy substituent on the phenyl ring, respectively, exhibited the highest overall cytotoxicity against the evaluated cell lines with a GI₅₀ range of 0.16–5.45 μM, with HCT-116 (GI₅₀ = 0.16) and HT29 (GI₅₀ = 0.42 μM) (colon cancer) representing best-case scenarios. Notably, several GI₅₀ values for these compounds were lower than those of the reference drugs doxorubicin and 5-FU. Docking studies performed on selected derivatives yielded very good binding energies in the active site of proteins that participate in key carcinogenic pathways.

Full text of DOI:10.1002/ardp.202100094

Received: 9 March 2021
Revised: 20 April 2021
Accepted: 23 April 2021
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DOI: 10.1002/ardp.202100094
F U L L P A P E R
Design, synthesis, and molecular docking study of novel
quinoline‐based bis‐chalcones as potential antitumor agents
Daniel Insuasty1,2 | Stephanie García2 | Rodrigo Abonia2
Braulio Insuasty2 | Jairo Quiroga2 | Manuel Nogueras3 | Justo Cobo3
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Gabriela L. Borosky4 | Kenneth K. Laali5
1Departamento de Química y Biología,
División de Ciencias Básicas, Universidad del
Norte, Barranquilla, Colombia
Abstract
A novel series of quinoline‐based symmetrical and unsymmetrical bis‐chalcones was
synthesized via a Claisen–Schmidt condensation reaction between 3‐formyl‐
quinoline/quinolone derivatives with acetone or arylidene acetones, respectively, by
using KOH/MeOH/H2O as a reaction medium. Twelve of the obtained compounds
were evaluated for their in vitro cytotoxic activity against 60 different human
cancer cell lines according to the National Cancer Institute protocol. Among the
screened compounds, the symmetrical N‐butyl bis‐quinolinyl‐chalcone 14g and
the unsymmetrical quinolinyl‐bis‐chalcone 17o bearing a 7‐chloro‐substitution on
the N‐benzylquinoline moiety and 4‐hydroxy‐3‐methoxy substituent on the phenyl
ring, respectively, exhibited the highest overall cytotoxicity against the evaluated
cell lines with a GI50 range of 0.16–5.45 µM, with HCT‐116 (GI50 = 0.16) and HT29
(GI50 = 0.42 μM) (colon cancer) representing best‐case scenarios. Notably, several
GI50 values for these compounds were lower than those of the reference drugs
doxorubicin and 5‐FU. Docking studies performed on selected derivatives yielded
very good binding energies in the active site of proteins that participate in key
carcinogenic pathways.
2Department of Chemistry, Research Group
of Heterocyclic Compounds, Universidad del
Valle, Cali, Colombia
3Departamento de Química Inorgánica y
Orgánica, Universidad de Jaén, Jaén, Spain
4INFIQC, CONICET and Departamento de
Química Teórica y Computacional, Facultad
de Ciencias Químicas, Universidad Nacional
de Córdoba, Ciudad Universitaria, Córdoba,
Argentina
5Department of Chemistry, University of
North Florida, Jacksonville, Florida, USA
Correspondence
Rodrigo Abonia, Department of Chemistry,
Research Group of Heterocyclic Compounds,
Universidad del Valle, A. A. 25360 Cali,
Colombia.
Email: rodrigo.abonia@correounivalle.edu.co
K E Y W O R D S
anticancer activity, Claisen–Schmidt condensation, molecular docking, quinoline‐based
bis‐chalcones
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1
INTRODUCTION
chalcone analogs (structures 1–5, Figure 1) represent important
classes of biologically active molecules.[1,2] They are α,β‐unsaturated
Although there are several therapeutic modalities for cancer treat-
ment, namely surgery, radiotherapy, or chemotherapy, the main
objective is to heal this disease or prolong and improve the quality of
the life of patients. Despite the availability of the above therapeutic
modalities, there is still a need for new and effective agents to help
fight this disease. Among the antitumor agents currently identified,
structures (i.e., Michael acceptors) and also are precursors in the
synthesis of various heterocyclic compounds.[3–5] Chalcones have
presented a broad spectrum of biological activities such as anti-
bacterial,[6] antifungal,[7] antitubercular,[8,9] anti‐inflammatory,[10]
antimalarial,[11] and antitumor,[12] among others. It is believed that
the presence of the double bond in conjugation with the carbonyl
This study was conducted in commemoration of the retirement of Prof. A. Sánchez Rodrigo.
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Arch Pharm. 2021;e2100094.
wileyonlinelibrary.com/journal/ardp © 2021 Deutsche Pharmazeutische Gesellschaft
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https://doi.org/10.1002/ardp.202100094

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Molecular hybridization
Dienone moiety
Aryl rings
This work
FIGURE 1 Design of new symmetrical and unsymmetrical quinoline‐based bis‐chalcones inspired by compound 5, curcumin, and quinolone
derivatives
functionality is the main property responsible for the biological
activities observed in chalcones.
hybrids such as quinoline–curcuminoid analog 5, as depicted in
Figure 1, which has been recently reported by our research group.
This compound showed antitumor activity in studies performed by
the National Cancer Institute (NCI).[2] These promising results en-
couraged us to continue the synthesis of new quinoline‐based chal-
cone derivatives.[28,29] Herein, we describe the structural
modifications performed on compound 5, in an effort to improve its
biological activity. We are also describing an attempt to establish a
possible structure–activity relationship supported by docking calcu-
lations, which could serve as a designing tool for the future.
Curcumin 2 is a natural component isolated from the root of the
Curcuma longa Linn. (Zingiberaceae), which is commonly used as a
dye in foods, spices, and cosmetics, as well as in traditional
medicine.[13,14] In the last few decades, curcumin has been widely
studied due to its numerous biological and pharmacological activities
such as antioxidant,[15] antitumor,[16,17] and anti‐inflammatory,[18]
among others. However, its clinical use in cancer therapy has been
limited due to its moderate anticancer activity, which is related to its
poor bioabsorption. This limitation, along with its great chemother-
apeutic potential, has inspired a large number of researchers to
design and synthesize novel symmetrical and unsymmetrical
curcumin‐based bis‐chalcones as curcumin mimetics (they should
exhibit activities similar to curcumin),[17] but, in turn, they should
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2
RESULTS AND DISCUSSION
Chemistry
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2.1
surpass its activity and overcome bioabsorption limitations.[19]
A
variety of these derivatives (3, 4, and 5) are shown in Figure 1.[20,21]
Quinoline is a heterocyclic system consisting of a benzene ring
fused to a pyridine ring. This is a recognized pharmacophore, which is
widely diffused in nature, being found in the structure of various
natural products. Quinoline derivatives are useful in various practical
applications including a number of pharmaceuticals available as
medicines today.[22–24] Therefore, the synthesis of these derivatives
has been extensively reported by different conventional and non-
conventional methods.[2,5,25,26]
The synthetic route for the novel symmetrical and unsymmetrical
bis‐quinolinyl‐chalcones 14 and 17 is outlined in Scheme 1 and
Tables
1 and 2. The key intermediate, 2‐chloroquinoline‐3‐
carbaldehyde 9, was prepared by following our previously reported
methodology,[30] which involved a Meth–Cohn‐type reaction,[31]
followed by hydrolysis and alkylation processes to afford the sub-
stituted 3‐formylquinolines (10–12) (Scheme 1).
Then, the symmetrical bis‐quinolinyl‐chalcones 14a–k were
synthesized via a Claisen–Schmidt condensation reaction between
two equivalents of the differently substituted 3‐formylquinolines
(10–12) with one equivalent of acetone in the presence of 40% aq.
KOH using a mixture of methanol/water as solvent. The reaction
mixture was stirred at ambient temperature, and after completion, it
Following a fragment‐based design strategy in the antitumor
drug discovery,[27] and combining the pharmacophoric fragments
found in curcumin–quinolinic systems and α,β‐unsaturated Michael
acceptors (chalcones), we have designed new quinoline–chalcone

