Synthesis of Novel Chalcone-Based L-Homoserine Lactones and Their Quorum Sensing Inhibitory Activity Evaluation

Article abstract of DOI:10.1134/S1068162020020132

Abstract: Two novel series of chalcone-based homoserine lactones were synthesized and their quorum sensing (QS) inhibitory activity was evaluated against Pseudomonas aeruginosa in vitro. Furthermore these compounds’ capacity for modulation of the LasR-dependent quorum sensing system of P. aeruginosa was identified. Among these compounds, (S)-2-((4-(3-(4-bromo-2-fluorophenyl) acryloyl) phenyl) amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide exerted the inhibition of LasR-dependent QS system of P. aeruginosa in contrast to brominated furanone C30. Worthy of particular note, this research has delivered novel potent quorum sensing inhibitors (QSIs), which strongly inhibit the production of virulence factors in a wild type strain of this pathogenic bacterium.

Full text of DOI:10.1134/S1068162020020132

ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2020, Vol. 46, No. 2, pp. 139–148. © Pleiades Publishing, Ltd., 2020.
Synthesis of Novel Chalcone-Based L-Homoserine Lactones
and Their Quorum Sensing Inhibitory Activity Evaluation
Chunying Luoa, b, c, Pan Lia, b, c, Haoyue Liua, b, c
,
Pengxia Fenga, b, c, Jieming Lia, b, c, Liutao Zhaoa, b, c, and Chun-Li Wua, b, c, 1
aSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001 China
bKey Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China,
Zhengzhou, 450001 China
cKey Laboratory of Henan Province for Drug Quality and Evaluation, Zhengzhou, 450001 China
Received May 14, 2019; revised June 25, 2019; accepted November 15, 2019
Abstract—Two novel series of chalcone-based homoserine lactones were synthesized and their quorum sens-
ing (QS) inhibitory activity was evaluated against Pseudomonas aeruginosa in vitro. Furthermore these com-
pounds’ capacity for modulation of the LasR-dependent quorum sensing system of P. aeruginosa was identi-
fied. Among these compounds, (S)-2-((4-(3-(4-bromo-2-fluorophenyl) acryloyl) phenyl) amino)-N-(2-oxo-
tetrahydrofuran-3-yl)acetamide exerted the inhibition of LasR-dependent QS system of P. aeruginosa in
contrast to brominated furanone C30. Worthy of particular note, this research has delivered novel potent quo-
rum sensing inhibitors (QSIs), which strongly inhibit the production of virulence factors in a wild type strain
of this pathogenic bacterium.
Keywords: chalcone, L-homoserine lactones, Pseudomonas aeruginosa, QS inhibitors
DOI: 10.1134/S1068162020020132
INTRODUCTION
Based on the widespread biological activity of chal-
cones [13], most previous studies have been focused
on development of analogues of the native AHLs sig-
naling molecules through modifying their acyl side
chains or lactone moieties [14]. However only a few
reports made effort to develop QS inhibitors via the
central amide moieties [15, 16].
Inspired by our previous research on the antiprolif-
erative evaluation of chalcone-based L-homoserine
lactone (HSL) analogues [17], we herein report the
design and synthesis of novel chalcone-containing
AHL derivatives (VIa)–(VIm), as well as evaluation of
their antibacterial activities against the P. aeruginosa
QS system. Furthermore, to investigate the function of
the central amide group, we specifically synthesized
another series of compounds (VIIIa)–(VIIIm) by
inserting one carbon atom between the HSL and acyl
scaffold. In addition, the structure–activity relation-
Diverse species of bacteria employ a mechanism of
intercellular communication known as quorum sens-
ing (QS), which is mediated by small diffusible signal-
ing molecules termed autoinducers. The most com-
mon class of autoinducer used by gram-negative bac-
teria are N-acylhomoserine lactones (AHLs) [1, 2].
