Synthesis and anticancer activity of chalcone–quinoxalin conjugates

Article abstract of DOI:10.1080/00397911.2021.1881124

Two series of quinoxaline–chalcone conjugates have been prepared by aldolic condensation and aromatic nucleophilic substitution reaction, and their anticancer activity against three cancer cell lines including benign prostatic hyperplasia epithelial cell (BPH-1), neuron-like rat pheochromocytoma cell line (PC12) and human breast cancer cell line (MCF-7) were evaluated in?vitro. All of the synthesized compounds exhibited moderate to good activity against the cancer cell lines selected. Particularly, Compound A5 showed the excellent potent activity against BPH-1 and MCF-7 with IC₅₀ values of 10.4 and 9.1 μM, respectively, which is similar to doxorubicin (14.1 and 9.2 μM, respectively). As well as compound B6 exhibited most excellent activity toward PC12 with IC₅₀ values of 16.4 μM. Compound A10 exhibited 55.4, 36.8 and 54.5 folds higher selectivity for BPH-1, PC12 and MCF-7 cells than for HEK-293 cell, respectively. In addition, theoretical biological activities of compounds A5 and A10 were evaluated by SwissADME.

Full text of DOI:10.1080/00397911.2021.1881124

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis and anticancer activity of
chalcone–quinoxalin conjugates
Xiaoyun Ma, Daoping Wang, Gang Wei, Qingdi Zhou & Xiuhai Gan
To cite this article: Xiaoyun Ma, Daoping Wang, Gang Wei, Qingdi Zhou & Xiuhai Gan (2021)
Synthesis and anticancer activity of chalcone–quinoxalin conjugates, Synthetic Communications,
51:9, 1363-1372, DOI: 10.1080/00397911.2021.1881124
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2021, VOL. 51, NO. 9, 1363–1372
https://doi.org/10.1080/00397911.2021.1881124
Synthesis and anticancer activity of
chalcone–quinoxalin conjugates
Xiaoyun Maa, Daoping Wangb, Gang Weic, Qingdi Zhoud, and Xiuhai Gana
b
aSchool of Chemistry and Materials Science, Guizhou Education University, Guiyang, China; The Key
Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences,
c
d
Guiyang, China; CSIRO Mineral Resources, Lindfield, NSW, Australia; School of Chemistry, The
University of Sydney, Sydney, NSW, Australia
ABSTRACT
ARTICLE HISTORY
Received 2 October 2020
Two series of quinoxaline–chalcone conjugates have been prepared
by aldolic condensation and aromatic nucleophilic substitution reac-
tion, and their anticancer activity against three cancer cell lines
including benign prostatic hyperplasia epithelial cell (BPH-1), neuron-
like rat pheochromocytoma cell line (PC12) and human breast cancer
cell line (MCF-7) were evaluated in vitro. All of the synthesized com-
pounds exhibited moderate to good activity against the cancer cell
lines selected. Particularly, Compound A5 showed the excellent
potent activity against BPH-1 and MCF-7 with IC50 values of 10.4 and
9.1 lM, respectively, which is similar to doxorubicin (14.1 and 9.2 lM,
respectively). As well as compound B6 exhibited most excellent
activity toward PC12 with IC50 values of 16.4 lM. Compound A10
exhibited 55.4, 36.8 and 54.5 folds higher selectivity for BPH-1, PC12
and MCF-7 cells than for HEK-293 cell, respectively. In addition, the-
oretical biological activities of compounds A5 and A10 were eval-
uated by SwissADME.
KEYWORDS
Anticancer; chalcone;
conjugate; quinoxalin
GRAPHICAL ABSTRACT
Introduction
Cancer is one of the major global health challenge and the second leading cause of
death worldwide.[1] Nowadays, chemotherapy plays an irreplaceable role in suppressing
tumor growth and eradication of tumors.[2] However, most of the anticancer agents
CONTACT Xiuhai Gan
University, Guiyang, China; Daoping Wang,
gxh200719@163.com
School of Chemistry and Materials Science, Guizhou Education
The Key Laboratory of Chemistry for Natural
wdp_7897@aliyun.com,
Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, China.
Supplemental data for this article can be accessed on the publisher’cs website.
ß 2021 Taylor & Francis Group, LLC

