Bioorganic Chemistry 98 (2020) 103748

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Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg

Synthesis and anti-inflammatory evaluation of new chalcone derivatives T

bearing bispiperazine linker as IL-1β inhibitors
Yan-Ling Tanga,1, Xi Zhengb,1, Yan Qib, Xiao-Jia Pua, Bei Liua, Xia Zhanga, Xiao-Si Lia,
Wei-Lie Xiaoc, , Chun-Ping Wanb, , Ze-Wei Maoa,
⁎ ⁎ ⁎

a
College of Pharmaceutical Science, Yunnan University of Chinese Medicine, Kunming 650500, PR China
b
Central Laboratory, The NO.1 Affiliated Hospital of Yunnan University of Chinese Medicine, Kunming 650021, PR China
c
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan
University, Kunming 650091, PR China

ARTICLE INFO ABSTRACT

Keywords: In this work, a series of novel chalcone derivatives bearing bispiperazine linker have been synthesized and in
Chalcone derivatives vitro anti-inflammatory, cytotoxic activity and anti-inflammatory mechanism have been screened. The results
Anti-inflammatory activity indicated that most bispiperazinochalcone derivatives displayed good inhibition of NO (IC50 < 20 μM) and low
Cytotoxicity cytotoxicity (CC50 > 40 μM), and selectively inhibited the production of IL-1β via inhibiting NLRP3 in-
IL-1β inhibitors
flammasome activation, as promising candidate compounds for the treatment of NLRP3 inflammasome-driven
diseases.

1. Introduction participating in the innate immune system to initiate downstream in-

Inflammation is a biological protective response of immune system
tissues to harmful stimuli including injuries and infections [1]. In-
flammation plays a vital role in the pathogenesis of several diseases
involving rheumatoid arthritis, autoimmune disease, lupus er-
ythematosus, neurodegenerative diseases, colitis and cancer [2]. Many
pro-inflammatory cytokines are released during inflammatory response,
such as nitric oxide (NO), interleukin-1β (IL-1β) [3], interleukin-6 (IL-
6) [4], interleukin-17 (IL-17) [5], cyclooxygenase-2 (COX-2) [6], tumor
necrosis factor alpha (TNF-a) [7] so on. However, when excess release
of pro-inflammatory mediators can result in various inflammatory dis-
eases. Although commercial and traditional non-steroidal anti-in-
flammatory drugs (NSAIDs) are commonly used in clinical treatment,
NSAIDs demonstrate various side-effects including gastrointestinal,
renal, hepatic toxicity and cardiovascular [8,9]. Therefore, it remains
an urgent challenge in medical diagnostics and therapeutic to develop
high-effect and low-toxicity drugs for the treatment of inflammation.
Inflammasomes are innate immune sensors that regulate the acti-
vation of inflammatory caspases in response to pathogen- and damage-
associated molecular patterns (PAMPs and DAMPs, respectively), and
maintain immune homeostasis ultimately. The NLRP3 inflammasome is
one kind of germline-encoded pattern recognition receptor
flammatory cascades [10]. Activators, including damage-associated
molecular patterns, initiate the assembly of NLRP3 inflammasome
complexes, leading to Caspase-1 (CASP1) activation. Caspase-1 pro-
cesses pro-inflammatory cytokines into their biologically active and
secreted forms (for example, it processes pro-interleukin 1β (pro-IL-1β)
into IL-1β) [11].These reports indicated that NLRP3 inflammasome
may be as a potential target for developing new anti-inflammatory drug
for the treatment of inflammatory and NLRP3 inflammasome-driven
diseases.
Chalcones (1,3-diaryl-2-propen-1-ones), consisting of two aromatic
rings through a three-carbon α, β-unsaturated carbonyl system, are
precursors for flavonoid and isoflavonoids, which can be found in many
medicinal and edible plants possessing several biological activities in-
cluding anti-Alzheimer's, anticancer, anti-inflammatory, antioxidant,
antibacterial and improving immunity properties [12–14]. Recent re-
searches indicated that chalcone derivatives could inhibit secretion of
phospholipase A2, COX, pro-inflammatory cytokines and so on [15,16].
For example, Licochalcone A was able to suppress production of IL-6
and TNF-α in immature monocyte derived human dendritic cells sti-
mulated with lipopolysaccharide [17]. Ban et al reported that meth-
oxychalcone could inhibit production of LPS-induced NO and TNF-α in
RAW 264.7 macrophages (Scheme 1) [18]. Thus, chalcones are playing