Previous studies have shown that N-(3-oxododeca-
noyl)-L-homoserine lactone (C12-HSL) regulates
the production of biofilm and virulence factors,
including elastase and pyocyanin [3–5]. Pseudomonas
aeruginosa is a clinically opportunistic gram-negative
bacterium known to use C12-HSL-mediated QS sys-
tems to regulate a variety of processes associated with
virulence [6, 7]. In the QS system, the production of
several virulence factors by P. aeruginosa can be con-
trolled via density of the cells. Expression of virulence
genes is also connected with las, rhl, and Pseudomonas ship (SAR) and molecular docking study were con-
ducted to explain the mechanism of action of the
QSIS activity of the synthesized compounds. A QSIS2
screening system based on the lasI-sacB reporter [18]
was applied to the detection of P. aeruginosa QS inhib-
itors, and a furanone compound (C30) was chosen as
LasR system positive control, which is an excellent
anti-virulence compound and the most widely studied
in the inhibition of biofilm formation [19, 20]. Also,
the position of substituents was varied in aryl group in
Quinolone Signal (PQS) system [8–11]. LasI directs
the synthesis of C12-HSL in the las QS system. Once
C12-HSL reaches a critical threshold concentration,
it binds to transcriptional regulatory protein LasR [12].
Due to the importance of the Las QS system during
bacterial pathogenesis, many reports have been
focused on inhibition of such systems.
1 Corresponding author: e-mail: kedi2009@126.com.
139

140
CHUNYING LUO et al.
order to obtain more active inhibitors. Biological homoserine lactone analogues (VIa)–(VIm) and
activity of these newly synthesized compounds was
evaluated as of potential QS inhibitors, from which a
preliminary structure–activity relationship (SAR) is
explored.
(VIIIa)–(VIIIm) is exhibited in Scheme 1. The target
compounds were obtained at high yields with the suit-
able reaction conditions of nucleophilic substitution.
In detail, compounds (Va)–(Vm) reacting with com-
pound (III) yielded compounds (VIa)–(VIm), and
compound (II) reacting with the key intermediates
(VIIa)–(VIIm) produced compounds (VIIIa)–
(VIIIm). The structures of compounds (VIa)–(VIm)
and (VIIIa)–(VIIIm) were fully characterized by
RESULTS AND DISCUSSION
Chemistry. L-Homoserine lactone hydrochloride
(III) was synthesized by previously reported methods
[21], and the crucial intermediates (III) and (VIIa)–
(VIIm) were efficiently prepared strictly following the
literature [22, 23]. The synthetic route towards target 1H NMR, 13C NMR, and HRMS.
O
O
H
N
NH2
NH2 · HCl
a
Cl
R
OH
O
(VIa)−(VIm)
O
O
3 steps O
S
O
(III)
O
O
(I)
H
N
(II)
R
c
N
H
O
O
CHO
O
b
R
H2N
(Va)−(Vm)
(IV)
O
O
O
d
R
R
O
Cl
O
H
N
R
N
H
H2N
(Va)−(Vm)
(VIIa)−(VIIm)
e
N
H
O
O
NH2 · HCl
(VIIIa)−(VIIIm)
O
(II)
(IV), (V), (VI), (VII), (VIII) R = 4-Cl (a), R = H (b), R = 4-Br (c), R = 4-Ph (d),
R = 3,5-dichloro (e), R = 2-F,4-Br (f), R = 3,4-dichloro (g), R = 3-OCH3 (h),
R = 2-Cl (i), R = 4-F (j), R = 2-Br (k), R = 4-i-Pr (l), R = 4-t-Bu (m).
Scheme 1.
Biological evaluation. The minimal inhibitory con- concentration at 26.52 μM. Compounds (VId), (VIl),
centrations (MICs) of all compounds were deter- (VIm), and (VIIIa)–(VIIIm) had no obvious antago-
mined and are shown in Table 1. In our experiments nistic activities upon the tested reporter strain.
all the compounds were used at sub-MICs due to the
Compounds (VIa)–(VIm), which all have an
facts that QS inhibition is a result of the interference of
unbroken central amide group, showed varying
bacterial signaling but not the antibacterial activity.
degrees of QSI activities, in contrast, the analogues
All compounds studied were found to have concen-
tration-dependent antagonistic activities. Their abili-
ties to inhibit LasR-dependent QS were also tested in
a P. aeruginosa QSIS2 assay. Their IC50 values are
summarized in Table 2.
(VIIIa)–(VIIIm) with central amide moiety separated
by one carbon atom did not have clear QSI inhibitory
activities. Therefore, we concluded that the central
amide group is an important factor determining the
QS inhibitory activities of these compounds.