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X. MA ET AL.
Scheme 1. Synthetic route of two series of quinoxaline–chalcone conjugates.
have toxic effects on the normal cells, and many patients undergoing chemotherapy suf-
fer from various serious and sometimes intolerable side effects.[3] Therefore, there is an
urgent need for safe and effective new anticancer drugs for treating the tumors, and the
search for novel anticancer agents continues to be an active area of research although
many research studies have reported potential chemotherapeutic effects of
novel compounds.[4]
Chalcones is widely found in nature, and exhibit a wide variety of biological activities
including antioxidant,[5] hypnotic,[6] anti-inflammatory,[7] antiobesity,[8] antiviral activ-
ity,[9] antimicrobial activity,[10] antiprotozoal[11] and antitumor activity.[4d,12]
Meanwhile, quinoxaline is a member of family of benzodiazine with its 1,4-nitrogens as
heteroatoms, various derivatives of quinoxaline are also known to possess wide range of
biological activities, such as antitubercular,[13] antimicrobials,[14] anti-inflammatory,[15]
antioxidants,[16] anti-HIVs,[17] kinase inhibitors[18] and anticancer.[19] Based on a litera-
ture survey, we found that anticancer activities of chalcone and quinoxaline have been
highlighted by many reviews.[20] Accordingly, presence of chalcone–quinoxalin hybrids
has encouraged medicinal chemists to develop novel anticancer agents bearing this
hybrid scaffold.
Recently, some hybrids of chalcone ꢀ quinoxaline derivatives have been reported to
possess a variety of antitumor activities.[21] In view of this fact, we herein report two
new series of quinoxaline–chalcone derivatives as anticancer agents, the synthetic route
was shown in Scheme 1. We thought that the conjugation of 6-chloroquinoxaline moi-
ety and chalcone scaffold might give highly active antitumor compounds. Results of bio-
assays indicated that some of chalcone–quinoxalin conjugates displayed good cytotoxic
activities against BPH-1, PC12 and MCF-7.
Results and discussion
Synthesis
The synthetic protocols of two series of chalcone derivatives are depicted in Scheme 1.
The first series of compounds (A1–A17) contain 6-chloroquinoxaline moiety linked to

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Table 1. Anticancer activity of chalcone–quinoxalin conjugates.
IC50 value (lmol/L)a
Compd.
Ar
BPH-1
PC12
MCF-7
A1
A2
A3
A4
A5
A6
A7
A8
4-CH3-C6H4
2-CF3-C6H4
3-OCH3-C6H4
2,4-diOCH3-C6H3
2,4-diF-C6H3
2,4-diCl-C6H3
3,4-diOCH3-C6H3
C6H5
2-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
2-F-C6H4
2-Br-C6H4
3-Br-C6H4
2,6-diF-C6H3
3-F-C6H4
2-furanyl
2,4-diCl-C6H3
2-Cl-C6H4
4-OCH3-C6H4
4-Cl-C6H4
4-CH3-C6H4
48.5 3.8
54.8 1.9
64.2 3.5
76.9 2.2
10.4 2.6
24.1 2.3
98.7 4.5
67.0 3.2
46.6 3.2
12.3 1.6
46.1 3.1
20.1 1.5
68.2 2.7
48.5 2.1
17.3 1.5
11.5 1.8
18.2 3.2
15.8 1.5
31.1 2.6
87.9 1.5
21.6 2.3
58.4 1.9
15.5 1.5
14.1 1.0
42.1 3.3
48.5 2.1
73.1 3.9
81.1 3.5
16.7 2.8
27.1 3.0
84.7 3.9
73.2 4.4
55.6 3.6
18.5 3.1
51.2 3.4
23.6 2.3
43.9 2.5
35.2 1.5
26.5 1.8
20.1 2.2
35.1 2.1
26.1 2.3
45.1 3.7
96.2 3.1
20.8 3.4
64.6 3.6
16.4 3.0
22.5 2.3
72.4 5.3
54.8 1.5
80.9 4.1
77.3 1.9
9.1 1.1
13.1 1.5
64.8 1.9
59.4 1.9
31.5 2.7
12.5 1.0
36.2 3.7
12.2 1.1
45.1 2.7
22.2 2.5
22.5 3.8
14.2 1.5
20.5 1.7
17.4 1.1
22.1 2.5
53.1 3.7
14.6 1.3
19.3 1.8
11.8 2.2
9.2 0.9
A9
A10
A11
A12
A13
A14
A15
A16
A17
B1
B2
B3
B4
B5
B6
2-F-C6H4
Doxorubicin
aIC50 values are indicated as the mean SD (standard deviation) of three independent experiments.
ring A of chalcone. In contrast, 6-chloroquinoxaline moiety was linked to ring B of
chalcone in the second series of compounds (B1–B6). Two series of chalcone–quinoxa-
lin conjugates were synthesized with similar ways. Firstly, intermediates 1a–1q and
2a–2f were prepared by aldol condensation according to a previously described
method.[22] Aldolic condensations were carried out in anhydrous ethanol with potas-
sium hydroxide as a catalyst, under magnetic stirring at room temperature. These inter-
mediates are known compounds, and they were characterized by melting point.
Secondly, 2,6-dichloroquinoxaline reacts with intermediates 1a–1q and 2a–2f to form
target molecules via nucleophilic addition-elimination reaction. Chlorine atom on pos-
ition 2 of quinoxaline is easily replaced by nucleophiles due to electron-withdrawing
effect of nitrogen atoms on the pyrazine ring of quinoxaline, and the substitution of
chlorine atom on 6 position is difficultly because there is no electron-withdrawing
group on the benzene ring of quinoxaline. Therefore, chloride substitution occurs at the
2-position, and the target molecules were obtained in moderate to good yield.
Biological evaluation
All the newly synthetic compounds (A11–A17 and B1–B6) were screened for their anti-
cancer activity in vitro against three representative cell lines of BPH-1, PC12 and MCF-
7 employing MTT assay. Doxorubicin was used as a positive control, the results were
expressed as growth inhibitory concentration (IC50) values after 24 h of incubation,
compared with the untreated controls (Table 1). As shown in Table 1, all the target
compounds showed moderate to good antiproliferative activity with IC50 values in
micro molar range (9.1–98.7 mM) against all tested cancer cells. Among them,