⁎
Corresponding authors.
E-mail addresses: xiaoweilie@ynu.edu.cn (W.-L. Xiao), wanchunping1012@163.com (C.-P. Wan), maozw@ynutcm.edu.cn (Z.-W. Mao).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.bioorg.2020.103748
Received 14 October 2019; Received in revised form 5 March 2020; Accepted 9 March 2020
Available online 10 March 2020
0045-2068/ © 2020 Elsevier Inc. All rights reserved.
Y.-L. Tang, et al.
Scheme 1. Design of novel bispiperazinochalcone compounds.
vital role in medicine research due to flexible skeleton and potential
biological activities.
Heterocycles are an important class of compounds having versatile
biological activities, which are used as building blocks in medicinal
compounds and functional materials. Among them, piperazine re-
presents a typical important organic unit that has attracted much more
interests in chemistry and pharmacology. Recently, there were much
more reports about piperazine linker compounds for good anti-in-
flammatory, antibacterial and anti-tumor activities [19,20]. For ex-
ample, dipiperazinociprofloxacin and bispiperazinobenzofuran deriva-
tives exhibited excellent inhibitory activity against cancer cells (Scheme
1) [21,22].
In previous work, we have reported the synthesis and biological
evaluation of a series of chalcone derivatives [23,24]. Among them, N-
heterocyclic substituted hybrids displayed good significant inhibitory
effect on the generation of NO in LPS-induced RAW 264.7, and piper-
azinochalcone significantly inhibited the production of TNF-α (Scheme
1) [25]. As an extension to that study, in this work we intended to focus
on the synthesis of chalcone derivatives bearing bispiperazine linker,
the anti-inflammatory activities and the effect on pro-inflammatory
cytokines (IL-1β, IL-6 and TNF-α).
2. Results and discussion
2.1. Chemistry
The general synthetic route of target molecules was shown in
Scheme 2. Piperazinochalcone 1 was prepared from 4-dimethylamino-
benzaldehyde and 4-fluoroacetophenone according to our previous
work [22–25]. Compound 2 was formed by condensation reactions
between compound 1 and chloracetyl chloride. Subsequently, the key
intermediate 3 was prepared by substitution with 2 and piperazine in
2
Bioorganic Chemistry 98 (2020) 103748
reflux EtOH. Finally, two series of chalcone derivatives (4, 5) possessing
piperazine linker were synthesized in turn by reaction of compound 3
with the corresponding acyl chloride and alkyl halides in good yields. In
addition, anti-inflammatory activities of novel chalcone analogues were
carried out. Comparative data for new derivatives with respective to
structures, formula, melting point and yields were outlined in Table 1.
2.2. Pharmacology
2.2.1. Anti-inflammatory activity
It is well-known that NO is an important pro-inflammatory med-
iator, and NO release is correlated with inflammatory. Excessive gen-
eration of NO has been found in playing an important role in many
inflammatory diseases [26]. In order to evaluate the anti-inflammatory
activity of synthetic compounds, RAW 264.7 cells is widely used in
screening anti-inflammatory agents as effective cell inflammatory
model. In present work, we investigated in vitro anti-inflammatory ac-
tivity of synthetic derivatives in LPS-induced RAW 264.7 on the pro-
duction of NO. The results of title compounds were summarized in
Table 1.
From the results, we could see that most bispiperazinochalcone
derivatives exhibited excellent anti-inflammatory activities. Among two
series of title compounds, hybrids 3a, 3b, 4a-4d, 4f-4h, 4j, 4o, 4p, 5a-
5g, 5i, 5k and 5s-5u displayed moderate inhibition of NO compared to
that of the positive control Dexamethasone (IC50 < 20 μM). Especially,
the IC50 value of 4a and 4b was 0.42 and 0.82 μM, respectively. The
preliminary SAR analysis indicated that the type of bispiper-
azinochalcone derivatives has an obvious influence on anti-in-
flammatory activities as well as the linkers of bispiperazine.
In general, anti-inflammatory activities of amides and propionamide
linker were superior to that of tertiary amines and acetamide, respec-
tively. Moreover, the substituents of the NH group of piperazine ring
Y.-L. Tang, et al.
Scheme 2. Synthetic routes of bispiperazinochalcone derivatives.
had an obvious influence on NO release. To our delight, the electron-
donating group and conjugated structure were beneficial to the anti-
inflammatory activity. For example, compounds 4f, 4h, 4j, 5g, 5i and
5k could inhibit the NO generation significantly and the IC50 value was
equivalent to Dexamethasone.
2.2.2. Assessment of toxicity
Preliminary anti-inflammatory activity results showed that many
derivatives had good inhibitory effect on the NO release. In addition, in