As shown in Table 2, in contrast to las system of
P. aeruginosa, compounds (VIa)–(VIc) and (VIe)–
(VIk) exhibited high levels of inhibitory activities with
IC50 values ranging from 26.52 to 67.83 μM. Particu-
larly, compound (VIf) (2-F, 4-Br) was observed to
have the strongest antagonistic activity with the IC50
To explore the structure–activity relationship
(SAR) for the series of compounds in our studies, a
molecular docking was performed by using DOCK 4.0
[14]. The compounds C12-HSL, (VIf), and (VIIIf)
were chosen in the docking simulations with the LasR
structure (PDB entry 3IX3). The C12-HSL binding to
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SYNTHESIS OF NOVEL CHALCONE-BASED L-HOMOSERINE LACTONES
141
Table 1. MIC values (mM) for the strain tested
the LasR from P. aeruginosa can effectively regulate
virulence determinants production. As shown in
Fig. 1a, C12-HSL has three hydrogen bonds to
SER129, TYR93, and THR75 groups, respectively, all
inside the receptor pocket. The docking results of the
compounds (VIf) and (VIIIf) are depicted in Figs. 1b, 1c,
respectively.
The docking results indicate that compound (VIf)
forms a hydrogen bond with SER129 in the catalytic
domain, while compound (VIIIf) forms a hydrogen
bond with ARG61. Clearly, both C12-HSL and the
compound (VIf) bound to LasR through the hydrogen
bonding interaction with the SER129 residue. Giving
that the compound (VIf) partially occupies the space
to that of the natural ligand C12-HSL, the fact may be
responsible for the inhibitory effect.
P. aeruginosa
P. aeruginosa
Compound
Compound
PAO1a QSIS2b
PAO1 QSIS2
(VIa)
(VIb)
(VIc)
(VId)
(VIe)
(VIf)
(VIg)
(VIh)
(VIi)
(VIj)
(VIk)
(VIl)
(VIm)
5
5
5
10
5
2.5
5
5
2.5
5
5
5
5
5
10
5
(VIIIa)
(VIIIb)
(VIIIc)
(VIIId)
(VIIIe)
10
5
2.5
10
5
2.5
5
5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5
2.5 (VIIIf)
5
5
2.5 (VIIIi)
5
5
(VIIIg)
(VIIIh)
(VIIIj)
(VIIIk)
(VIIIl)
(VIIIm)
Compound (VIIIf) is located outside of the recep-
tor pocket, it has lower QS inhibitory activity. Overall,
the docking simulation can provide some possible
basis for the SAR results above.
5
10
5
10
5
5
C30C
In conclusion, two novel series of chalcone-con-
taining homoserine lactone derivatives (VIa)–(VIm)
and (VIIIa)–(VIIIm) were developed, their QS inhib-
itory activities towards P. aeruginosa. were evaluated.
Preliminary SAR studies showed that the central
amide group of these compounds had significant
impact on QS inhibitory activity. Moreover, amino
acid residue SER129 providing binding interaction
with the compound is essential for the QS inhibitory
activity. Further analogue synthesis and SAR studies
are on-going, and the results will be reported in due
course.
2.5
2.5
a P. aeruginosa PAO1 is a wild-type strain.
b QS inhibition selector strain QSIS2 is a P. aeruginosa lasI rhlI
double mutant (PAO-MW1) harboring pLasB-SacB1 encoding
an AHL-inducible killing system.
c C30 (Furanone compound 30) served as the positive control and
acetonitrile served as the negative control.
chromatography with silica gel (300 meshes). The
structures of target compounds were characterized by
NMR (Bruker Avance-400 (400 MHz) spectrometer)
in DMSO-d6 or CDCl3 with TMS as an internal stan-
dard and HRMS (Waters Micromass Q-TOF). Melt-
ing points were determined on X-5 Microdigital melt-
ing point apparatus and reported uncorrected.
EXPERIMENTAL
All commercial reagents, intermediates (Va)–(Vm)
and (VIIa)–(VIIm) were used without further purifi-
cation. The reaction process was monitored by TLC
Synthesis of рomoserine lactone hydrochloride (II).
