Hydroxyl- and Halogen-containing Chalcones for the Inhibition of LPS-stimulated ROS Production in RAW 264.7 Macrophages: Design, Synthesis and Structure–Activity Relationship Study

Article abstract of DOI:10.1002/bkcs.11813

Oxidative stress due to overproduction of reactive oxygen species (ROS) plays a major role in inflammation, cancer, and neurodegenerative disorders. In this study, 60 chalcone derivatives with fluorine (F), trifluoromethyl (CF₃), trifluoromethoxy (OCF₃), chlorine (Cl), and bromine (Br) in ring A and with or without hydroxy (OH) in ring B were designed, synthesized, and screened for inhibitory activity against lipopolysaccharide (LPS)-stimulated ROS production in RAW 264.7 macrophages. Structure–activity relationship study revealed the importance of a hydroxyl moiety in ring B for enhancing inhibitory activity of ROS production. Furthermore, a hydroxyl group at the ortho-position is more essential for inhibition of ROS production followed by meta- and para-positions. Among all, compound 27 that contains para-chlorine moiety in ring A and ortho-hydroxy in ring B displayed the strongest inhibitory activity (IC₅₀ = 3.42 μM) against LPS-stimulated ROS production in RAW264.7 macrophages.

Full text of DOI:10.1002/bkcs.11813

Article
DOI: 10.1002/bkcs.11813
BULLETIN OF THE
A. Shrestha et al.
KOREAN CHEMICAL SOCIETY
Hydroxyl- and Halogen-containing Chalcones for the Inhibition
of LPS-stimulated ROS Production in RAW 264.7 Macrophages:
Design, Synthesis and Structure–Activity Relationship Study
†
†
*
*
Aarajana Shrestha, Aastha Shrestha, Pil-Hoon Park, and Eung-Seok Lee
College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
*E-mail: parkp@yu.ac.kr; eslee@yu.ac.kr
†These authors contributed equally to this work.
Received March 8, 2019, Accepted May 10, 2019
Oxidative stress due to overproduction of reactive oxygen species (ROS) plays a major role in inflamma-
tion, cancer, and neurodegenerative disorders. In this study, 60 chalcone derivatives with fluorine (F),
trifluoromethyl (CF3), trifluoromethoxy (OCF3), chlorine (Cl), and bromine (Br) in ring A and with or
without hydroxy (OH) in ring B were designed, synthesized, and screened for inhibitory activity against
lipopolysaccharide (LPS)-stimulated ROS production in RAW 264.7 macrophages. Structure–activity rela-
tionship study revealed the importance of a hydroxyl moiety in ring B for enhancing inhibitory activity of
ROS production. Furthermore, a hydroxyl group at the ortho-position is more essential for inhibition of
ROS production followed by meta- and para-positions. Among all, compound 27 that contains para-
chlorine moiety in ring A and ortho-hydroxy in ring B displayed the strongest inhibitory activity
(IC50 = 3.42 μM) against LPS-stimulated ROS production in RAW264.7 macrophages.
Keywords: Chalcone, Halogen substitution, Hydroxy substitution, Inhibition of reactive oxygen species
production, RAW 264.7 macrophages
Introduction
by α,β-unsaturated ketone bridge which allow structural
modification to design novel bioactive compounds. Its sim-
ple structure, low molecular weight, synthetic chemistry,
and broad pharmacological importance10,11 such as
anticancer,12 antioxidant,13 antibacterial,14 antifungal,15
antiviral,16 and anti-inflammatory17–19 effect have increased
scientific interest in the field of drug discovery. Many stud-
ies on natural, semi-synthetic, and synthetic chalcone ana-
logs have reported their significant anti-inflammatory
activity that inhibit potential targets, such as prostaglandins
(PGs), lipoxygenase (LOX), cyclooxygenase (COX), inter-
leukins (IL), leukotriene D4 (LTD4), and nitric oxide
synthase (NOS).18
Many chalcone derivatives substituted with hydroxy and
halogen moiety in ring A and/or B (Figure 1) were reported
to enhance anti-inflammatory effect by inhibiting various
molecular targets.20–23 In addition, presence of bulky and
highly electronegative halogen atoms like fluorine, chlorine,
and bromine tend to increase lipophilicity of compounds
and occupy large space of deeper targets aiding improve-
ment in therapeutic effect.24,25 Moreover, many researchers
are interested to substitute fluorine containing atoms due to
its exclusive physio-chemical properties, such as its influ-
ence in pKa, membrane permeability, metabolic resistance,
and pharmacokinetic properties.26,27 Similarly, our group
members have also reported hydroxylated chalcones
substituted with thienyl, furyl, and halogen moieties that
showed significant inhibitory activity of ROS
During normal phenomena of catabolism and aerobic respi-
ration, there is a partial reduction of oxygen to form hyper-
active radicals such as superoxide radical, hydrogen
peroxide, hydroxyl radical, and peroxyl radical which are
grouped as reactive oxygen species (ROS).1,2 The limited
dose of these reactive intracellular signals is beneficial in
various biological responses in order to maintain homeosta-
sis.3 However, the overproduction of ROS due to failure in
antioxidant defense system are detrimental for cells and tis-
sues as it causes oxidative stress and damage to DNA, pro-
teins, membrane lipids, and lipoproteins.4,5 This deleterious
effect by excessive ROS has been reported to be involved
in etiology of various physiological disorders such as
inflammation, neurodegenerative and cardiovascular dis-
eases, aging, and cancer.6 Macrophages are innate immune
cells which produce necessary amount of ROS in order to
mediate the inflammatory response.7 However, exposure to
bacterial lipopolysaccharide (LPS) can trigger macrophage
to produce excessive amount of ROS leading to adverse
inflammatory conditions.8 Thus, inhibition of excessive
ROS production may be one of the strategies for attenua-
tion of various inflammatory diseases.