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SCHEME 1 Synthesis of 2‐chloroquinoline‐3‐carbaldehyde 9 and its conversion to 3‐formylquinolines 10–12. DMF, dimethylformamide
was neutralized with acetic acid and the crudes were purified by
recrystallization or column chromatography on silica gel. In all cases,
the reactions proceeded with the same behavior, affording the
expected bis‐quinolinyl‐chalcones 14a–k in good to excellent yields
(Table 1).
(NSC: D‐796110/1), 17n (NSC: D‐796111/1), 17o (NSC: D‐796112/
1), 17s (NSC: D‐789977/1), 17v (NSC: D‐789976/1), and 17w (NSC:
D‐796109/1)). The obtained results for each compound are reported
in NCI one‐dose mean graphs as growth percent (GP) (negative
values mean lethality, see Supporting Information) and mean and
range values of the tested cell (see Supporting Information). Table 3
summarizes the most remarkable results for the evaluated com-
pounds in terms of growth inhibition percentage (GI% = 100 – GP),
lethality (values shown in parentheses), and mean values.
The structure of the symmetrical bis‐quinolinyl‐chalcone 14 was
ascertained by infrared (IR), 1D and 2D nuclear magnetic resonance
(NMR) (in dimethyl sulfoxide [DMSO]‐d6), and mass spectrometric
analysis. Taking compound 14a as model, in the 1H NMR spectrum, a
singlet observed at 2.52 ppm was assigned to the CH3 protons. Two
doublets at 7.74 and 7.81 ppm with coupling constant J = 15.9 Hz
were assigned to the vinylic protons (Hα and Hβ, Table 1), confirming
the E configuration of the new double bonds formed. Two doublets
and two singlets, integrating for a total of eight protons, corre-
sponded to the C–H protons of the quinolin‐2‐onyl moiety. The
13C NMR spectrum showed signals for 13 carbons (corresponding to
one methyl, six methine, and six quaternary carbon atoms) in
agreement with structure 14a. Finally, the IR spectrum exhibited
absorptions at 3154 cm−1 assigned to the NH functionality and two
According to the data analysis of the one‐dose mean graphs, low
GP values afford better growth inhibition (GI%) results because
GI = 100 – GP. As negative values correspond to lethal activity, hence,
values that are more negative represent higher activity of the assayed
compound (see Supporting Information). In addition, low mean values
represent better activity; indeed, mean values ≤50 indicate that the
compound is active. Moderately active compounds afford mean values
around 50–60. Thus, in terms of the lower (GP and mean) and higher
(GI% and lethality) values for one‐dose criteria, among the 12
quinolinyl–chalcones evaluated, five of them were active (i.e., 14g, 17d,
17e, 17n, and 17o), whereas three compounds were moderately active
(i.e., 17b, 17c, and 17m), as shown in Table 3.
C═O absorptions at 1661 and 1659 cm−1
.
The synthesis of the unsymmetrical quinolinyl‐bis‐chalcones
17a–w was performed in two steps. Initially, the arylidene acet-
ones 16a–d were prepared by simple aldol condensation between
benzaldehydes 15a–d and an excess of acetone at 0°C. In the second
step, crude products 16a–d were condensed with the respective
3‐formylquinolines 10–12 in similar fashion but at ambient tem-
perature to furnish the desired unsymmetrical quinolinyl‐bis‐
chalcones 17a–w in satisfactory yields (Table 2).
As the abovementioned compounds displayed the highest anti-
proliferative activity at one‐dose assays, they were selected by NCI
for advanced assays against the full 60 human cell lines at five dif-
ferent concentrations (five‐dose assay) (i.e., 100, 10, 1.0, 0.1, and
0.001 μM), through a protocol in which sulforhodamine B (SRB)
protein is used to estimate the cell growth.[33,34] The results were
expressed in GI50 and LC50 values, and they are summarized in
Table 4.
The structures of the new compounds 17a–w were also con-
sistent with their spectral data IR, 1D and 2D NMR, mass spectro-
metry, and microanalysis, and they are summarized in Section 4.
In general, the selected quinolinyl–chalcones displayed moder-
ate to excellent activity against the evaluated cell lines, with several
of them having GI50 values lower than 1.00 µM (red color values).
Compounds 17b and 17c displayed a moderate activity against the
evaluated cancer cell lines, with HCT‐116 (colon) and MCF7 (breast)
cancer cell lines being the most sensitive strains, with GI50 of 1.55
and 0.92 μM, respectively. The quinolinyl‐bis‐chalcone 17e showed
better activity against RPMI‐8226 (leukemia), HCT‐116 (colon), and
MCF7 (breast) cancer cell lines with GI50 values of 0.33, 0.26,
and 0.36 μM, respectively, whereas compound 17n displayed
considerable cytotoxic activity against HT29 (colon) with GI50 of
0.85 μM.
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2.2
Anticancer activity evaluation
The new quinolinyl–chalcones 14 and 17 were submitted to the
Developmental Therapeutics Program (DTP) at NCI, Bethesda, MD,
USA, for in vitro anticancer screening against 60 human cell lines
corresponding to nine human cancer panels: leukemia, non‐small‐cell
lung, melanoma, colon, central nervous system (CNS), ovary, renal,
breast, and prostate cancer.[32] The process started with a primary in
vitro evaluation against the 60 human tumor cell lines at a single
dose of 10 µM for 12 selected compounds (i.e., 14g (NSC: D‐796113/
1), 17b (NSC: 768474/1), 17c (NSC: 768473/1), 17d (NSC:
D‐796114/1), 17e (NSC: D‐787549/1), 17j (NSC: D‐789980/1), 17m
Compound 17d was found to be highly sensitive against RPMI‐
8226 (GI50 = 0.36 μM, leukemia), SR (GI50 = 0.38 μM, leukemia),
HCT‐116 (GI50 = 0.16 μM, colon), HT29 (GI50 = 0.78 μM, colon),
MDA‐MB‐435 (GI50 = 0.30 μM, melanoma), and MCF7 (GI50 = 0.39

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TABLE 1 Synthesis of symmetrical bis‐quinolinyl‐chalcones 14a–k
μM, breast), whereas the quinolinyl‐bis‐chalcone 17o showed better
results against SR (GI50 = 0.46 μM, leukemia), HCT‐116 (GI50 = 0.77
In addition, mean GI50 values (per cancer cell panel) were de-
termined for six chalcones (14g and 17b–d,n,o) to be compared with
those for the standard anticancer agents doxorubicin and 5‐FU. For a
better understanding, the values were drawn and depicted in Figure 2
(compound 17e was omitted in this analysis due to its lower activity and
lack of several GI50 data). According to Figure 2, the symmetrical bis‐
quinolinyl‐chalcone 14d displayed higher activity against almost all panels
(six of them) in comparison with the remaining evaluated chalcones 17.
Indeed, based on the number of hits per panels, the order of activity of
the evaluated chalcones would be as follows: 14g > 17d ≈ 17o > 17n >
17b > 17c. Compound 14g also displayed higher activity against most
panels (except for colon and CNS) than the standard drug 5‐FU and even
was more active than the standard drug doxorubicin for the colon panel.
Remarkably, the six evaluated chalcones displayed higher activity in four
panels (non‐small‐cell lung, melanoma, renal, and breast cancer) than the
standard drug 5‐FU. It is worth mentioning that the quinolinyl‐bis‐
chalcones 17d,o also afforded outstanding mean GI50 values in each
panel, with seven of them being better than the standard drug 5‐FU in
both cases.
μM, colon), HT29 (GI50 = 0.42 μM, colon), MDA‐MB‐435 (GI50
=
0.86 μM, melanoma), OVCAR‐3 (GI50 = 0.71 μM, ovarian), OVCAR‐8
(GI50 = 0.50 μM, ovarian), and MCF7 (GI50 = 0.42 μM, breast). Indeed,
17d and 17o displayed significant cytotoxic activity against all
screened cell lines with GI50 values varying from 0.16 to
5.95 μM.
However, the symmetrical bis‐quinolinyl‐chalcone 14g exhibited
potent anticancer activity against all 60 tested cancer cell lines, 12 of
them, with GI50 values ≤1.00 µM. Compound 14g showed significant
activity against the leukemia cell lines K‐562 (GI50 = 0.88 μM),
RPMI‐8226 (GI50 = 0.32 μM), and SR (GI50 = 0.32 μM), Colon cancer
cell lines HT29 (GI50 = 0.32 μM), KM12 (GI50 = 0.68 μM), and SW‐620
(GI50 = 0.86 μM), melanoma cell line M14 (GI50 = 0.45 μM), and
breast cancer cell lines MCF7 (GI50 = 0.31 μM) and BT‐549 (GI50
0.70 μM). However, the best cytostatic activity of compound 14g was
displayed against the HCT‐116 (colon) cancer cell line, with GI50
=
=
0.16 μM, and MDA‐MB‐435 (melanoma) cell line, with GI50 = 0.21
μM. It is also worth mentioning that the evaluated chalcones showed
better GI50 values than the reference drug 5‐FU in 107 cases (blue
background values) and better GI50 values than the reference drug
doxorubicin in 11 cases (gray background values), as shown in
Table 4.
The above findings indicate that the symmetrical bis‐quinolinyl‐
chalcone 14 g and the unsymmetrical quinolinyl‐bis‐chalcone 17o are
most superior among the structures of the evaluated series, reflecting
that such compounds might be used as promising lead molecules for
discovering a new class of anticancer agents.

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TABLE 2 Synthesis of unsymmetrical quinolinyl‐bis‐chalcones 17a–w
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2.3
Computational docking studies
some hydrogen bonds were also observed (Figure 3). Most of the
obtained docking affinities were comparable to or even better than
those of usually applied anticancer drugs (Table 5). As the selected
chalcones docked in the same binding site of the receptors as the
known inhibitors, and presented significant binding scores, these
computational results, thus, indicate the studied derivatives as po-
tential new anticancer agents. In particular, HER1, HER2, protea-
some, and hTS appear as promising targets for these compounds.
Considering the remarkable anticancer activity exhibited by
bis‐chalcones 14g and 17o in the described in vitro studies, the
binding interactions of these molecules were analyzed and compared
with some reference inhibitors. The bis‐chalcone 14g showed its best
cytostatic activity against CRC cell lines; interestingly, this molecule
yielded a more favorable binding affinity than the known HER1 in-
hibitors (Table 5). Comparison of the binding interactions of 14g and
gefitinib in HER1 showed common interactions with nine residues
(Figure 4). Derivative 14g presented only hydrophobic contacts,
whereas one hydrogen bond was observed between gefitinib and
Met793. The more favorable binding energy of 14g could be ascribed
to its bigger volume, which enabled this molecule to interact with
13 amino acids, whereas gefitinib made contacts with 11 residues.
Molecular docking calculations for quinolinyl–chalcones 14g and
17b–e,n,o were carried out with the aim to elucidate the factors
influencing their bioactivities. Selection of these representative
compounds was made according to their higher (14g, 17d,o) and
moderate (17b,c,e,n) anticancer activity determined in vitro. The
binding energies of these compounds in the active site of various
proteins involved in carcinogenic processes were determined and
compared with the binding affinities of known inhibitors employed in
chemotherapy. The proteins selected for these docking studies par-
ticipate in diverse oncogenic pathways, which were described in
previous works.[35] Very good correspondences were observed be-
tween the binding modes obtained in the present computations and
the crystallographic structures of the complexes for the reference
inhibitors (PDB codes are shown in Table 5). This accordance sup-
ports the validation of the docking protocol applied.
As a general observation, the studied selected compounds
docked properly in the binding pockets of the considered enzymes
and afforded very good binding energies. The main interactions be-
tween these ligands and the proteins were hydrophobic; however,