It was efficiently synthesized from methionine follow-
with silica gel plates (thickness 250 μm, Indicator ing previously reported methods [17, 21]. Therefore,
F-254). The target analogues were purified by column the synthetic details are not discussed here.
(а)
(b)
(c)
Fig. 1. The docking mode of compounds C12-HSL, (VIf), and (VIIIf) with LasR (PDB entry 3IX3). (a) The docking pose of
C12-HSL with LasR. (b) The docking pose of compound (VIf) with LasR. (c) The docking pose of compound (VIIIf) with LasR.
Compounds C12-HSL, (VIf), and (VIIIf) are shown as sticks. Hydrogen bonds sre shown as green balls.
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CHUNYING LUO et al.
Table 2. The substituents and IC50 values of (VIa)–(VIm) and (VIIIa)–(VIIIm) for inhibiting the LasR QS systema
IC50b, μM
IC50, μM
Compound
(VIa)
(VIb)
(VIc)
(VId)
R
Compound
(VIIIa)
(VIIIb)
(VIIIc)
(VIIId)
R
4-Cl
H
4-Br
4-Ph
48.27 2.45
62.54 2.18
46.82 2.12
4-Cl
H
4-Br
4-Ph
NS
NS
NS
NS
NSC
(VIe)
(VIf)
(VIg)
(VIh)
(VIi)
(VIj)
(VIk)
(VIl)
(VIm)
3,5-Cl
56.47 2.30
26.52 0.82
57.82 1.95
56.48 2.17
67.83 2.47
52.19 2.35
37.64 1.26
NS
(VIIIe)
(VIIIf)
(VIIIg)
(VIIIh)
(VIIIi)
(VIIIj)
(VIIIk)
(VIIIl)
(VIIIm)
3,5-Cl
NS
NS
NS
NS
NS
NS
NS
NS
NS
2-F,4-Br
3,4-Cl
3-OCH3
2-Cl
4-F
2-Br
4-i-Pr
4-t-Bu
/
2-F,4-Br
3,4-Cl
3-OCH3
2-Cl
4-F
2-Br
4-i-Pr
4-t-Bu
NS
C30d
17.42 0.89
a See experiment for details of reporter strain and method.
b Values determined by testing compounds over a range of concentration (1–200 μM) against 20 nM C12-HSL. All data are presented as
mean SD (n = 3).
c NS means no significant inhibition.
d C30 (Furanone compound 30) served as the positive control and methanol served as the negative control.
Homoserine lactone hydrochloride (II). Three steps
yield 59%, white solid, T 218–220°С, 20 –27.5°, (c
(S)-2-((4-(3-(4-Chlorophenyl)acryloyl)phenyl)-
amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIa).
[α]D
m
1
Yield 73%, yellow solid, mp 177–179°С. H NMR
0.2, water) [24]. 1H NMR spectrum (DMSO-d6) 9.04
(s, 3H, NH2 ⋅ HCl), 4.45 (t, J = 8.8 Hz, 1H, –O–
CH2), 4.37–4.21(m, 2H, –O–CH2, –CH–CO),
2.62–2.51 (m, 1H, –O–CH2–CH2–CH), 2.42–2.27
(m, 1H, –O–CH2–CH2–CH).
(DMSO-d6): 8.61–8.59 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.02–8.00 (d, J = 8.0 Hz, 2H, Ar-H), 7.96–7.89
(t, 3H, –CO–HC=CH– and Ar-H), 7.64–7.61 (d,
J = 12.0 Hz, 1H, –CO–HC=CH–), 7.52–7.50 (d,
J = 8.0 Hz, 2H, Ar-H), 7.08–7.06 (t, J = 4.0 Hz, 1H,
Ar-NH), 6.66–6.64 (d, J = 8.0 Hz, 2H, Ar-H), 4.66–
4.59 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–CH2–),
4.37–4.32 (t, J = 8.0 Hz, 1H, –CH–NH), 4.22–4.18
(dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–CH2–), 3.85–
3.84 (d, J = 4.0 Hz, 2H, –HN–CH2–), 2.41–2.35 (m,
1H, –O–CH2–CH2–CH), 2.24–2.14 (m, 1H, –O–
Synthesis of intermediates (Va)–(Vm). General
approach. To a solution of 4-aminoacetophenone
(2.0 mmol) dissolved in CH2Cl2 (25 mL), correspond-
ing aldehyde (2.02 mmol) and NaOH (0.12 g, 3.0
mmol) were added. The reaction mixture was stirred at
room temperature overnight. After the reaction fin-
ished, the mixture was poured into 20 mL ice water.