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X. MA ET AL.
Table 2. Cytotoxicity against normal cell line (HEK-293).
Selectivity indexb
PC12
HEK-293
Compd.
IC50 (lM)a
BPH-1
MCF-7
A5
A6
13.4 0.1
8.6 0.9
1.3
0.4
0.8
0.3
1.5
0.7
A10
A12
A16
B6
681.0 64
33.0 5.8
53.3 2.4
16.8 0.5
0.054 0.002
55.4
1.6
4.6
1.1
0.004
36.8
1.4
2.7
1.0
0.002
54.5
2.7
3.8
1.4
0.006
Doxorubicin
aIC50 values are indicated as the mean SD (standard deviation) of three independent experiments.
bSelectivity index (SI) ¼ IC50 on HEK-293 cell/IC50 on cancer cell.
compound A5 gave the best antiproliferative activities in BPH-1 cell line and MCF-7
cell line (IC50¼10.4 lM for BPH-1 and 9.1 lM for MCF-7), compound B6 endowed the
most significant activity against PC12 cell line with a lowest IC50 value of 16.4 lM.
A simple structure–activity relationship analysis showed that the antiproliferative
activity was closely related to substituent group, group position and the number of sub-
stituents in chalcon moiety. The introduction of methyl group, trifluoromethyl group or
halogen atom to the aromatic ring of chalcone moiety resulted in increased cytotoxic
activity. Among these substituents, halogen atom, especially fluorine atom, is more
beneficial for enhancing the cytotoxic activity of chalcone–quinoxalin hybrids.
Compound A5, A6, A10, A12, A15, A16, B1, B4, and B6, containing fluorine atom or
chlorine atom in the chalcone moiety, exhibited good activity against the three cancer
cell lines. Use of furan ring in place of B ring of chalcone moiety also increased the
cytotoxic activity (compound A17), methoxy group in the aromatic ring of chalcone
moiety decreased the cytotoxic activity of the hybrids (compound A3, A4, A7, and B3).
Group position and number of substituents also have impacted on the activity of the
hybrids, but there is a lack of regularity according to the experimental results available.
For example, considering the fluoro substituted hybrids A5, A12, A15, A16, and B6,
compound A5 with two fluorine atoms situated in the 2- and 4-position of ring B of
chalcone exhibited best activity toward the two cell lines BPH-1 and MCF-7, compound
B6 bearing a fluorine atom situated in the 2-position of ring A of chalcone exhibited
highest activity toward PC12.
In addition, in order to investigate the selectivity of these compounds for cancer cell
and normal cell, compounds A5, A6, A10, A12, A16, B6, & doxorubicin were evaluated
against the human embryonic kidney-293 cell line (HEK-293), and selectivity index (SI)
of each compound with different cell lines was calculated as follow, SI ¼ IC50 of HEK-
293 cell/IC50 of compound on different tested cancer cell line. Doxorubicin was used as
a reference drug.
As represented in Table 2, compound A10 showed the highest SI. It exhibited 55.4,
36.8 and 54.5 folds higher selectivity for BPH-1, PC12 and MCF-7 cells than for HEK-
293 cell, respectively. However, other chalcone–quinoxalin conjugates showed low
selectivity index (SI: 0.3–4.6), compound A5 showed SI lower than 2, indicating that
this compound was similarly toxic to HEK-293 cell and cancer cells. In addition, the
reference drug doxorubicin exhibited the lowest SI, and the selectivity indexes were
0.004, 0.002, and 0.006, respectively.