order to study the cytotoxic effect on normal cells, we evaluated the
cytotoxicity of all compounds by MTT assay on the normal macrophage
cell line (RAW264.7). As shown in Fig. 1, the results showed that CC50
value of most hybrids was above 40 μM on the survival of RAW264.7
cells, which displayed weak toxicity. On the other hand, there was
nonobvious distinction on the toxicity of two amide linker compounds.
Among all synthetic compounds, derivatives 3b, 5d, 5f, 5g, 5i and 5k
show lower cytotoxicity, which could be considered as the potential
anti-inflammatory agents.
2.2.3. Mechanism of anti-inflammatory activity
Increasing evidence have demonstrated that the inflammasome
pathway involved inflammatory response in sepsis. Upon the cellular
infection or stress, promoted the inflammasome activated and the pro-
inflammatory cytokines maturation and secretion, such as IL-1β, to
engage innate immune defenses. Based on the elementary screening
results of anti-inflammatory activity and cytotoxicity, to further study
the role of compounds in LPS-induced inflammation, we determined the
level of inflammatory cytokines in LPS -Stimulated RAW264.7 macro-
phage cell line. The results indicated that compounds 3b, 5g and 5k
could markedly inhibited LPS-induced inflammatory cytokine IL-1β
production in a dose-dependent manner (Table 2), however, have no
influence on the secretion of inflammatory cytokine TNF-α and IL-6β,
suggesting that the inhibitory ability against IL-1β of compounds 3b, 5g
and 5k is selectivity. Currently, the NLRP3 inflammasome is the most
studied inflammasome. The NLRP3 inflammasome is a cytosolic protein
complex, it composed of NLRP3, caspase-1, and ASC, and assembled to
form an activity protein complex in response to both microbial infection
and endogenous “danger signal”. Recently, nigericin was considered as
an activator of NLRP3 inflammasome. To further investigate the effect
of compounds 3b on NLRP3 inflammasome activation and IL-1β ma-
turation secretion, we elucidated the activity characteristics of com-
pounds 3b on against the inflammasome activation in Nigericin-in-
duced mouse peritoneal macrophages. The results demonstrated that
compounds 3b significantly suppressed Nigericin-induced
3
Bioorganic Chemistry 98 (2020) 103748
inflammatory cytokine IL-1β production. Western blot assay showed
that pretreatment with compounds 3b also decreased NLRP3 protein
expression and caspase-1 cleavage (Fig. 1), implying that compounds
3b represents a new anti-inflammatory drug for treatment of NLRP3
inflammasome-associated disease.
2.2.4. Effect on collagen induced-arthritis in DBA/1 mice model
Pro-inflammatory cytokines (such as IL-1β) are abundantly ex-
pressed in the arthritic joints of mice, blockade of these factors is ef-
fective in reducing the severity of disease. From above study, chalcone
derivatives could significantly suppress inflammatory cytokine IL-1β
production, thus we performed the continuous investigation to study
effect on collagen induced-arthritis in DBA/1 mice model. The pre-
liminary histopathological analysis results indicated that arthritis sy-
novitis, lymphocyte infiltration and joint loss had no change after
treatment of 3a (40 mg/kg) and 3b (40 mg/kg). Therefore, oral min-
istration of 3a and 3b had no influence on clinical score in collagen-
induced arthritis (Supporting Information). In the following study,
more inflammatory models will be performed.
3. Conclusions
In summary, two series of novel chalcone derivatives bearing bis-
piperazine linker have been synthesized and in vitro anti-inflammatory,
cytotoxic activity and anti-inflammatory mechanism have been
screened. The results indicated that the amide linker of compounds had
an obvious influence on anti-inflammatory activities. Especially, deri-
vative possessing propionamide linker displayed better inhibitory effect
on LPS-induced inflammatory cytokine IL-1β production and low cy-
totoxic activity, respectively. The results of mechanism study demon-
strated that bispiperazinochalcone derivatives could selectively inhibit
the production of IL-1β via inhibiting NLRP3 inflammasome activation,
which could be considered as IL-1β inhibitors. Further research is
currently undergoing and the results will be reported in due course.
4. Experimental section
4.1. Chemistry
Starting chemical reagents were analytically pure and used without
purification. All reactions were monitored by analytical thin layer
chromatography (TLC) on silica gel plates GF254 (Qingdao Haiyang Inc.
China). Column chromatography was performed with silica gel
(200–300 mesh). Melting points were measured on a YANACO
Y.-L. Tang, et al. Bioorganic Chemistry 98 (2020) 103748