Chalcone (1,3-diphenyl-2-propenones, Figure 1) is an
open chain intermediate which is ubiquitously present in
plants as a precursor for the biosynthesis of flavonoids and
isoflavonoids.9 It consists of two aryl rings that are linked
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KOREAN CHEMICAL SOCIETY
Figure 1. Structures of chalcone and its derivatives.
production.28–33 Interestingly, in previous report (Figure 2),
few compounds with hydroxyl moiety in ring A and fluo-
rine functionalities in ring B exhibited strong inhibition of
ROS production.30 Based on the importance of hydroxyl
and halogen moieties in both ring A and B, here in this
study, we systematically designed 60 chalcone derivatives
by interchanging hydroxy group at ring B and fluorine
functionalities including chlorine and bromine moieties in
ring A (Figure 2). This study allowed us to compare inhibi-
tory activity of ROS production by these compounds with
previous work.
In addition, presence of substituted functional groups in
ortho, meta, and para aids to explore structure–activity
relationships (SARs) of hydroxy and halogen containing
chalcones in order to discover safe and effective anti-
inflammatory agent.
Scheme 1. General synthetic representation for the synthesis of
compounds 1–60. Reagents and conditions: (i) 50% aq. KOH,
EtOH, 1–24 h, 25 ꢀC, 14.9 to 99.1% yield.
chalcones (1–15) without hydroxyl moiety. Series B (16–
30), C (31–45), and D (46–60) contain halogenated
chalcones with presence of hydroxyl moiety at ortho, meta,
and para position, respectively. Experimental including
yield, HPLC purities (%), mass and NMR data of the pre-
pared compounds are given in Supporting Information.
All the synthesized compounds 1–60 were evaluated for
their safety and inhibitory activity against ROS production
in LPS-stimulated Raw 264.7 macrophages using Malvidin
(IC50 = 9.0 Æ 0.8 μM)34 as a positive control and data are
tabulated in Tables 1–4.
Results and Discussion
Synthetic Chemistry. Based on reported methods,30,32,33
compounds 1–60 were synthesized by base (50% aqueous
potassium hydroxide) catalyzed Claisen-Schmidt condensa-
tion reaction using aryl methyl ketones (R = a-o) and aryl
aldehydes (R1 = p-s) in ethanol at 25 ꢀC for 1–24 h in yields
ranging from 14.9 to 99.1% (Scheme 1). The synthesized
compounds (Figure 3) were divided into four different series
in order to investigate SARs. Series A contains halogenated
Inhibition of LPS-Stimulated ROS Production by Com-
pounds 1–60 in RAW 264.7 Macrophages. As shown in
Table 1, all the non-hydroxylated series A (1–15) showed
weak inhibition of ROS production in LPS-stimulated
RAW 264.7 macrophages.
Interestingly, among ortho-hydroxylated series B (16–
30), seven compounds (18, 20, 22, 26, 27, 29, and 30)
showed stronger inhibition of ROS production (IC50
= 3.42–8.24 μM) than positive control, malvidin (Table 2).