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Table 3. Predict druggability parameters using SwissADME.
Models
Compound A5
Compound A10
Molecular weight
Num. rotatable bonds
Num. H-bond acceptors
Num. H-bond donors
TPSA
Consensus logPO/W
Log S (ESOL)
GI absorption
BBB permeant
Log KP (skin permeation)
Bioavailability score
Lipinski
422.81 g/mol
421.28 g/mol
5
6
0
5
4
0
52.08 Å2
52.08 Å2
5.40
5.51
–6.25
Low
No
–4.85 cm/s
–6.48
High
No
–4.60 cm/s
0.55
0.55
Yes; 1 violation: MLOGP > 4.15
Yes; 1 violation: MLOGP > 4.15
Among these chalcone–quinoxalin conjugates, compound A5 showed the excellent
potent activity against cancer cells and compound A10 showed the highest selectivity
index. Thus, the preliminary test in the potential application for theoretical biological
activities of these two compounds has been evaluated by SwissADME (http://www.swis-
sadme.ch): a free web tool to predict ADME parameters, pharmacokinetic properties,
drug-likeness, and medicinal chemistry friendliness.
From SwissADME calculation (Table 3), both compound A5 and A10 have good
hydrogen bonds donor and acceptor. According to Lipnski’s rule of five poor absorption
or permeation is more likely when there are more than 5 H-bond donors and 10 H-
bond acceptors.[23] Topological polar surface area (TPSA) used for optimization of
drug’s ability to permeate cell, molecule with TPSA less than 140 Å2 have good perme-
ating cell membranes.[24] Compounds A5 and A10 had the same TPSA with 52.08 Å2,
indicating that compounds A5 and A10 could permeate cell membranes. Log PO/W val-
ues of compounds A5 and A10 were slight high according to Lipnski’s rule of five,
which require that the Log PO/W value should be less than 5.[23] Predictions of water
solubility (Log S) of the compounds revealed that the compounds A5 as well as A10
had poor water solubility. Pharmacokinetics studies indicated that compound A5 had
low GI absorption (gastrointestinal absorption) and compound A10 had high GI
absorption, both of them could not permeate BBB (blood brain barrier). Based on these
data, it could be concluded that compound A5 and A10 may be not suitable for oral
administration. The skin permeation (Log KP) of compounds A5 and A10 were ꢀ4.85
and ꢀ4.60 cm/s, respectively. Finally, both compounds A5 and A10 partially obeyed the
Lipinski’s rule of five (1 violation, MLOGP > 4.15), and we thought that the introduc-
tion of hydrophilic group to these chalcone–quinoxalin conjugates may obtain better
antitumor lead compound.
Experimental
Materials
The melting points of title compounds were recorded on an XT-4 binocular microscope
1
13
melting point apparatus (Beijing Tech Instrument Co., China, uncorrected). H,
C
19
and F NMR data were collected on a Bruker Avance III 400 MHz NMR (Bruke Ltd.,
Switzerland) and JEOL-ECX 500 MHz NMR (JEOL Ltd., Japan) using DMSO-d6 and