The precipitate was filtrated and washed with water.
The product was dried under vacuum to obtain (Va)–
(Vm) as solid without any further purification.
Preparation of analogues (VIa)–(VIm). General
approach. To a solution of compound (III) (96 mg,
0.54 mmol) dissolved in DMF (10 mL), KI (0.27 g,
1.62 mmol) was added. The reaction mixture was
stirred at 60°С for 2 h. Then compound (Va)–(Vm)
(0.54 mmol) was added to the mixture cautiously, the
mixture was continued to stir at 120°С for another 6 h.
Upon completion (monitored by TLC), the mixture
was extracted with ethyl acetate, washed with water,
dried with anhydrous Na2SO4, and concentrated
under reduced pressure. The residue was purified with
column chromatography to obtain analogues (VIa)–
(VIm) as solid.
CH2–CH2–CH). 13C NMR (DMSO-d6): 186.42,
175.64, 170.15, 153.30, 140.72, 134.95, 134.55, 131.36,
130.76, 129.34, 126.49, 123.53, 112.01, 65.75, 48.39,
46.33, 28.52. HR-MS (ESI) Calcd. for C21H20ClN2O4
[M + H]+: 399.1112, found: 399.1115.
(S)-2-((4-Cinnamoylphenyl)amino)-N-(2-oxotet-
rahydrofuran-3-yl)acetamide (VIb). Yield 64%, brown
1
solid, mp 154–156°C. H NMR(DMSO-d6): 8.59–
8.57 (d, J = 8.0 Hz, 1H, –CO–NH), 8.02–8.00 (d,
J = 8.0 Hz, 2H, Ar-H), 7.93–7.89 (d, J = 16.0 Hz, 1H,
–CO–HC=CH–), 7.87–7.85 (m, 2H, Ar-H), 7.67–
7.63 (d, J = 16.0 Hz, 1H, –CO–HC=CH–), 7.47–
7.43 (m, 3H, Ar-H), 7.02 (brs, 1H, Ar-NH), 6.67–
6.65 (d, J = 8.0 Hz, 2H, Ar-H), 4.66–4.59 (dd, J =
20.0 Hz, J = 8.0 Hz, 1H, –O–CH2–), 4.35–4.33 (t,
J = 8.0 Hz, 1H, –CH–NH), 4.22–4.19 (dd, J = 20.0
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SYNTHESIS OF NOVEL CHALCONE-BASED L-HOMOSERINE LACTONES
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Hz, J = 8.0 Hz, 1H, –O–CH2–), 3.85 (s, 2H, –HN– 7.60–7.56 (d, J = 16.0 Hz, 1H, –CO–HC=CH–),
7.11–7.08 (t, 1H, Ar-NH), 6.66–6.64 (d, J = 8.0 Hz,
2H, Ar-H), 4.66–4.59 (dd, J = 20.0 Hz, J = 8.0 Hz,
1H, –O–CH2–), 4.37–4.33 (t, J = 8.0 Hz, 1H,
‒CH–NH), 4.23–4.18 (dd, J = 20.0 Hz, J = 8.0 Hz,
1H, –O–CH2–), 3.86–3.85 (d, J = 4.0 Hz, 2H,
‒HN–CH2–), 2.42–2.35 (m, 1H, –O–CH2–CH2–
CH2–), 2.41–2.36 (m, 1H, –O–CH2–CH2–CH),
2.25–2.14 (m, 1H, –O–CH2–CH2–CH). C NMR
(DMSO-d6): 186.56, 175.59, 170.13, 153.22, 142.15,
135.56, 131.27, 130.51, 129.31, 129.02, 126.60, 122.77,
112.01, 65.74, 48.39, 46.37, 31.15, 28.54. HR-MS
(ESI) Calcd. for C21H21N2O4 [M + H]+: 365.1501,
found: 365.1504.