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14g
17b
17c
17d
17n
17o
Doxorubicin
5-FU
FIGURE 2 Comparison of the mean GI50 values, per panel, displayed by chalcones 14g, 17b–d,n,o, and the standard drugs doxorubicin and
5‐fluorouracil (5‐FU) against the 60 human cancer cell lines
The unsymmetrical bis‐chalcone 17o exhibited an excellent in vitro
activity against leukemia cell lines. In accordance with these observa-
tions, this compound presented a clearly superior binding affinity to Bcl‐
2 as compared with the reference chemotherapeutic drugs (Table 5).
Inspection of the binding modes of 17o and navitoclax in the active site
of Bcl‐2 revealed common interactions with 12 residues (Figure 5).
Most of the interactions were hydrophobic, with the exception of one
hydrogen bond with Ala97 in the case of 17o and with Gly142 for
navitoclax. This hydrogen‐bond contact was slightly shorter for 17o (the
distance between heavy atoms was 3.07 Å) than for navitoclax (3.14 Å).
This stronger interaction would explain the improved binding affinity of
17o. According to this, docking calculations point to the 4‐hydroxy‐3‐
methoxy‐substituted phenyl ring as the main pharmacophoric moiety
for this bis‐chalcone derivative.
doxorubicin and 5‐FU. In addition, molecular docking calculations
for six of the studied compounds exhibited remarkable binding
affinities (mainly compounds 17o and 14g) in the binding pockets
of several enzymes involved in carcinogenesis. Most of the ob-
served binding energies were comparable to or even superior to
the values obtained for known anticancer drugs typically em-
ployed in chemotherapy. Analysis of the binding modes of com-
pounds 17o and 14g in selected protein active sites revealed
several interactions in common with some reference inhibitors.
Moreover, these studied derivatives presented stronger binding
interactions as compared with the known chemotherapeutic
drugs, suggesting they could be potential new anticancer agents.
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4
EXPERIMENTAL
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Chemistry
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3
CONCLUSION
4.1
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General
In summary, a series of new symmetrical and unsymmetrical quinoline‐
based bis‐chalcones was prepared and characterized. Twelve of them
were subjected to in vitro anticancer screening, against 60 NCI human
cancer cell lines at a single concentration of 10−5 M (one dose). Com-
pounds 14g, 17d, 17e, 17n, and 17o were most active, whereas com-
pounds 17b, 17c, and 17m were moderately active. Subsequently,
compounds (14g and 17b–e,n,o) were evaluated at five different
concentrations (five doses), and among them, the symmetrical
N‐butylquinolin–chalcone 14g and the unsymmetrical bis‐chalcone 17o
exhibited the highest cytotoxicity with an overall GI50 value range of
0.16–5.45 µM, with HCT‐116 (GI50 = 0.16) and HT29 (GI50 = 0.42 μM)
(colon cancer) being exceptionally active. Remarkably, several GI50 values
for these compounds were better than those for the reference drugs
4.1.1
All organic chemicals and solvents were procured from Sigma‐Aldrich,
Fluka, and Merck (analytical grade reagent), and used without further
purification. IR spectra were recorded on a Shimadzu FTIR 8400 ATR
spectrophotometer. Melting points were measured using a Stuart SMP3
melting point apparatus and were uncorrected. 1H and 13C NMR
spectra (see the Supporting Information) were recorded on a Bruker
Avance 400 spectrophotometer operating at 400 and 100 MHz, re-
spectively, using DMSO‐d6 and CDCl3 as solvents and tetramethylsilane
as the internal standard. Mass spectra were run on a SHIMADZU‐
GCMS 2010‐DI‐2010 spectrometer (equipped with a direct inlet probe)
operating at 70 eV. Microanalyses were performed on an Agilent CHNS

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TABLE 4 In vitro cytotoxic activities for compounds 14g and 17b–e,n,o expressed as 50% of growth inhibition and lethal concentration,
against 60 human cancer cell lines, compared with the standard drugs doxorubicin and 5‐fluorouracil (5‐FU)a
(Continues)

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Abbreviation: SRB, sulforhodamine B.
aData are obtained from NCI's in vitro disease‐oriented human cancer cell lines screen in μM.
bGI50 is the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug
incubation, determined at five concentration levels (100, 10, 1.0, 0.1, and 0.01 μM).
cLC50 is a parameter of cytotoxicity that reflects the molar concentration needed to kill 50% of the cells.
dThe values of activity against human cancer cell lines displayed by adriamycin/doxorubicin correspond to that reported by NCI at highest concentration
of 100 μM. For more details, please visit https://dtp.cancer.gov/dtpstandard/cancerscreeningdata/index.jsp. The most outstanding GI50 values are
highlighted in red color.
elemental analyzer, and the values are within 0.4% of the theoretical
values. Thin‐layer chromatography (TLC) analyses were performed on
silica gel aluminum plates (Merck 60 F254) and spots were visualized
with ultraviolet irradiation.
was stirred at ambient temperature for 11–13 h. Then, the reac-
tion mixture was neutralized with acid acetic. The resulting pre-
cipitate was collected by filtration under vacuum and washed with
methanol (2 ×3 ml), followed by water (2 ×3 ml), and then dried
and purified by recrystallization or by column chromatography on
silica gel.
The InChI codes of the investigated compounds, together
with some biological activity data, are provided as Supporting
Information.
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(6‐methylquinolin‐
2(1H)‐one) 14a
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4.1.2
General procedure for the synthesis of
Yellow solid, m.p. >300°C. FTIR (ATR): ν = 3154 (NH), [1661, 1659]
.
(C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 2.30 (s, 6H, CH3 × 2),
symmetrical bis‐quinolinyl‐chalcones 14a–k
7.27 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.52 (s, 2H), 7.74 (d,
J = 15.9 Hz, 2H, ═CH × 2), 7.81 (d, J = 15.9 Hz, 2H, ═CH × 2), 8.44 (s,
2H), 12.03 (s, 2H, NH). 13C NMR (101 MHz, DMSO‐d6) δ = 27.9,
A mixture of substituted 3‐formylquinolines (10–12) (1 mmol),
acetone (0.5 mmol), and 20% aq. KOH (0.5 ml) in MeOH (10 ml)

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TABLE 5 Binding affinities for the selected quinolinyl‐chalcones 14g and 17b–e,n,o compared with known chemotherapeutic drugs
Binding energy (kcal/mol)a
Protein (treatment)
Known inhibitors (PDB code)b
14g
17b
17c
17d
17e
17n
17o
HER2 (colorectal cancer [CRC] breast cancer)
SYR127063 (3PP0)
Lapatinib
−11.4
−10.7
−9.4
‐
−8.7
−10.0
−10.5
−10.2
−10.9
−9.5
−10.3
Afatinib
HER1 (CRC, breast cancer)
VEGFR2 (CRC)
Rociletinib (5XDL)
Gefitinib (4WKQ)
Erlotinib (1M17)
Axitinib (4AG8)
Sorafenib (3WZE)
Lenvatinib (3WZD)
Regorafenib
−7.3
−6.3
−9.2
−10.8
−8.9
−10.8
−9.3
−12.9
‐
−8.1
−9.1
−7.8
−8.1
−7.7
−8.2
−7.6
−9.5
−8.3
−10.8
‐
−10.1
−11.4
−10.4
BRAF (melanoma)
Vemurafenib (3OG7)
Dabrafenib (4XV2)
PRD_001075 (3SDK)
Bortezomib (5LF3)
Ixazomib (5LF7)
Carfilzomib (4R67)
Navitoclax (4LVT)
Venetoclax (6O0K)
dUMP (5X5D)
−9.0
−8.5
−10.1
−9.3
‐
‐
−9.7
−9.3
‐
‐
−9.7
−9.6
Proteasome (leukemia, CRC)
−7.8
−7.8
−8.5
−8.3
−8.2
‐
−9.5
−8.9
Bcl‐2 (Leukemia)
hTS (CRC)
−8.5
−8.1
−7.9
−9.2
‐
‐
−8.0
−8.6
−8.0
−8.9
‐
−9.7
−8.8
Raltitrexed (5X5Q)
5FdUMP (6QXG)
−8.0
−7.7
−8.5
aBest binding energies for known inhibitors, and for the studied compounds that yielded similar or better results than the reference inhibitors for each
protein, are shown in bold numbers.
bPDB codes for the complexes of the known inhibitors with the considered proteins (PDB codes shown in bold are those corresponding to each protein
structure employed in the docking calculations).
117.4, 120.5, 126.5, 127.3, 127.81, 130.4, 131.9, 137.9, 138.0, 140.1,
160.9, 198.8 ppm. Electrospray ionization mass spectroscopy (EI MS)
(70 eV): m/z (%): 396 (M+, 1). 368 (11), 313 (10), 236 (28), 57 (100).
Anal. calcd. for C25H20N2O3: C, 75.74; H, 5.09; N, 7.07. Found:
C, 75.48; H, 4.88; N, 7.23.
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(8‐methylquinolin‐
2(1H)‐one) 14c
Yellow solid, m.p. >300°C. FTIR (ATR): ν = 3161 (NH), [1671, 1649]
.
(C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 2.16 (s, 6H, CH3 × 2),
7.12 (t, J = 7.5 Hz, 2H), 7.16 (d, J = 16.3 Hz, 2H, ═CH × 2), 7.35 (d,
J = 7.2 Hz, 2H), 7.43 (d, J = 16.6 Hz, 2H, ═CH × 2), 7.53 (d, J = 7.8 Hz,
2H), 8.17 (s, 2H, NH). 13C NMR (101 MHz, DMSO‐d6) δ = 12.4, 119.9,
122.5, 123.7, 126.7, 127.7, 129.0, 132.2, 132.3, 136.9, 137.6, 161.8,
179.2 ppm. EI MS (70 eV): m/z (%): 396 (M+, 1), 368 (15), 236 (27), 57
(100). Anal. calcd. for C25H20N2O3: C, 75.74; H, 5.09; N, 7.07. Found:
C, 75.86; H, 5.20; N, 6.89.
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(7‐chloroquinolin‐
2(1H)‐one) 14b
Yellow solid, m.p. >300°C. FTIR (ATR): ν = 3151 (NH), [1662, 1654]
.
(C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 7.21 (dd, J = 8.4,
2.0 Hz, 2H), 7.41 (d, J = 2.0 Hz, 2H), 7.68 (s, 4H, ═CH × 4), 7.72 (d,
J = 8.5 Hz, 2H), 8.35 (s, 2H), 11.65 (s, 2H, NH). 13C NMR (101 MHz,
DMSO‐d6) δ = 113.8, 117.4, 121.7, 126.1, 128.0, 129.6, 135.5, 136.5,
139.2, 139.2, 159.9, 188.6 ppm. EI MS (70 eV): m/z (%): 256 (5), 236
(3), 149 (12), 137 (12), 97 (23), 69 (100). Anal. calcd. for
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(6‐chloroquinolin‐
2(1H)‐one) 14d
Yellow solid, m.p. >300°C. FTIR (ATR): ν = 3154 (NH), 1658 (2 × C═O)
cm−1. 1H NMR (400 MHz, DMSO‐d6) δ = 7.38 (d, J = 8.8 Hz, 2H), 7.62 (dd,
J = 8.8, 2.3 Hz, 2H), 7.72 (d, J = 15.9 Hz, 2H, ═CH × 2), 7.80 (d, J = 15.9 Hz,
C
23H14Cl2N2O3: C, 63.18; H, 3.23; N, 6.41. Found: C, 63.29; H, 3.10;
N, 6.60.