Moreover, compounds with ortho-trifluoromethoxy, para-
bromine, meta- and para-chlorine moieties in ring A dis-
played significant inhibition of ROS production with IC50
Figure 2. Rational design for hydroxyl and halogen containing
chalcone derivatives.
less than
5
μM (4.87, 4.80, 4.73, and 3.42 μM,
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Article Hydroxyl- and Halogen-containing Chalcones for the Inhibition of LPS-stimulated KOREAN CHEMICAL SOCIETY
Figure 3. Structures of hydroxyl and halogen containing chalcone derivatives.
respectively). On comparison with previous studies30
(Figure 2), some of the compounds with ortho-hydroxyl
group in ring A were reported to be toxic whereas, tested
ortho-hydroxylated series in this study are found to be non-
toxic. In addition, more than half of the compounds dis-
played stronger inhibitory activity of ROS production. This
result indicates that interconversion of functional groups in
ring A and B is essential for exhibiting better inhibitory
activity.
In case of meta-hydroxylated series C (31–45), five com-
pounds (33, 34, 36, 37, and 42) exhibited better inhibition
of ROS production (IC50 = 3.99–8.63 μM) than malvidin
(Table 3). Two compounds 37 and 42 with ortho-
trifluoromethoxy and para-chlorine moieties showed signif-
icant inhibition of ROS production with IC50 less than
5 μM (IC50 = 3.99 and 4.85 μM, respectively). Interest-
ingly, tested compounds 33, 34, and 36 exhibited more
effective inhibitory activity of ROS production than
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Article Hydroxyl- and Halogen-containing Chalcones for the Inhibition of LPS-stimulated KOREAN CHEMICAL SOCIETY
Table 1. Inhibitory activity against LPS-stimulated ROS
production by non-hydroxylated series A in RAW 264.7
macrophages.
Table 2. Inhibitory activity against LPS-stimulated ROS
production by ortho-hydroxylated series B in RAW 264.7
macrophages.
ROS Inhibition (IC50, μM)a Toxicity
Compounds
R
ROS Inhibition (IC50, μM)a Toxicity
Compounds
R
1
2
3
4
5
6
7
8
2-F
3-F
4-F
2-CF3
3-CF3
4-CF3
2-OCF3
3-OCF3
4-OCF3
2-Cl
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2-F
3-F
4-F
2-CF3
3-CF3
4-CF3
2-OCF3
3-OCF3
4-OCF3
2-Cl
>10
9.77 Æ 0.32
8.24 Æ 0.57
>10
6.95 Æ 0.038
>10
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
4.87 Æ 0.074
>10
9
10
11
12
13
14
15
Malvidin
>10
>10
3-Cl
4-Cl
2-Br
3-Br
3-Cl
4-Cl
2-Br
3-Br
4.73 Æ 0.54
3.42 Æ 0.67
>10
6.85 Æ 0.57
4.80 Æ 0.46
4-Br
4-Br
9.0 Æ 0.8
NT, non-toxic.
a Each data represents mean SEM from at least three different
experiments.
NT, non-toxic.
a Each data represents mean SEM from at least three different
experiments.
Table 3. Inhibitory activity against LPS-stimulated ROS
production by meta-hydroxylated series C in RAW 264.7
macrophages.
previously synthesized corresponding compounds.30 In
addition, none of the tested compounds showed toxic
effect, suggesting that these synthesized compounds are
possibly safe to use as compared to previously synthesized
compounds.
Furthermore, as shown in Table 4, among para-
hydroxylated series D, five compounds (48, 52–54, and 59)
Compounds
R
ROS Inhibition (IC50, μM)a Toxicity
showed
better
inhibition
of
ROS
production
(IC50 = 5.52–8.63 μM) than malvidin (Table 3). On com-
parison with para-hydroxylated series30 (Figure 2), tested
compounds 48, 53, and 54 exhibited more effective inhibi-
tory activity of ROS production than previously synthe-
sized corresponding compounds. In addition, all the
synthesized para-hydroxylated series were confirmed to be
non-toxic.
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
2-F
3-F
4-F
2-CF3
3-CF3
4-CF3
2-OCF3
3-OCF3
4-OCF3
2-Cl
>10
>10
8.63 Æ 0.68
5.27 Æ 1.35
>10
6.60 Æ 0.08
3.99 Æ 1.34
>10
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
>10
>10
>10
Structure–Activity Relationship Studies. Introduction of
various halogen functionalities in ring A along with or
without hydroxyl moiety in ring B at ortho, meta, and para
position allowed us to investigate SARs. None of the non-
hydroxylated compounds 1–15 showed significant inhibi-
tory activity (IC50 = >10 μM). Interestingly, on substitution
of hydroxyl moiety in ring B, compounds showed stronger
inhibitory activity than malvidin revealing the importance
of hydroxyl moiety to improve inhibitory potency against
ROS production (Figure 4(a)).