Table 1
Structures and biological results of derivatives.
Compound R M. p (°C) Yields (%)a NO generation (IC50, μM) RAW 264.7 cell (CC50, μM)

3a H 158–160 86 15.43 > 40

3b H 166–168 72 10.29 > 40
4a 170–173 80 0.42 1.81

4b 154–156 86 0.82 4.28

4c 181–183 85 7.11 20.79

4d 190–192 78 4.34 20.71

4e 167–169 84 24.37 > 40

4f 201–203 75 11.54 > 40

4g 151–153 85 15.45 > 40

4h 156–158 87 11.92 > 40

4i 183–185 84 > 40 > 40

4j 191–193 82 10.23 > 40

4k 179–181 80 > 40 > 40

4l 193–195 74 36.45 > 40

4m 177–179 72 18.58 34.22

4n 146–148 90 29.38 > 40

4o 203–205 82 6.05 23.67

4p 190–192 80 9.41 20.97

4q 172–174 84 23.50 > 40

4r 169–170 72 > 40 > 40

4s 168–170 82 > 40 > 40

4t 199–201 84 > 40 > 40

4u 209–211 69 > 40 37.06

4v 212–213 74 > 40 > 40

5a 163–165 76 4.55 8.17

5b 169–171 82 4.04 9.03

5c 143–145 86 15.79 > 40

5d 152–154 85 6.07 > 40

5e 177–178 82 13.68 > 40

5f 188–190 74 7.98 > 40

(continued on next page)

4
Y.-L. Tang, et al. Bioorganic Chemistry 98 (2020) 103748

Table 1 (continued)

Compound R M. p (°C) Yields (%)a NO generation (IC50, μM) RAW 264.7 cell (CC50, μM)

5g 207–209 72 3.07 > 40

5h 173–175 86 28.11 > 40

5i 184–186 80 6.44 > 40

5j 200–202 78 > 40 > 40

5k 199–201 80 8.67 > 40

5l 181–183 76 > 40 > 40

5m 176–178 82 > 40 > 40

5n 169–171 84 > 40 > 40

5o 141–143 88 > 40 > 40

5p 176–178 75 18.69 17.76

5q 174–176 84 28.94 > 40

5r 163–165 82 30.56 > 40

5s 193–195 78 5.26 11.64

5t 177–179 72 3.72 14.51

5u 182–184 80 6.72 21.35

dexamethasone – – – 10.80 ND

a
Isolated yields. ND: not determined.