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FIGURE 3 (a) Two‐dimensional (2D) representation of the most favorable binding pose of ligand 17o in the active site of Bcl‐2. Hydrophobic
interactions between the ligand atoms and the protein residues are depicted as red radial lines, and hydrogen bonds as green dotted lines. (b)
Three‐dimensional (3D) representation of the most favorable binding mode of ligand 17o in the active site of Bcl‐2. Hydrogen‐bond interactions
are shown as green lines. (c) 2D representation of the most favorable binding pose of ligand 14g in the active site of HER1. Hydrophobic
interactions between the ligand atoms and the protein residues are depicted as red radial lines. (d) 3D representation of the most favorable
binding mode of ligand 14g in the active site of HER1
2H, ═CH × 2), 7.83 (d, J = 2.2 Hz, 2H), 8.49 (s, 2H, NH). Compound 14d is
barely soluble in CDCl3 and DMSO, thus, made the registration of a high‐
resolution 13C NMR spectrum impossible. EI MS (70 eV): m/z (%): 396
(M+, 5), 313 (10), 236 (24), 57 (100). Anal. calcd. for C23H14Cl2N2O3: C,
63.18; H, 3.23; N, 6.41. Found: C, 63.01; H, 3.05; N, 6.60.
J = 8.4 Hz, 2H), 7.42 (d, J = 15.9 Hz, 2H, ═CH × 2), 8.16 (s, 2H), 11.81
(s, 2H, NH). Compound 14e is barely soluble in CDCl3 and DMSO,
which thus made the registration of a high‐resolution 13C NMR
spectrum impossible. EI MS (70 eV): m/z (%): 249/247 (98/100). Anal.
calcd. for C23H14Br2N2O3: C, 52.50; H, 2.68; N, 5.32. Found: C,
52.67; H, 2.51; N, 5.19.
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(6‐bromoquinolin‐
2(1H)‐one) 14e
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(6‐methoxyquinolin‐
2(1H)‐one) 14f
Yellow solid, m.p. >300°C. FTIR (ATR): ν = 3135 (NH), [1671, 1668]
(C═O) cm−1
.
1H NMR (400 MHz, DMSO‐d6) δ = 6.92 (dd, J = 8.4,
Yellow solid, m.p. >300°C. FTIR (ATR): ν = 3161 (NH), 1657
.
(2 × C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 3.92 (s, 6H, OCH3),
1.8 Hz, 2H). 7.00 (s, 2H), 7.35 (d, J = 15.9 Hz, 2H, ═CH × 2), 7.40 (d,

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FIGURE 4 (a) Two‐dimensional representations of the most favorable binding pose of ligand 14g (left) and of gefitinib (right) in the
active site of HER1. Red circles indicate residues involved in interactions with both ligands. (b) Superimposed three‐dimensional
representations of the most favorable binding modes for 14g (in yellow) and gefitinib (in purple) in the active site of HER1. Hydrogen‐bond
interactions are shown as cyan lines
7.26 (d, J = 16.6 Hz, 2H, ═CH × 2), 7.35 (d, J = 9.0 Hz, 2H), 7.46 (d,
J = 16.6 Hz, 2H, ═CH × 2), 7.57 (d, J = 9.1 Hz, 2H), 8.23 (s, 2H). 13C NMR
(101 MHz, DMSO‐d6) δ = 60.7, 115.8, 121.3, 124.7, 125.9, 132.4, 132.8
134.0, 137.1, 138.9, 140.0, 159.6, 184.0 ppm. EI MS (70 eV): m/z (%):
428 (M+, 12), 200 (100). 236 (22). Anal. calcd. for C25H20N2O5: C,
70.09; H, 4.71; N, 6.54. Found: C, 69.90; H, 4.88; N, 6.44.
(d, J = 8.3 Hz, 2H), 7.81 (d, J = 15.9 Hz, 2H, ═CH × 2), 7.90 (d,
J = 15.9 Hz, 2H, ═CH × 2), 8.01 (s, 2H), 13C NMR (101 MHz, CDCl3)
δ = 13.9, 20.4, 29.6, 42.7, 114.2, 120.5, 122.3, 126.4, 129.0, 129.9,
131.7, 138.4, 139.3, 139.9, 160.7, 190.3 ppm. EI MS (70 eV): m/z
(%): 480 (M+, 10), 381 (41), 204 (47). 194 (100), 57 (32). Anal.
calcd. for C31H32N2O3: C, 77.47; H, 6.71; N, 5.83. Found: C, 77.60;
H, 6.83; N, 5.71.
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(1‐butylquinolin‐
2(1H)‐one) 14g
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(1‐butyl‐6‐
methoxyquinolin‐2(1H)‐one) 14h
Yellow solid, m.p. 180–181°C. FTIR (ATR): ν = [1668, 1659]
(C═O) cm−1
.
1H NMR (400 MHz, CDCl3) δ = 1.06 (t, J = 7.3 Hz, 6H,
Yellow solid, m.p. 174–175°C; FTIR (ATR) ν = [1650, 1603] (C═O)
CH3 × 2), 1.63–1.42 (m, 4H, CH2 × 2), 1.85–1.71 (m, 4H, CH2 × 2),
4.42–4.23 (m, 4H, NCH2 × 2), 7.28 (t, J = 7.5 Hz, 2H), 7.29 (d,
J = 6.1 Hz, 2H), 7.39 (t, J = 8.6 Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H), 7.66
cm−1 1H NMR (400 MHz, CDCl3) δ = 1.09 (t, J = 7.4 Hz, 6H, CH3 × 2),
.
1.57–1.66 (m, 4H, CH2 × 2), 1.90–1.97 (m, 4H, CH2 × 2), 3.93 (s, 6H,
OCH3 × 2), 4.58 (t, J = 6.5 Hz, 4H, NCH2 × 2), 7.02 (d, J = 16.3 Hz, 2H,

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FIGURE 5 (a) Two‐dimensional representations of the most favorable binding pose of ligand 17o (left) and of navitoclax (right) in the active site
of Bcl‐2. Red circles indicate residues involved in interactions with both ligands. (b) Superimposed three‐dimensional representations of the most
favorable binding modes for 17o (in green) and navitoclax (in magenta) in the active site of Bcl‐2. Hydrogen‐bond interactions are shown as cyan lines
═CH × 2), 7.31 (d, J = 10.7 Hz, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.89 (d,
J = 15.7 Hz, 2H, ═CH × 2), 8.08 (s, 2H), 13C NMR (400 MHz, CDCl3)
δ = 14.0, 19.6, 31.1, 55.6, 66.5, 106.3, 120.3, 122.5, 125.49, 127.23,
128.21, 135.5, 137.6, 142.2, 156.4, 158.7, 183.5 ppm. EI MS (70 eV):
m/z (%): 540 (M+, 6), 256 (100). 200 (51). Anal. calcd. for
C33H36N2O5: C, 73.31; H, 6.71; N, 5.18. Found: C, 73.50; H, 6.64;
N, 5.06.
3,3ʹ‐((1E,4E)‐3‐Oxopenta‐1,4‐diene‐1,5‐diyl)bis(1‐butyl‐6‐
chloroquinolin‐2(1H)‐one) 14i
Yellow solid, m.p. 162–163°C. FTIR (ATR): ν = [1653, 1642] (C═O)
.
cm−1 1H NMR (400 MHz, CDCl3) δ = 1.07 (t, J = 7.2 Hz, 6H, CH3 × 2),
1.52–1.58 (m, 4H, CH2 × 2), 1.75–1.82 (m, 4H, CH2 × 2), 4.32 (t,
J = 7.4 Hz, 4H, NCH2 × 2), 7.25 (d, J = 8.2 Hz, 2H), 7.37 (s, 2H), 7.49 (d,
J = 15.7 Hz, 2H, ═CH × 2), 7.59 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 15.7 Hz,