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X. MA ET AL.
CDCl3 as a solvent and TMS as an internal standard. The following abbreviations were
used to designate chemical shift multiplicities, s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet, and brs ¼ broad singlet. Reaction progress was monitored
with thin-layer chromatography (TLC) on silica gel GF254. Column chromatographic
purification was carried out using silica gel 200 to 300 mesh. All reagents were pur-
chased from Aladdin Chemicals Co. (Shanghai, China), the solvents were of analytical
reagent grade and were used without further purification.
Chemicals
Synthesis of intermediates 1a–1q and 2a–2f
To a mixture of 20 mmol 4-hydroxyacetophenone (4-hydroxybenzaldehyde) and
20 mmol corresponding aromatic aldehyde (aromatic ketone) in 70 mL of ethanol was
added 0.8 g (20 mmol) of sodium hydroxide, and stirred at room temperature for 12 h,
upon reaction completion (monitored by TLC), the mixture was then acidified by drop-
wise addition of aqueous HCl, filtered, washed, and dried to obtain intermediates 1a–1q
and 2a–2f. Intermediates 1a–1q and 2a–2f are known compounds, and they were char-
acterized by melting point.[22]
General synthetic procedures for compounds A1–A17 and B1–B6
As shown in Scheme 1, A round-bottomed flask equipped with a magnetic stirrer was
charged with intermediates 1a–1q or 2a–2f (1.0 mmol), potassium hydroxide (1.1 mmol)
and DMF (5 mL). The reaction mixture was stirred at room temperature for 1 h, and a
solution of 2,6-dichloroquinoxaline (1.0 mmol) in DMF (5 mL) was added to the mix-
ture, warmed to 80 ꢁC, and stirring was continued for 4–6 h. Upon reaction completion
(indicated by TLC), followed by dropwising addition of cold saturated salt solution, the
solid was filtered off, and washed with cold water. Then the crude product was recrys-
tallized from methanol, filtered, washed, and dried to obtain the title compounds
A1–A17 and B1–B6. The properties and analytical data for these compounds are shown
in the supporting information.
Cytotoxic activity assay
The synthetic compounds and reference compound were evaluated for their cytotoxic
activities against BPH-1, PC12, MCF-7 and HEK-293 in vitro employing MTT assay,
which was performed according to reported methods.[4d,25] This colorimetric assay is
based on the conversion of the yellow tetrazolium bromide (MTT) to a purple formazan
derivative by mitochondrial succinate dehydrogenase in viable cells.
BPH-1, PC12 and MCF-7 cell lines were obtained from the American Type Culture
Collection (ATCC, USA), HEK-293 was purchased from iCell Bioscience Inc. (Shanghai,
China). The cells were cultured in 96-well tissue culture plate with high-glucose
Dulbecco’s modified eagle medium (DMEM) supplemented with 10% fetal bovine
serum (FBS). 24 h after seeded, cells were treated with different concentration of com-
pounds A1–A17 and B1–B6 respectively and incubated at 37 ꢁC with 5% CO2 for 24 h.
Then 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was

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added to each well with a final concentration of 0.5 mg/mL. After additional incubation
for 4 h, DMSO in volume of 200 mL was added to each well to dissolve the blue crystal.
The colorimetric assay is measured and recorded at absorbance of 570 nm using a
microplate reader (Bio-Rad, USA). Each experiment was conducted in triplicate repeat.
Conclusions
In summary, we have synthesized twenty-three quinoxaline–chalcone conjugates, the
structures of these compounds were characterized by spectroscopic methods including
1H NMR,13C NMR, 19F NMR and element analysis. The in vitro anticancer activity of
these compounds was evaluated by MTT assay against BPH-1, PC12 and MCF-7, all the
synthesized conjugates exhibited moderate to good anticancer activity and the chalco-
ne–quinoxalin conjugates having fluorine atom in the A ring or B ring of chalcone moi-
ety exhibited excellent activity. In addition, compound A10 showed relatively high
selective cytotoxicity for cancer cell lines with respect to normal HEK-293 cell, and
cytotoxicity study on cancer cells and normal cell along with the SwissADME prediction
suggested that quinoline-chalcone conjugates could be promising lead compounds for
further development of anticancer agents.
Funding
This work was supported by the National Key Research and Development Program of China
[grant number 2017YFD0201404], Doctor of Management of Guizhou Education University
[grant number 2017BS006], the Chunhui Project of Ministry of Education [grant number
[2013]2213] and the Construction Project of Key Laboratories from the Education Department of
Guizhou Province [grant number QJHKY[2018]001].
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