13
13
CH), 2.24–2.14 (m, 1H, –O–CH2–CH2–CH). C
NMR (DMSO-d6): 186.17, 175.60, 170.09, 153.47,
139.41, 139.06, 135.03, 131.56, 129.33, 127.45, 126.34,
125.81, 112.01, 65.74, 48.40, 46.32, 28.54. HR-MS
(ESI) Calcd. for C21H19Cl2N2O4 [M + H]+: 433.0722,
found: 433.0724.
(S)-2-((4-(3-(4-Bromophenyl)acryloyl)phenyl)-
amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIc).
1
Yield 58%, yellow solid, mp 164–166 °C. H NMR
(DMSO-d6): 8.61–8.59 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.02–8.00 (d, J = 8.0 Hz, 1H, Ar-H), 7.98–7.94
(d, J = 16.0 Hz, 1H, –CO–HC=CH–), 7.84–7.82 (d,
J = 8.0 Hz, 1H, Ar-H), 7.75–7.73 (d, J = 8.0 Hz, 1H,
Ar-H), 7.66–7.59 (m, 3H, Ar-H and –CO–HC=CH–),
7.07 (brs, 1H, Ar-NH), 6.66–6.64 (d, J = 8.0 Hz, 1H,
Ar-H), 6.60–6.58 (d, J = 8.0 Hz, 1H, Ar-H), 4.64–
4.57 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–CH2–),
4.36–4.32 (t, J = 8.0 Hz, 1H, ‒CH–NH), 4.22–4.18
(dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–CH2–), 3.85–
3.80 (m, 2H, –HN–CH2–), 2.39–2.35 (m, 1H, –O–
CH2–CH2–CH), 2.25–2.17 (m, 1H, –O–CH2–
(S)-2-((4-(3-(4-Bromo-2-fluorophenyl)acryloyl)-
phenyl)amino)-N-(2-oxotetrahydrofuran-3-yl)acet-
amide (VIf). Yield 72%, yellow solid, mp 153–155°. 1H
NMR (DMSO-d6): 8.59–8.57 (d, J = 8.0 Hz, 1H,
‒CO–NH), 8.10–8.08 (d, J = 8.0 Hz, 1H, Ar-H),
8.01–7.97 (3H, CO–HC=CH– and Ar-H), 7.70–
7.66 (2H, CO–HC=CH– and Ar-H), 7.53–7.51 (d,
J = 8.0 Hz, 1H, Ar-H), 7.10–7.07 (brs, 1H, Ar-NH),
6.67–6.65 (d, J = 8.0 Hz, 2H, Ar-H), 4.66–4.59 (dd,
J = 20.0 Hz, J = 8.0 Hz, 1H, –O–CH2–), 4.37–4.32
(t, J = 8.0 Hz, 1H, –CH–NH), 4.25–4.19 (dd, J =
20.0 Hz, J = 8.0 Hz, 1H, –O–CH2–), 3.86–3.85 (d,
J = 4.0 Hz, 2H, –HN–CH2–), 2.42–2.36 (m, 1H,
‒O–CH2–CH2–CH), 2.22–2.17 (m, 1H, –O–
CH2–CH). 13C NMR (DMSO-d6): 195.72, 186.40,
175.63, 170.20, 170.13, 153.32, 153.00, 140.80, 134.90,
132.26, 131.36, 130.99, 130.74, 126.48, 126.09, 123.79,
123.60, 112.00, 111.72, 65.74, 48.38, 46.34, 28.52,
26.43. HR-MS (ESI) Calcd. for C21H20BrN2O4 [M +
CH2–CH2–CH). 13C NMR (DMSO-d6): 186.10,
175.61, 170.09, 159.62, 153.46, 132.22, 131.43, 130.70,
128.59, 126.25, 125.55, 124.06, 123.96, 122.76, 122.65,
120.02, 119.77, 112.07, 65.75, 48.40, 46.32, 28.54,
22.81. HR-MS (ESI) Calcd. for C21H19BrFN2O4 [M +
H]+: 443.0606, found: 443.0603.
(S)-2-((4-(3-([1,1'-Biphenyl]-4-yl)acryloyl)phenyl)-
amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VId).