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2H, ═CH × 2), 7.88 (s, 2H). 13C NMR (400 MHz, CDCl3) δ = 14,0, 19.5,
31.0, 66.8, 120.5, 123.3, 125.4, 126.2, 127.5, 129.0, 134.9, 136.5,
137.9, 147.1, 160.6, 183.3 ppm. EI MS (70 eV): m/z (%): 550/548 (M+,
18/57), 260 (100), 204 (43). Anal. calcd. for C31H30Cl2N2O3: C,
67.76; H, 5.50; N, 5.10. Found: C, 67.85; H, 5.42; N, 5.23.
J = 8.2 Hz, 1H), 7.43 (s, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.67 (d,
J = 15.9 Hz, 1H, ═CH), 7.74 (d, J = 8.2 Hz), 7.74 (d, J = 15.9 Hz, 1H,
═CH), 7.82 (d, J = 15.9 Hz, 1H, ═CH), 8.46 (s, 1H), 12.08 (s, 1H, NH),
OH was not observed. 13C NMR (101 MHz, DMSO‐d6) δ = 56.2,
111.9, 115.6, 116.2, 119.6, 122.8, 123.7, 124.2, 126.7, 126.7, 128.6,
129.1, 132.1, 137.7, 139.3, 141.6, 144.0, 148.5, 150.2, 161.4,
189.0 ppm. EI MS (70 eV): m/z (%): 347 (M+, 24), 170 (100). Anal.
calcd. for C21H17NO4: C, 72.61; H, 4.93; N, 4.03. Found: C, 72.73; H,
5.05; N, 3.86.
(1E,4E)‐1,5‐Bis(2‐butoxyquinolin‐3‐yl)penta‐1,4‐dien‐3‐one 14j
.
Yellow solid, m.p. 157–158°C. FTIR (ATR): ν = 1666 (C═O) cm−1 1H
NMR (400 MHz, CDCl3) δ = 1.08 (t, J = 7.4 Hz, 6H, CH3 × 2).
1.71–1.56 (m, 4H, CH2 × 2), 2.04–1.91 (m, 4H, CH2 × 2), 4.66 (t,
J = 6.7 Hz, 4H, NCH2 × 2), 7.42 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 16.2 Hz,
2H, ═CH × 2), 7.69 (t, J = 7.6 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.88 (d,
J = 8.4 Hz, 2H), 8.03 (d, J = 16.0 Hz, 2H, ═CH × 2), 8.29 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ = 14.0, 31.1, 19.6, 66.6, 120.3, 124.6,
125.0, 127.0, 128.0, 128.5, 130.8, 138.0, 138.9, 147.9, 160.1,
189.5 ppm. EI MS (70 eV): m/z (%): 381 (M+, 56), 204 (25), 179 (24).
Anal. calcd. for C31H32N2O3: C, 77.47; H, 6.71; N, 5.83. Found: C,
77.60; H, 6.50; N, 5.93.
3‐((1E,4E)‐5‐(4‐Methoxyphenyl)‐3‐oxopenta‐1,4‐dien‐1‐yl)quinolin‐
2(1H)‐one 17b
Yellow solid, m.p. 259–260°C. FTIR (ATR): ν = 3240 (NH), [1681,
.
1679] (C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 3.83 (s, 3H,
OCH3). 7.03 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 16.0 Hz, 1H, ═CH), 7.25 (t,
J = 7.5 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.71 (d,
J = 16.0 Hz, 1H, ═CH), 7.74 (d, J = 6.6 Hz, 1H), 7.86–7.75 (m, 4H,
═CH, Ar–H), 8.47 (s, 1H, NH). 13C NMR (101 MHz, DMSO‐d6)
δ = 55.9, 115.0, 115.6, 119.6, 122.8, 124.2, 126.6, 127.7, 128.5,
129.1, 131.0, 132.2, 138.0, 139.5, 141.6, 143.1, 161.4, 161.8,
189.1 ppm. EI MS (70 eV): m/z (%): 331 (M+, 41), 303 (19), 170 (100),
57 (24). Anal. calcd. for C21H17NO3: C, 76.12; H, 5.17; N, 4.23.
Found: C, 76.00; H, 5.30; N, 4.42.
(1E,4E)‐1,5‐Bis(2‐butoxy‐8‐methylquinolin‐3‐yl)penta‐1,4‐dien‐3‐
one 14k
.
Yellow solid, m.p. 150–151°C. FTIR (ATR): ν = 1665 (C═O) cm−1 1H
NMR (400 MHz, CDCl3) δ = 1.08 (t, J = 7.4 Hz, 6H, CH3 × 2). 1.70‐1.57
(m, 4H, CH2 × 2), 2.05–1.92 (m, 4H, CH2 × 2), 2.73 (s, 6H, CH3 × 2),
4.67 (t, J = 6.7 Hz, 4H, OCH2 × 2), 7.33 (t, J = 7.6 Hz, 2H), 7.50 (d,
J = 16.0 Hz, 2H, ═CH × 2), 7.55 (d, J = 6.9 Hz, 2H), 7.64 (d, J = 8.0 Hz,
2H), 8.03 (d, J = 16.0 Hz, 2H, ═CH × 2), 8.26 (s, 2H), 13C NMR
(101 MHz, CDCl3) δ = 14.0, 17.7, 19.6, 31.0, 66.2, 119.7, 124.2, 124.8,
125.9, 128.3, 130.9, 135.2, 138.2, 139.2, 145.8, 159.0, 189.7 ppm. EI
MS (70 eV): m/z (%): 508 (M+, 1), 503 (28), 432 (27), 306 (160), 43
(100). Anal. calcd. for C33H36N2O3: C, 77.92; H, 7.13; N, 5.51. Found:
C, 78.10; H, 7.01; N, 5.70.
3‐((1E,4E)‐5‐(4‐Chlorophenyl)‐3‐oxopenta‐1,4‐dien‐1‐yl)quinolin‐
2(1H)‐one 17c
Yellow solid, m.p. 259–260°C. FTIR (ATR): ν = 3248 (NH), [1663,
.
1658] (C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 7.25 (t,
J = 7.5 Hz, 1H), 7.37 (d, J = 7.7, Hz, 1H), 7.39 (d, J = 16.0 Hz, 1H, ═CH),
7.53 (d, J = 8.3 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 16.0, Hz,
1H, ═CH), 7.74 (d, J = 7.3 Hz, 1H), 7.81 (s, 2H, ═CH × 2), 7.86 (d,
J = 8.4 Hz, 2H), 8.47 (s, 1H), NH was not observed. 13C NMR
(101 MHz, DMSO‐d6) δ = 115.7, 119.6, 122.8, 126.5, 127.0, 128.5,
129.2, 129.5, 130.8, 132.3, 134.2, 135.5, 138.8, 139.5, 141.6, 142.0,
161.4, 189.3 ppm. EI MS (70 eV): m/z (%): 337/335 (M+, 12/37), 170
(100). Anal. calcd. for C20H14ClNO2: C, 71.54; H, 4.20; N, 4.17.
Found: C, 71.66; H, 4.45; N, 4.01.
|
4.1.3
General procedure for the synthesis of
unsymmetrical quinolinyl‐bis‐chalcones 17a–w
A
mixture of the arylidene acetones 16a–d (0.05 mmol), 3‐
formylquinolines 10–12 (0.05 mmol), and 20% aq. KOH (0.5 ml) in
MeOH (10 ml) was stirred at ambient temperature for 4–20 h until
the starting reagents were not detected by TLC. Then, the reaction
mixture was neutralized with acetic acid. The resulting precipitate
was collected by filtration under vacuum and washed with methanol
(2 × 3 ml), followed by water (2 × 3 ml), and then dried and purified by
recrystallization or by column chromatography on silica gel.
3‐((1E,4E)‐5‐(4‐Hydroxy‐3‐methoxyphenyl)‐3‐oxopenta‐1,4‐dien‐1‐
yl)−6‐methoxyquinolin‐2(1H)‐one 17d
Yellow solid, m.p. 259–260°C. FTIR (ATR): ν = [3435, 3176] (OH,
.
NH), [1662, 1639] (C═O) cm−1 1H NMR (400 MHz, DMSO‐d6)
δ = 3.82 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.85 (d, J = 8.1 Hz, 1H),
7.16 (d, J = 15.9 Hz, 1H, ═CH), 7.28–7.20 (m, 3H), 7.31 (d, J = 9.7 Hz,
1H), 7.43 (s, 1H), 7.67 (d, J = 15.9 Hz, 1H, ═CH), 7.72 (d, J = 15.9 Hz,
1H, ═CH), 7.83 (d, J = 15.9 Hz, 1H, ═CH), 8.39 (s, 1H), 11.99 (s, 1H,
NH). 13C NMR (101 MHz, DMSO‐d6) δ = 56.0, 56.2, 109.8, 111.9,
116.2, 116.9, 120.1, 121.8, 123.7, 124.2, 126.7, 126.9, 128.6, 134.1,
137.8, 141.2, 144.0, 148.5, 150.2, 154.9, 160.9, 189.0 ppm. EI MS
(70 eV): m/z (%): 377 (M+, 32), 262 (14), 200 (100), 157 (57). Anal.
calcd. for C22H19NO5: C, 70.02; H, 5.07; N, 3.71. Found: C, 70.20; H,
5.16; N, 3.50.
3‐((1E,4E)‐5‐(4‐Hydroxy‐3‐methoxyphenyl)‐3‐oxopenta‐1,4‐dien‐1‐
yl)quinolin‐2(1H)‐one 17a
Yellow solid, m.p. 259–260°C. FTIR (ATR): ν = [3264, 3238] (OH,
.
NH), [1669, 1666] (C═O) cm−1 1H NMR (400 MHz, DMSO‐d6)
δ = 3.88 (s, 1H, OCH3), 6.86 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 15.9 Hz,
1H, ═CH), 7.23 (d, J = 7.7 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.36 (d,