microscopic melting point meter and were uncorrected. 1H NMR and
13
C NMR spectra were recorded on a Bruker Avance 400 MHz spec-
trometer, using Tetramethylsilane (TMS) as internal standard and
DMSO‑d6 or CDCl3 as solvent, respectively. High-resolution mass
spectrometry (HRMS) was performed on an Agilent LC/MSD spectro-
meter.
4.1.1. Synthesis of the key intermediates 3a and 3b
To a stirred solution of compound 1 [25] (3.35 g, 10 mmol) and
K2CO3 (2.76 g, 20 mmol) in anhydrous CH2Cl2 (40 mL), chloroacetyl
chloride (1.36 g, 12 mmol) or chloropropanoyl chloride (1.52 g,
12 mmol) was added and left to react for 5 h at room temperature. After
completion of the reaction as indicated by TLC (2% CH3OH/DCM), the
reaction was quenched by the addition of diluted NaOH (30 mL) and
was extracted with CH2Cl2 (3 × 20 mL). The organic layer was dried by

Fig. 1. Compound 3b inhibited LPS-induced NLRP3

inflammasome activation and IL-1β production.
Mouse peritoneal macrophages were pretreated
with Compound 3b (4 mM, 8 mM) for 2 h, fol-
lowing stimulated LPS(100 ng/ml) for 3 h, then
cultured with nigericin (10 µM) for 45 min. (A) The
culture supernatants were harvested to detect the
level of IL-1β using ELISA assay; (B) The cells ly-
sates were immunoblotted with specific antibodies.
Results presented are mean ± s.e.m, n = 3. *
P < 0.05, ** P < 0.01 versus LPS + nigericin
group.

5
Y.-L. Tang, et al. Bioorganic Chemistry 98 (2020) 103748

Table 2
The effect of compound 3b, 5g and 5k on inflammatory cytokine production in LPS-stimulated RAW264.7 macrophage cell line.
No Conc. (µM) Inhibitory rates (%)a

IL-1β (pg/mL) (%) TNF-α (pg/mL) (%) IL-6β (pg/mL) (%)

Control 2.44 ± 0.05 267 ± 4 18 ± 0.5

38.24 ± 0.13 785 ± 5 3161 ± 21
3b 2 27.96 ± 0.95 −26.90 803 ± 17 2.37 3504 ± 25 10.83
4 20.99 ± 0.31 −45.15 799 ± 10 1.77 3179 ± 93 0.58
8 16.30 ± 0.60 −57.39 777 ± 13 −0.93 3073 ± 107 −2.80
5g 2 31.69 ± 0.41 −17.14 777 ± 10 −0.96 3264 ± 39 3.27
4 28.94 ± 0.12 −24.34 794 ± 17 1.20 3497 ± 22 10.61
8 24.77 ± 0.23 −35.24 805 ± 15 2.56 3528 ± 14 11.59
5k 2 36.01 ± 0.82 −5.84 760 ± 5 −3.10 2974 ± 55 −5.93
4 24.73 ± 1.1 −35.35 765 ± 3 −2.53 3144 ± 11 −0.56
8 22.18 ± 0.39 −42.03 779 ± 17 −0.76 3255 ± 21 2.95

a
The ‘-’ indicates samples had inhibition activity, ≥15% showed the sample was effective.