1
Yield 65%, yellow solid, mp 174–176°C. H NMR
H]+: 461.0512, found: 461.0514.
(DMSO-d6): 8.60–8.58 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.04–8.02 (d, J = 8.0 Hz, 2H, Ar-H), 7.98–7.95
(t, 3H, –CO–HC=CH– and Ar-H), 7.77–7.74 (m,
4H, Ar-H), 7.71–7.67 (d, 1H, J = 16.0 Hz, –CO–
HC=CH–), 7.52–7.48 (t, J = 8.0 Hz, 2H, Ar-H),
7.42–7.40 (d, J = 8.0 Hz, 1H, Ar-H), 7.06–7.03 (t,
1H, Ar-NH), 6.67–6.65 (d, J = 8.0 Hz, 2H, Ar-H),
4.67–4.60 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–
CH2–), 4.37–4.33 (t, J = 8.0 Hz, 1H, –CH–NH),
4.25–4.19 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–
CH2–), 3.86–3.85 (d, J = 4.0 Hz, 2H, –HN–CH2–),
2.41–2.36 (m, 1H, –O–CH2–CH2–CH), 2.22–2.17
(S)-2-((4-(3-(3,4-Dichlorophenyl)acryloyl)phenyl)-
amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIg).
1
Yield 77%, brown solid, mp 171–173°C. H NMR
(DMSO-d6): 8.59–8.57 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.26 (s, 1H, Ar-H), 8.04–8.00 (d, 3H, CO–
HC=CH– and Ar-H), 7.86–7.84 (d, J = 8.0 Hz, 1H,
Ar-H), 7.71–6.99 (d, J = 8.0 Hz, 1H, Ar-H), 7.62–
7.58 (d, J = 16.0 Hz, 1H, –CO–HC=CH–), 7.07
(brs, 1H, Ar-NH), 6.66–6.64 (d, J = 8.0 Hz, 2H, Ar-
H), 4.66–4.59 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–
CH2–), 4.37–4.33 (t, J = 8.0 Hz, 1H, –CH–NH),
4.25–4.18 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–
CH2–), 3.86–3.85 (d, J = 4.0 Hz, 2H, –HN–CH2–),
2.42–2.36 (m, 1H, –O–CH2–CH2–CH), 2.22–2.17
13
(m, 1H, –O–CH2–CH2–CH). C NMR (DMSO-
d6): 186.53, 175.64, 170.17, 153.24, 142.01, 141.72,
139.77, 134.73, 131.32, 129.74, 129.51, 127.50, 127.17,
126.65, 122.70, 112.01, 65.75, 48.40, 46.36, 28.53. HR-
MS (ESI) Calcd. for C27H25N2O4 [M + H]+: 441.1814,
found: 441.1812.
13
(m, 1H, –O–CH2–CH2–CH). C NMR (DMSO-
d6): 186.23, 175.61, 170.10, 162.78, 153.41, 139.40,
136.53, 132.57, 132.22, 131.48, 131.37, 130.32, 129.37,
126.39, 124.93, 112.00, 65.74, 65.70, 48.39, 48.35,
46.32, 36.25, 31.23, 28.76, 28.54, 22.82. HR-MS
(ESI) Calcd. for C21H19Cl2N2O4 [M + H]+: 433.0722,
found: 433.0724.
(S)-2-((4-(3-(3,5-Dichlorophenyl)acryloyl)phenyl)-
amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIe).
1
Yield 64%, yellow solid, mp 154–156°C. H NMR
(DMSO-d6): 8.60–8.58 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.09–8.02 (m, 5H, –CO–HC=CH– and Ar-
(S)-2-((4-(3-(3-Methoxyphenyl)acryloyl)phenyl)-
H), 7.93 (s, 1H, Ar-H), 7.56–7.55 (d, 1H, Ar-H), amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIh).
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CHUNYING LUO et al.
1
28.52. HR-MS (ESI) Calcd. for C21H20FN2O4 [M +
H]+: 383.1407, found: 383.1404.