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3‐((1E,4E)‐5‐(4‐Chlorophenyl)‐3‐oxopenta‐1,4‐dien‐1‐yl)−8‐
methylquinolin‐2(1H)‐one 17e
385 (M+, 12), 220 (100). Anal. calcd. for C24H16ClNO2: C, 74.71; H,
4.18; N, 3.63. Found: C, 74.93; H, 4.02; N, 3.83.
Yellow solid, m.p. 256–257°C. FTIR (ATR): ν = 3150 (NH), [1672,
1665] (C═O) cm−1
.
1H NMR (400 MHz, DMSO‐d6) δ = 2.34 (s, 3H,
(1E,4E)‐1‐(2‐Butoxyquinolin‐3‐yl)‐5‐(4‐methoxyphenyl)penta‐1,4‐
dien‐3‐one 17i
CH3), 7.24 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.37 (d,
J = 16.0 Hz, 1H, ═CH), 7.46 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.67 (d,
J = 16.0 Hz, 1H, ═CH), 7.78 (s, 2H, ═CH × 2), 7.83 (d, J = 8.5 Hz, 2H),
8.33 (s, 1H). 13C NMR (101 MHz, DMSO‐d6) δ = 20.3, 115.4, 119.1,
125.7, 126.4, 127.8, 127.9, 129.0, 130.2, 131.0, 133.1, 133.7, 134.9,
137.7, 138.8, 140.9, 141.3, 161.1, 188.8 ppm. EI MS (70 eV): m/z (%):
351/349 (M+, 16/58), 184 (100), 157 (35). Anal. calcd for
C21H16ClNO2: C, 72.10; H, 4.61; N, 4.00. Found: C, 69.96; H, 4.82;
N, 4.21.
Yellow solid, m.p. 123–125°C; FTIR (ATR) ν = 1668 (C═O) cm−1 1H
.
NMR (400 MHz, CDCl3) δ = 1.09 (t, J = 8.0 Hz, 3H, CH3), 1.60–1.70
(m, 2H, CH2), 1.92–2.02 (m, 2H, CH2), 3.89 (s, 3H, OCH3), 4.63 (t,
J = 8.0 Hz, 2H, OCH2), 6.98 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 16.0 Hz, 1H,
═CH), 7.42 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 16.0 Hz, 1H, ═CH), 7.61 (d,
J = 8.0 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 16.0 Hz, 1H, ═CH),
7.77 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 16.0 Hz, 1H, ═CH),
8.26 (s, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ = 14.0, 19.6, 31.1,
55.5, 66.6, 114.5, 120.4, 123.8, 124.6, 125.0, 127.0, 127.6, 128.0,
128.3, 130.2, 130.7, 137.4, 138.8, 143.3, 146.8, 160.1, 160.7,
189.2 ppm. EI MS (70 eV): m/z (%): 387 (M+, 14), 314 (11), 302 (10),
170 (100), 133 (24), 41 (31). Anal. calcd. for C25H25NO3: C, 77.49; H,
6.50; N, 3.61. Found: C, 77.30; H, 6.67; N, 3.42.
6‐Chloro‐3‐((1E,4E)‐5‐(4‐chlorophenyl)‐3‐oxopenta‐1,4‐dien‐1‐
yl)quinolin‐2(1H)‐one 17f
Yellow solid, m.p. >300°C. FTIR (ATR): ν = 3248 (NH), [1663, 1658]
.
(C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 7.22 (d, J = 16.0 Hz,
1H, ═CH), 7.38 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.53 (dd,
J = 8.8, 2.3 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H, ═CH), 7.68–7.77 (m, 5H,
═CH, Ar–H), 8.30 (s, 1H). 13C NMR (101 MHz, DMSO‐d6) δ = 116.3,
119.6, 125.6, 126.2, 126.6, 127.1, 128.2, 128.3, 129.3, 130.5, 133.2,
134.4, 136.6, 137.1, 138.6, 140.3, 159.8, 188.2 ppm. EI MS (70 eV):
m/z (%): 206/204 (31/100). Anal. calcd. for C20H13Cl2NO2: C, 64.88;
H, 3.54; N, 3.78. Found: C, 65.01; H, 3.71; N, 3.60.
(1E,4E)‐1‐(2‐Butoxy‐6‐methylquinolin‐3‐yl)‐5‐(4‐chlorophenyl)‐
penta‐1,4‐dien‐3‐one 17j
Yellow solid, m.p. 120–125°C; FTIR (ATR) ν = 1670 (C═O) cm−1 1H
.
NMR (400 MHz, CDCl3) δ = 1.08 (t, J = 8.0 Hz, 3H, CH3), 1.55–1.70
(m, 2H, CH2), 1.90–2.00 (m, 2H, CH2), 2.51 (s, 3H, CH3), 4.60 (t,
J = 8.0 Hz, 2H, OCH2), 7.07 (d, J = 16.0 Hz, 1H, ═CH), 7.42 (d,
J = 8.0 Hz, 2H), 7.46, (d, J = 16.8 Hz, 1H, ═CH), 7.47–7.54 (m, 2H),
7.56 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 16.0 Hz, 1H, ═CH), 7.75 (s, 1H),
7.97 (d, J = 16.0 Hz, 1H, ═CH), 8.16 (s, 1H) ppm. 13C NMR (101 MHz,
CDCl3) δ = 14.0, 19.6, 21.3, 31.2, 66.3, 119.9, 124.9, 126.2, 126.8,
127.1, 127.8, 129.3, 129.5, 132.9, 133.4, 134.2, 136.4, 138.5, 138.5,
141.8, 145.4, 159.6, 189.0 ppm. EI MS (70 eV): m/z (%): 407/405 (M+,
2/6), 240 (20), 202 (19), 184 (100), 159 (50), 130 (23), 41 (19). Anal.
calcd. for C25H24ClNO2: C, 73.97; H, 5.96; N, 3.45. Found: C, 80.12;
H, 6.08; N, 3.21.
3‐((1E,4E)‐5‐(4‐Methoxyphenyl)‐3‐oxopenta‐1,4‐dien‐1‐yl)−8‐
methylquinolin‐2(1H)‐one 17g
Yellow solid, m.p. 260–261°C. FTIR (ATR): ν = 3253 (NH), [1668,
.
1657] (C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 2.48 (s, 3H,
CH3), 3.84 (s, 3H, OCH3), 7.01 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 15.9 Hz,
1H, ═CH), 7.13 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.55 (d,
J = 7.7 Hz, 1H), 7.63 (d, J = 16.3 Hz, 1H, ═CH), 7.67 (d, J = 16.0 Hz, 2H,
═CH), 7.68 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 16.0 Hz, 1H, ═CH), 8.32 (s,
1H), 10.56 (s, 1H, NH). 13C NMR (101 MHz, DMSO‐d6) δ = 15.8, 54.8,
114.1, 118.7, 121.3, 122.7, 123.5, 125.6, 126.0, 127.0, 127.8, 129.4,
132.0, 136.3, 136.8, 140.1, 141.6, 160.4, 160.9, 188.1 ppm. EI MS
(70 eV): m/z (%): 184 (100) 133 (23), 41 (31). Anal. calcd. for
(1E,4E)‐1‐(2‐Butoxy‐8‐methylquinolin‐3‐yl)‐5‐(4‐hydroxy‐3‐
methoxyphenyl)penta‐1,4‐dien‐3‐one 17k
Yellow solid, m.p. 142–143°C. FTIR (ATR): ν = 3320 (OH), 1662,
C
22H19NO3: C, 76.50; H, 5.54; N, 4.06. Found: C, 76.77; H, 5.30;
(C═O) cm−1 1H NMR (400 MHz, CDCl3) δ = 1.09 (t, J = 7.4 Hz, 3H,
.
N, 4.18.
CH3), 1.70–1.54 (m, 2H, CH2), 2.02–1.85 (m, 2H, CH2), 2.72 (s,
3H, CH3), 3.99 (s, 3H, OCH3), 4.65 (t, J = 6.6 Hz, 2H, OCH2), 6.03
(s, 1H, OH), 6.97 (d, J = 15.9 Hz, 1H, ═CH), 7.00 (d, J = 8.2 Hz, 1H),
7.16 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 8.2, 1.8 Hz, 1H), 7.30 (s, 1H),
7.32 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 16.0 Hz, 1H, ═CH), 7.53 (d,
J = 7.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 15.9 Hz, 1H,
═CH), 7.99 (d, J = 16.0 Hz, 1H, ═CH), 8.23 (s, 1H). 13C NMR
(101 MHz, CDCl3) δ = 9.3, 12.9, 14.9, 26.3, 51.3, 61.5, 105.0,
110.2, 115.0, 118.8, 119.2, 119.4, 120.01, 121.1, 122.7, 123.1,
126.1, 130.5, 133.0, 134.4, 139.9, 140.9, 142.2, 143.6, 154.3,
184.5 ppm. EI MS (70 eV): m/z (%): 417 (M+, 17), 212 (62), 184
(100), 172 (51). Anal. calcd. for C26H27NO4: C, 74.80; H, 6.52; N,
3.35. Found: C, 74.63; H, 6.35; N, 3.53.
3‐((1E,4E)‐5‐(4‐Chlorophenyl)‐3‐oxopenta‐1,4‐dien‐1‐yl)benzo[h]‐
quinolin‐2(1H)‐one 17h
Yellow solid, m.p. 270–271°C. FTIR (ATR): ν = 3231 (NH), [1659,
.
1652] (C═O) cm−1 1H NMR (400 MHz, DMSO‐d6) δ = 7.26 (d,
J = 16.0 Hz, 1H, ═CH). 7.48 (d, J = 8.5 Hz, 2H), 7.71–7.61 (m, 4H),
7.68 (d, J = 16.1 Hz, 1H, ═CH), 7.75 (d, J = 16.1 Hz, 1H, ═CH), 7.76 (d,
J = 8.4 Hz, 2H), 7.82 (d, J = 16.1 Hz, 1H, ═CH), 7.99–7.94 (m, 1H),
8.46 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 11.95 (s, 1H, NH). 13C NMR
(101 MHz, DMSO‐d6) δ = 111.4, 122.0, 122.1, 123.9, 124.6, 125.8,
126.3, 127.4, 127.7, 128.2, 129.3, 133.3 ×2, 133.7, 133.8, 133.9,
134.3, 137.1, 140.0, 140.8, 160.5, 188.2 ppm. EI MS (70 eV): m/z (%):