3-Cl
4-Cl
2-Br
3-Br
4.85 Æ 1.25
>10
>10
>10
4-Br
NT, non-toxic.
a Each data represents mean SEM from at least three different
experiments.
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Article Hydroxyl- and Halogen-containing Chalcones for the Inhibition of LPS-stimulated KOREAN CHEMICAL SOCIETY
Table 4. Inhibitory activity against LPS-stimulated ROS
production by para-hydroxylated series D in RAW 264.7
macrophages.
activity than malvidin, out of which two compounds dis-
played significant inhibitory activity with IC50 less than
5 μM. Moreover, five compounds containing para-hydroxyl
group showed better inhibitory activity than malvidin with
IC50 more than 5 μM. These results indicate importance of
hydroxyl moiety in given order: ortho-OH > meta-OH >
para-OH (Figure 4(b)). Interestingly, except compound
7 without hydroxyl group in ring B, all the compounds with
trifluoromethoxy group at the ortho-position showed signif-
icant inhibitory activity than malvidin revealing importance
of ortho-trifluoromethoxy group. As shown in Figure 4(c),
among compounds with ortho-trifluoromethoxy group,
compound 37 with meta-hydroxyl group showed the strong
inhibitory activity (IC50 = 3.99 μM). Among all the synthe-
sized compounds, compound 27 with para-chlorine group
in ring A and ortho-hydroxy group in ring B exhibited the
strongest inhibitory activity (IC50 = 3.42 μM) against LPS-
stimulated ROS production in RAW264.7 macrophages.
Compounds
R
ROS Inhibition (IC50, μM)a Toxicity
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-F
3-F
4-F
2-CF3
3-CF3
4-CF3
2-OCF3
3-OCF3
4-OCF3
2-Cl
>10
>10
6.85 Æ 1.91
>10
>10
>10
5.52 Æ 1.67
8.63 Æ 1.00
7.63 Æ 0.81
>10
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
3-Cl
4-Cl
2-Br
3-Br
>10
>10
>10
Conclusion
In this study, based on importance of hydroxyl moiety and
halogen functionalities, we designed and synthesized
60 chalcones with fluorine (F), trifluoromethyl (CF3),
trifluoromethoxy (OCF3), chlorine (Cl), and bromine
(Br) in ring A and with or without hydroxy in ring B. All
the prepared compounds were evaluated for their inhibitory
activity against LPS-stimulated ROS production in RAW
264.7 macrophages. Compounds 18, 20, 22, 26, 27, 29,
and 30 from ortho-hydroxylated series, 33, 34, 36, 37, and
45 from meta-hydroxylated series and 48, 52–54, and 56
from para-hydroxylated series exhibited strong inhibitory
activity (IC50 = 3.42–8.63 μM) against LPS-stimulated
ROS production in RAW 264.7 macrophages. On compari-
son with previously synthesized compounds with reverse
substitution of ring A and B, synthesized compounds in this
study showed safer and quantitatively stronger inhibition of
ROS production in LPS-stimulated RAW 264.7 macro-
phages. SAR study revealed that ortho- > meta- > para-
hydroxyl group are essential for inhibition of ROS produc-
tion. Among all, compound 27 displayed the strongest
inhibitory activity (IC50 = 3.42 μM) against LPS-stimulated
ROS production in RAW264.7 macrophages. Thus, these
findings would provide valuable information to scientists
who are involved in development of new anti-inflammatory
agents for the treatment of oxidative stress in various
inflammatory diseases.
8.24 Æ 0.71
>10
4-Br
NT, non-toxic.
a Each data represents mean SEM from at least three different
experiments.
On comparing position of hydroxyl group, seven com-
pounds containing ortho-hydroxyl group showed stronger
inhibitory activity than malvidin, out of which four com-
pounds displayed significant inhibitory activity with IC50
less than 5 μM. In case of compounds containing meta-
hydroxyl group, five compounds exhibited better inhibitory
(a)
(b)
(c)
Acknowledgments. This research was supported by the
Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the Minis-
try of Education, Science and Technology (NRF-
2017R1A2B2003944) and the Yeungnam University
Research Grants in 2018.
Figure 4. SAR study based on (a) non-hydroxylated and hydrox-
ylated chalcone derivatives, (b) position of hydroxyl group in
chalcone derivatives, (c) position of hydroxyl group on chalcones
with ortho-trifluoromethoxy moiety in ring A.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
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