anhydrous Na2SO4, concentrated in vacuo. The residue was dissolved in
CH3CN (40 mL), Et3N (2 mL) and piperazine (1.72 g, 20 mmol) was
added, and the mixture was reflux overnight. After the reaction is
completed, the mixture was poured in cold water (100 mL) and ex-
tracted with CH2Cl2 (3 × 20 mL). The organic layer was dried by an-
hydrous Na2SO4, concentrated in vacuo and purified by column chro-
matography (4% CH3OH/DCM) to afford 3a and 3b, respectively.
4.1.2. General procedure for the preparation of title derivatives 4 and 5
To a stirred solution of compound 3a or 3b (0.2 mmol) and K2CO3
(70 mg, 0.5 mmol) in dry DCM (5 mL), acyl chloride or halogenoalkane
(0.3 mmol) was added and stirred for 2–12 h at rt. After completion of
the reaction as indicated by TLC (5% CH3OH/DCM), the reaction was
quenched by the addition of diluted Na2CO3 (10 mL) and extracted with
CH2Cl2 (3 × 5 mL). The organic layer was dried using anhydrous
Na2SO4, concentrated in vacuo and purified by column chromato-
graphy (2% CH3OH/DCM) to afford respective title products.
4.2. Anti-inflammatory activity
Murine RAW264.7 macrophages were plated in 96 well plate at a
density of 1 × 105 cells/well and stimulated with 1 μg/mL LPS in the
present or absence of various concentration of compound for 24 h, the
production of NO was determined by assaying culture supernatant for
NO2−. 100 μL of supernatant was mixed with an equal volume of Griess
reagent at rt for 10 min. Absorbance was measured at 540 nm in a
microplate reader.
4.3. Assessment of toxicity
The assay was carried out using the method previously described
[22,23]. About 1 × 104 cell/well were seeded into 96-well microtiter
plates. After twenty-four hours post-seeding, cells were treated with
vehicle control or various concentrations of samples for 48 h. 20 μL of
MTT solution (5 mg/mL) was added to each well and the RAW 264.7
cell was incubated at 37 °C in a humidified atmosphere of 5% CO2 air
for 4 h. Upon removal of MTT/medium, 150 μL of DMSO was added to
each well and the plate was agitated at oscillator for 5 min to dissolve
the MTT-formazan. The assay plate was read at a wavelength of 570 nm
using a microplate reader.
The production of NO was determined by assaying culture supernatant
for NO2−, a stable reaction product of NO, 100 μL of supernatant was
mixed with an equal volume of Griess reagent at room temperature for
10 min. Absorbance was measured at 540 nm in a microplate reader.
Nitrite concentration was calculated from a NaNO2 standard curve. For
the cytokines detection, culture supernatants were harvested at 36 h to
measure TNF-α, IL-6 and IL-1β level by ELISA following the manu-
facture’s instruction.
4.5. The effect on collagen induced-arthritis in DBA/1 mice
Collagen was dissolved in 0.1 M acetic acid at 4 °C overnight. Male
DBA/1 mice were immunized at the tail base with 125 µg of collagen
emulsified in Freund’s complete adjuvant (CFA) containing
Mycobacterium tuberculosis strain H37Rv. Each mouse was then
boosted with the same amount of collagen plus CFA 21 days later (taken
as Day 0). Starting from Day 9 for 10 consecutive days, the mice were
administered daily with 3a (40 mg/kg) or 3b (40 mg/kg) by p.o.
The severity of arthritis were assessed daily and expressed as the
clinical score according to the following scale: [0 = normal; 1 = er-
ythema or swelling of one or several digits; 2 = erythema and moderate
swelling extending from the ankle to the mid-foot (Tarsal); 3 = er-
ythema and severe swelling extending from the ankle to the metatarsal
joints; and 4 = complete erythema and swelling encompassing the
ankle, foot and digits, resulting in deformity and/or ankylosis]. The
scores of four limbs were summed and maximum score for each animal
was 16.
Upon sacrificing the mice, joints were fixed with 4% formalin, fol-
lowed by decalcification, embedding, sectioning (with a thickness of
5 mm each) and staining with hematoxylin-eosin (H&E).
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgment

4.4. Mechanism of anti-inflammatory activity
Briefly, murine RAW264.7 macrophages (American Type Culture
Collection, Manassas) were plated in 96 well plate at a density of
1 × 105 cells/well and stimulated with 1 μg/ml LPS in the present or
absence of various concentration of compound for 24 h, the culture
supernatant were harvested to measure NO and cytokines production.
This work was financially supported by the National Natural Science
Foundation of China (81960754), the Yunnan Provincial Science and
Technology Department-Applied Basic Research Joint Special Funds of
Yunnan University of Traditional Chinese Medicine (2017FF117(-023),
2017FF117(-041), 2018FF001(009)), and Yunnan Applicative and
Basic Research Program (2018FY001-001).

6
Y.-L. Tang, et al.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bioorg.2020.103748.
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