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(1E,4E)‐1‐(2‐Butoxy‐7‐chloroquinolin‐3‐yl)‐5‐(4‐hydroxy‐3‐
methoxyphenyl)penta‐1,4‐dien‐3‐one 17l
OCH3). 5.60 (s, 2H, Ph‐CH2), 6.97 (d, J = 7.9 Hz, 1H), 6.99 (d,
J = 15.8 Hz, 1H, ═CH), 7.16 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.23
(d, J = 5.9 Hz, 1H), 7.45–7.25 (m, 7H), 7.61 (d, J = 5.7 Hz, 1H), 7.74
(d, J = 15.5 Hz, 1H, ═CH), 7.80 (d, J = 15.4 Hz, 1H, ═CH), 7.98 (d,
J = 15.8 Hz, 1H, ═CH), 8.02 (s, 1H). 13C NMR (101 MHz, CDCl3)
δ = 46.6. 56.1, 109.7, 114.9, 115.0, 119.0, 123.4, 123.9, 124.0,
126.3, 126.5, 127.4, 127.7, 129.1, 129.4, 130.8, 135.4, 137.6,
138.2, 140.1, 140.7, 144.0, 146.9, 148.4, 161.0, 189.6 ppm. EI MS
(70 eV): m/z (%): 471 (M+, 3), 294 (10), 91 (100). Anal. calcd. for
Yellow solid, m.p. 130–131°C. FTIR (ATR): ν = 3315 (OH), 1660
.
(C═O) cm−1 1H NMR (400 MHz, CDCl3) δ = 1.08 (t, J = 7.4 Hz, 3H,
CH3), 1.68–1.56 (m, 2H, CH2), 2.00–1.89 (m, 2H, CH2), 3.98 (s, 3H,
OCH3), 4.60 (t, J = 6.6 Hz, 2H, OCH2), 6.95 (d, J = 15.9 Hz, 1H, ═CH),
6.99 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.2,
1.8 Hz, 1H), 7.30 (s, 1H), 7.36 (dd, J = 8.6, 2.0 Hz, 1H), 7.45 (d,
J = 16.0 Hz, 1H, ═CH), 7.68 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 16.0 Hz, 1H,
═CH), 7.84 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 16.0 Hz, 1H, ═CH), 8.20 (s,
1H). 13C NMR (101 MHz, CDCl3) δ = 14.0, 19.6, 31.1, 56.0, 66.7,
109.8, 115.0, 120.5, 123.3, 123.6, 123.8, 125.4, 126.3, 127.3, 128.2,
129.0, 136.6, 137.1, 138.2, 143.9, 146.9, 147.4, 148.4, 160.7,
189.1 ppm. EI MS (70 eV): m/z (%): 437 (M+, 3), 204 (14), 129 (16), 57
(99), 43 (100). Anal. calcd. for C25H24ClNO4: C, 68.57; H, 5.52; N,
3.20. Found: C, 68.80; H, 5.25; N, 3.09.
C
28H22ClNO4: C, 71.26; H, 4.70; N, 2.97. Found: C, 71.51; H, 5.01;
N, 3.15.
(1E,4E)‐1‐(2‐(Benzyloxy)‐7‐chloroquinolin‐3‐yl)‐5‐(4‐hydroxy‐3‐
methoxyphenyl)penta‐1,4‐dien‐3‐one 17p
Yellow solid, m.p. 152–153°C. FTIR (ATR): ν = 3320 (OH), 1670
.
(C═O) cm−1 1H NMR (400 MHz, CDCl3) δ = 3.97 (s, 3H, OCH3). 5.68
(s, 2H, Ph‐CH2), 6.01 (s, 1H, OH), 6.87 (d, J = 15.9 Hz, 1H, ═CH). 6.98
(d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.37 (t,
J = 4.9 Hz, 1H), 7.40 (d, J = 7.5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.50 (d,
J = 16.2 Hz, 1H, ═CH), 7.58 (d, J = 16.3 Hz, 1H, ═CH), 7.62 (d,
J = 7.4 Hz, 2H), 7.71 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H, ═CH),
7.94 (d, J = 15.9 Hz, 1H, ═CH), 8.23 (s, 1H). 13C NMR (101 MHz,
CDCl3) δ = 56.0, 68.6, 109.6, 114.9, 120.5, 123.6, 123.8, 124.0, 125.7,
126.4, 127.3, 128.1, 128.3, 128.3, 128.6, 129.1, 136.7, 136.8, 136.9,
138.8, 143.9, 146.9, 147.1, 148.4, 160.3, 189.0 ppm. EI MS (70 eV):
m/z (%): 473/471 (M+, 5/14), 380 (15), 236 (25), 149 (56), 92 (100).
Anal. calcd. for C28H22ClNO4: C, 71.26; H, 4.70; N, 2.97. Found: C,
71.46; H, 4.48; N, 2.72.
1‐Butyl‐6‐chloro‐3‐((1E,4E)‐5‐(4‐methoxyphenyl)‐3‐oxopenta‐1,4‐
dien‐1‐yl)quinolin‐2(1H)‐one 17m
Yellow solid, m.p. 177–179°C. FTIR (ATR) ν = 1649, 1601 (C═O)
cm−1. 1H NMR (CDCl3) δ = 1.06 (t, J = 8.0 Hz, 3H, CH3), 1.50–1.62 (m,
2H, CH2), 1.75–1.83 (m, 2H, CH2), 3.89 (s, 3H, OCH3) 4.36 (t,
J = 8.0 Hz, 2H, NCH2), 6.96 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 16.0 Hz, 1H,
═CH), 7.34 (d, J = 12.0 Hz, 1H), 7.55–7.66 (m, 3H), 7.66 (d, J = 4.0 Hz,
1H), 7.77 (d, J = 16.0 Hz, 1H, ═CH), 7.77 (d, J = 16.0 Hz, 1H, ═CH),
7.90 (d, J = 16.0 Hz, 1H, ═CH), 7.90 (s, 1H) ppm; 13C NMR (101 MHz,
CDCl3) δ = 13.9, 20.4, 29.6, 43.0, 56.1, 114.5, 115.7, 121.5, 123.9,
127.5, 127.6, 127.8, 128.6, 129.7, 130.2, 131.6, 137.5, 137.6, 139.2
143.5, 160.4, 161.7, 189.6 ppm. EI MS (70 eV): m/z (%): 423/421 (M+,
8/21), 260 (76), 204 (66), 161 (45), 133 (59), 84 (100), 48 (17). Anal.
calcd. for C25H24ClNO3: C, 71.17; H, 8.40; N, 3.32. Found: C, 71.30;
H, 8.51; N, 3.21.
(1E,4E)‐1‐(2‐(Benzyloxy)benzo[h]quinolin‐3‐yl)‐5‐(4‐chlorophenyl)‐
penta‐1,4‐dien‐3‐one 17q
.
Yellow solid, m.p. 150–153°C. FTIR (ATR): ν = 1672 (C═O) cm−1 1H
NMR (400 MHz, DMSO‐d6) δ = 5.78 (s, 2H, Ph‐CH2), 7.23 (d,
J = 16.0 Hz, 1H, ═CH), 7.30–8.05 (m, 17H, Ar–H, ═CH), 8.76 (s, 1H),
9.05 (brs, 1H) ppm; 13C NMR (101 MHz, DMSO‐d6) δ = 68.3, 119.1,
122.5, 124.8, 125.7, 126.0, 127.3, 127.5, 128.0, 128.0, 128.4, 128.6,
129.0, 129.1, 129.5, 130.1, 130.6, 134.0, 134.5, 135.6, 136.7, 137.7,
139.2, 142.0, 144.6, 159.3, 188.8 ppm. EI MS (70 eV): m/z (%): 477/
475 (M+, 3/8), 368 (10), 310 (63), 165 (22), 91 (100). Anal. calcd. for
1‐Butyl‐7‐chloro‐3‐((1E,4E)‐5‐(4‐hydroxy‐3‐methoxyphenyl)‐3‐
oxopenta‐1,4‐dien‐1‐yl)quinolin‐2(1H)‐one 17n
Yellow solid, m.p. 194–195°C. FTIR (ATR): ν = 3322 (OH), [1651, 1643]
(C═O) cm−1. 1H NMR (400 MHz, CDCl3) δ = 1.07 (t, J = 7.3 Hz, 3H, CH3),
1.63–1.47 (m, 2H, CH2), 1.85–1.70 (m, 2H, CH2), 3.98 (s, 3H, OCH3),
4.35–4.25 (m, 2H, NCH2), 6.98 (s, 1H), 6.98 (d, J = 15.8.4 Hz, 1H, ═CH),
7.16 (d, J = 6.5 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H),
7.37 (d, J = 1.1 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 15.8 Hz, 1H,
═CH), 7. 74 (d, J = 15.7 Hz, 1H, ═CH), 7.91 (d, J = 15.8 Hz, 1H, ═CH), 7.93
(s, 1H). 13C NMR (101 MHz, CDCl3) δ = 13.9. 20.4, 29.5, 43.0, 56.1, 109.6,
114.3, 114.9, 119.0, 123.0, 123.9 (×2), 126.2, 127.4, 129.2, 130.8, 137.7,
138.6, 139.8, 140.2, 143.9, 146.9, 148.4, 160.6, 189.6 ppm. EI MS (70 eV):
m/z (%): 437 (M+, 5), 341 (44), 313 (29), 260 (100), 204 (67). Anal. calcd
for C25H24ClNO4: C, 68.57; H, 5.52; N, 3.20. Found: C, 68.81; H, 5.31;
N, 3.03.
C31H22ClNO2: C, 78.23; H, 4.66; N, 2.94. Found: C, 78.04; H, 4.83;
N, 3.10.
(1E,4E)‐1‐(2‐(Benzyloxy)benzo[h]quinolin‐3‐yl)‐5‐(4‐
methoxyphenyl)‐penta‐1,4‐dien‐3‐one 17r
Yellow solid, m.p. 155–157°C; FTIR (ATR): ν = 1647 (C═O) cm−1
.
1H NMR (400 MHz, DMSO‐d6) δ = 3.83 (s, 3H, OCH3), 5.80 (s, 2H,
Ph‐CH2), 7.04 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 16.0 Hz, 1H, ═CH),
7.36 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 16.0 Hz, 1H, ═CH), 7.46 (d,
J = 4.0 Hz, 1H), 7.63–7.78 (m, 8H), 7.84 (d, J = 4.0 Hz, 2H), 7.96 (d,
J = 16.0 Hz, 1H, ═CH), 7.99–8.03 (m, 1H), 8.81 (s, 1H), 9.05–9.10
(m, 1H) ppm; 13C NMR (101 MHz, DMSO‐d6) δ = 55.9, 68.3, 115.0,
119.3, 122.5, 124.7, 124.8, 125.7, 125.9, 127.3, 127.6, 128.1,
128.4, 128.6, 129.0, 129.1, 130.1, 130.9, 134.5, 136.4, 137.7,
1‐Benzyl‐7‐chloro‐3‐((1E,4E)‐5‐(4‐hydroxy‐3‐methoxyphenyl)‐3‐
oxopenta‐1,4‐dien‐1‐yl)quinolin‐2(1H)‐one 17o
Yellow solid, m.p. 190–191°C. FTIR (ATR): ν = 3312 (OH), [1660,
.
1645] (C═O) cm−1 1H NMR (400 MHz, CDCl3) δ = 3.98 (s, 3H,

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138.9, 143.5, 144.5, 159.4, 161.9, 188.6 ppm; EI MS (70 eV): m/z
(%): 471 (M+, 26), 364 (36), 310 (63), 219 (17), 161 (98), 133 (42),
91 (100). Anal. calcd. for C33H36N2O3: C, 77.92; H, 7.13; N, 5.51.
Found: C, 78.12; H, 7.34; N, 5.22.
C24H21Cl2NO2: C, 67.61; H, 4.97; N, 3.29. Found: C, 67.78; H, 5.10;
N, 3.05.
(1E,4E)‐1‐(2‐Butoxy‐6‐chloroquinolin‐3‐yl)‐5‐(4‐methoxyphenyl)‐
penta‐1,4‐dien‐3‐one 17v
.
Yellow solid. Mp. 125–128°C; FTIR (ATR) ν = 1649 (C═O) cm−1 1H
3‐((1E,4E)‐5‐(Benzo[d][1,3]dioxol‐5‐yl)‐3‐oxopenta‐1,4‐dien‐1‐yl)‐1‐
butyl‐7‐chloroquinolin‐2(1H)‐one 17s
NMR (CDCl3) δ = 1.08 (t, J = 8.0 Hz, 3H, CH3), 1.58–1.67 (m, 2H,
CH2), 1.90–1.98 (m, 2H, CH2), 3.88 (s, 3H, OCH3), 4.59 (t, J = 8.0 Hz,
2H, OCH2), 6.96 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 16.0 Hz, 1H, ═CH),
7.43 (d, J = 16.0 Hz, 1H, ═CH), 7.54–7.62 (m, 3H), 7.70–7.78 (m, 3H),
7.92 (d, J = 16.0 Hz, 1H, ═CH), 8.12 (s, 1H, Quin‐H) ppm; 13C NMR
(CDCl3) δ = 14.0, 19.6, 31.1, 55.4, 66.6, 114.5, 121.3, 123.7, 125.6,
126.5, 127.5, 128.5, 128.8, 129.8, 130.2, 131.1, 136.8, 137.4, 143.5,
145.2, 160.2, 161.8, 189.0 ppm. EI MS (70 eV) m/z (%): 423/421 (20/
52, M+), 348 (42), 204 (100), 161 (77), 133 (51), 94 (77), 57 (55), 41
(49). Anal. calcd. for C25H24ClNO3: C, 71.17; H, 5.73; N, 3.32. Found:
C, 71.02; H, 6.81; N, 3.10.
Yellow solid, m.p. 200–202°C; FTIR (ATR): ν = [1653. 1597] (C═O)
.
cm−1 1H NMR (400 MHz, CDCl3) δ = 1.07 (t, J = 8.0 Hz, 3H, CH3),
1.50–1.62 (m, 2H, CH2), 1.70–1.83 (m, 2H, CH2), 4.32 (t, J = 8.0 Hz,
2H, NCH2), 6.05 (s, 2H, CH2), 6.86 (d, J = 8.0 Hz, 1H), 6.95 (d,
J = 16.0 Hz, 1H, ═CH), 7.10–7.15 (m, 2H), 7.25 (dd, J = 8.0 Hz,
J = 4.0 Hz, 1H), 7.36 (d, J = 4.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.69
(d, J = 16.0 Hz, 1H, ═CH), 7.74 (d, J = 16.0 Hz, 1H, ═CH), 7.85 (d,
J = 16.0 Hz, 1H, ═CH), 7.93 (s, 1H) ppm; 13C NMR (101 MHz, CDCl3)
δ = 13.9, 20.4, 29.5, 43.0, 101.6, 106.7, 108.7, 114.3, 119.0, 123.0,
124.1, 125.1, 126.2, 129.2, 129.3, 130.8, 137.8, 138.0, 139.9, 139.9,
143.3, 148.4, 149.9, 180.6, 189.5 ppm. MS (70 eV) m/z (%): 437/435
(3.7/7.8, M+), 260 (100), 206/204 (43/95), 94 (95), 57 (75), 41 (33).
Anal. calcd. for C25H22ClNO4: C, 68.89; H, 5.09; N, 3.21. Found: C,
69.03; H, 4.86; N, 3.46.
(1E,4E)‐1‐(Benzo[d][1,3]dioxol‐5‐yl)‐5‐(2‐butoxy‐6‐methylquinolin‐
3‐yl)penta‐1,4‐dien‐3‐one 17w
Yellow solid, m.p. 160–162°C. FTIR (ATR) ν = 1647 (C═O) cm−1
.
1H NMR (101 MHz, CDCl3) δ = 1.08 (t, J = 8.0 Hz, 3H, CH3),
1.57–1.70 (m, 2H, CH2), 1.90–2.00 (m, 2H, CH2), 2.53 (s, 3H, CH3),
4.62 (t, J = 8.0 Hz, 2H, CH2), 6.07 (s, 2H), 6.88 (d, J = 8.0 Hz, 1H),
6.95 (d, J = 16.0 Hz, 1H, ═CH), 7.14 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H),
7.17 (d, J = 1.2 Hz, 1H), 7.43 (d, J = 16.0 Hz, 1H, ═CH), 7.51 (dd,
J = 1.6 Hz, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.71 (d, J = 16.0 Hz, 1H,
═CH), 7.77 (d, J = 12.0 Hz, 1H), 7.97 (d, J = 16.0 Hz, 1H, ═CH),
8.18 (s, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ = 14.0, 19.7, 21.3,
31.2, 66.5, 101.7, 106.6, 108.7, 120.1, 124.0, 124.9, 125.1, 126.7,
127.1, 128.1, 129.4, 132.9, 134.2, 137.8, 138.4, 143.2, 145.2,
148.5, 149.9, 159.7, 189.1 ppm. EI MS (70 eV) m/z (%): 415 (28),
184 (100), 172 (42), 89 (38). Anal. calcd. for C26H25NO4: C, 75.16;
H, 6.07; N, 3.37. Found: C, 75.28; H, 5.88; N, 3.51.
(1E,4E)‐1‐(Benzo[d][1,3]dioxol‐5‐yl)‐5‐(2‐butoxy‐6‐chloroquinolin‐3‐
yl)penta‐1,4‐dien‐3‐one 17t
Yellow solid, m.p. 191–193°C; FTIR (ATR): ν = 1649 (C═O) cm−1 1H
.
NMR (400 MHz, CDCl3) δ = 1.08 (t, J = 8.0 Hz, 3H, CH3), 1.56–1.72
(m, 2H, CH2), 1.90–2.00 (m, 2H, CH2), 4.62 (t, J = 8.0 Hz, 2H, NCH2),
6.07 (s, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 16.0 Hz, 1H, ═CH),
7.14 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.43 (d, J = 16.0 Hz, 1H, ═CH),
7.60 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.71 (d, J = 16.0 Hz, 1H, ═CH),
7.76 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 16.0 Hz,
1H, ═CH), 8.17 (s, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ = 14.0,
19.6, 31.1, 66.7, 101.7, 106.6, 108.7, 121.3, 123.9, 125.2, 125.6,
126.6, 128.6, 128.9, 129.3, 129.9, 131.2, 137.0, 137.4, 143.5, 145.3,
148,5, 150.0, 160.2, 188.9 ppm. EI MS (70 eV) m/z (%): 437/435 (11/
31, M+), 381/379 (8/26), 206/204 (36/100), 175 (29), 145 (37), 89
(32). Anal. calcd. for C25H22ClNO4: C, 68.89; H, 5.09; N, 3.21. Found:
C, 68.68; H, 5.23; N, 2.98.
|
4.2
Anticancer activity
The human cancer cell lines of the cancer screening panel were grown
in an RPMI‐1640 medium containing 5% fetal bovine serum and 2 mM
L‐glutamine. For a typical screening experiment, cells were inoculated
into 96‐well microtiter plates. After cell inoculation, the microtiter
plates were incubated at 37°C, 5% CO2, 95% air, and 100% relative
humidity for 24 h before the addition of the tested compounds. After
24 h, two plates of each cell line were fixed in situ with trichloroacetic
acid (TCA), to represent a measurement of the cell population for each
cell line at the time of sample addition (Tz). The samples were solu-
bilized in DMSO at 400‐fold the desired final maximum test con-
centration and stored frozen before use. At the time of compound
addition, an aliquot of frozen concentrate was thawed and diluted to
twice the desired final maximum test concentration with a complete
medium containing 50 μg/ml gentamicin. An additional four 10‐fold or
(1E,4E)‐1‐(2‐Butoxy‐6‐chloroquinolin‐3‐yl)‐5‐(4‐chlorophenyl)penta‐
1,4‐dien‐3‐one 17u
Yellow solid, m.p. 160–164°C. FTIR (ATR) ν = 1655 (C═O) cm−1 1H
.
NMR (400 MHz, CDCl3) δ = 1.08 (t, J = 8.0 Hz, 3H, CH3), 1.57–1.68
(m, 2H, CH2), 1.90–2.00 (m, 2H, CH2), 4.61 (t, J = 8.0 Hz, 2H, OCH2),
7.07 (d, J = 16.0 Hz, 1H, ═CH), 7.43 (d, J = 4.0 Hz, J = 12.0 Hz, 3H),
7.59 (d, J = 16.0 Hz, 1H, ═CH), 7.60 (d, J = 9.6 Hz, 2H), 7.73 (d,
J = 16.0 Hz, 1H, ═CH), 7.78 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 16.0 Hz, 1H,
═CH), 8.16 (s, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ = 14.0, 19.6,
31.1, 66.7, 121.1, 125.5, 126.1, 126.6, 128.6, 128.6, 129.0, 129.3,
129.3, 129.5, 129.9, 131.3, 133.3, 136.6, 137.6, 142.1, 145.4, 160.2,
188.8 ppm. EI MS (70 eV) m/z (%): 425 (M+, 18), 260 (42), 204 (100),
165 (64), 137 (68), 102 (66), 69 (97), 41 (81). Anal. calcd. for

INSUASTY ET AL.
19 of 20
|
1/2 log serial dilutions were made to provide a total of five drug
concentrations plus the control. Aliquots of 100 μl of these different
sample dilutions were added to the appropriate microtiter wells al-
ready containing 100 μl of medium, resulting in the required final
sample concentrations.[32] After the tested compounds were added,
the plates were incubated for an additional 48 h at 37°C, 5% CO2,
95% air, and 100% relative humidity. For adherent cells, the assay was
terminated by the addition of cold TCA. Cells were fixed in situ by the
gentle addition of 50 μl of cold 50% (w/v) TCA (final concentration,
10% TCA) and incubated for 60 min at 4°C. The supernatant was
discarded, and plates were washed five times with tap water and air‐
dried. SRB solution (100 μl) at 0.4% (w/v) in 1% acetic acid was added
to each well, and plates were incubated for 10 min at room tem-
perature. After staining, the unbound dye was removed by washing
five times with 1% acetic acid and the plates were air‐dried. The
bound stain was subsequently solubilized with 10 mM Trizma base,
and the absorbance was read on an automated plate reader at a
wavelength of 515 nm. Using the seven absorbance measurements
(time zero [Tz], control growth in the absence of drug [C], and test
growth in the presence of drug at the five concentration levels [Ti]),
the percentage growth was calculated at each of the drug con-
centrations levels. Percentage growth inhibition was calculated as
follows: [(Ti – Tz)/(C – Tz)] × 100 for concentrations for which Ti > Tz,
and [(Ti – Tz)/Tz] × 100 for concentrations for which Ti < Tz. Two
dose–response parameters were calculated for each compound.
Growth inhibition of 50% (GI50) was calculated from [(Ti – Tz)/
(C – Tz)] × 100 = 50, which is the drug concentration resulting in a
50% lower net protein increase in the treated cells (measured by SRB
staining) as compared with the net protein increase seen in the control
cells and the LC50 (concentration of drug resulting in a 50% reduction
in the measured protein at the end of the drug treatment as compared
with that at the beginning), indicating a net loss of cells, calculated
from [(Ti – Tz)/Tz] × 100 = –50). Values were calculated for each of
these two parameters if the level of activity was reached; however, if
the effect was not reached or was exceeded, the value for that
parameter was expressed as greater or less than the maximum or
minimum concentration tested.[32,33]
computations. Co‐crystallized ligands and crystallographic water
molecules were removed. The addition of hydrogens, merger of
nonpolar hydrogens to the atom to which they were linked, and
the assignment of partial charges were computed with Auto-
DockTools. Docking areas were constrained to a 30 × 30 × 30 Å
box centered at the active site of the proteins, providing proper
space for rotational and translational movement of the ligands.
The most stable docking pose for each compound was selected to
determine its binding affinity.
ACKNOWLEDGMENTS
The authors thank COLCIENCIAS, Universidad del Valle—Project
Number 110680864255, and Universidad del Norte for financial sup-
port, and “Centro de Instrumentación Científico‐Técnica of Universidad
de Jaén” for data collection. This study also was supported in part by
the Spanish Ministerio de Ciencia, Innovación y Universidades, project
#RTI2018‐098560‐B‐C22, Universidad de Jáen, Consejería de Innova-
ción, Ciencia y Empresa (Junta de Andalucía, Spain).
ORCID
Rodrigo Abonia
Braulio Insuasty
http://orcid.org/0000-0003-3256-0961
http://orcid.org/0000-0001-8371-3310
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How to cite this article: D. Insuasty, S. García, R. Abonia, B.
Insuasty, J. Quiroga, M. Nogueras, J. Cobo, G. L. Borosky, K. K.
Laali. Design, synthesis, and molecular docking study of novel
quinoline‐based bis‐chalcones as potential antitumor agents.
Arch. Pharm. 2021;e2100094.
https://doi.org/10.1002/ardp.202100094