Yield 56%, brown solid, mp 161–163°C. H NMR
(DMSO-d6): 8.59–8.57 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.03–8.01 (d, J = 8.0 Hz, 2H, Ar-H), 7.93–7.89
(d, J = 16.0 Hz, 1H, –CO–HC=CH–), 7.63–7.59 (d,
J = 16.0 Hz, 1H, –CO–HC=CH–), 7.45 (s, 1H, Ar-
H), 7.41–7.33 (m, 2H, Ar-H), 7.01–6.99 (d, J = 8.0
Hz, 1H, Ar-NH), 6.66–6.64 (d, J = 8.0 Hz, 2H, Ar-
H), 4.66–4.59 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–
CH2–), 4.37–4.33 (t, J = 8.0 Hz, 1H, –CH–NH),
4.25–4.18 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–
CH2–), 3.84 (s, 2H, –HN–CH2–), 3.83 (s, 3H, –
OCH3–), 2.42–2.35 (m, 1H, –O–CH2–CH2–CH),
(S)-2-((4-(3-(2-Bromophenyl)acryloyl)phenyl)-
amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIk).
1
Yield 63%, yellow solid, mp 177–179°C. H NMR
(DMSO-d6): 8.60–8.58 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.20 (s, 1H, Ar-H), 8.05–8.03 (d, J = 8.0 Hz,
2H, Ar-H), 8.02–7.98 (d, J = 16.0 Hz, 1H, –CO–
HC=CH–), 7.84–7.82 (d, J = 8.0 Hz, 1H, Ar-H),
7.62–7.58 (m, 2H, Ar-H and –CO–HC=CH–),
7.42–7.38 (t, J = 8.0 Hz, 1H, Ar-H), 7.09–7.07 (t, J =
4.0 Hz, 1H, Ar-NH), 6.66–6.64 (d, J = 8.0 Hz, 2H,
Ar-H), 4.66–4.59 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –
O–CH2–), 4.37–4.33 (t, J = 8.0 Hz, 1H, –CH–NH),
4.23–4.18 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H, –O–
CH2–), 3.86–3.84 (d, J = 8.0 Hz, 2H, –HN–CH2–),
2.42–2.35 (m, 1H, –O–CH2–CH2–CH), 2.24–2.14
13
2.25–2.14 (m, 1H, –O–CH2–CH2–CH). C NMR
(DMSO-d6): 186.57, 175.61, 170.15, 160.10, 153.24,
142.18, 136.99, 131.33, 130.33, 126.59, 123.03, 121.84,
116.62, 113.65, 112.00, 65.75, 55.75, 48.39, 46.37,
28.54. HR-MS (ESI) Calcd. for C22H23N2O5 [M +
H]+: 395.1607, found: 395.1609.
13
(m, 1H, –O–CH2–CH2–CH). C NMR (DMSO-
d6): 186.33, 175.63, 170.12, 153.36, 140.45, 138.13,
132.98, 131.46, 131.36, 130.97, 128.49, 126.44, 124.30,
122.85, 111.99, 65.74, 48.39, 46.33, 28.53. HR-MS
(ESI) Calcd. for C21H20BrN2O4 [M + H]+: 443.0606,
found: 443.0603.
(S)-2-((4-(3-(2-Chlorophenyl)acryloyl)phenyl)-
amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIi).
1
Yield 61%, yellow solid, mp 143–145°C. H NMR
(DMSO-d6): 8.60–8.58 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.21–8.19 (d, 1H, –CO–HC=CH–), 8.03–
8.01 (d, J = 8.0 Hz, 2H, Ar-H), 7.96 (s, 2H, Ar-H),
7.56–7.55 (d, 1H, Ar-H), 7.46–7.44 (d, 2H, –CO–
HC=CH–), 7.09 (brs, 1H, Ar-NH), 6.67–6.65 (d,
J = 8.0 Hz, 2H, Ar-H), 6.66–6.64 (d, J = 8.0 Hz, 2H,
Ar-H), 4.66–4.59 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H,
‒O–CH2–), 4.37–4.33 (t, J = 8.0 Hz, 1H, –CH–
NH), 4.25–4.18 (dd, J = 20.0 Hz, J = 8.0 Hz, 1H,
‒O–CH2–), 3.85 (s, 2H, –HN–CH2–), 2.42–2.35
(m, 1H, –O–CH2–CH2–CH), 2.25–2.14 (m, 1H,
(S)-2-((4-(3-(4-Isopropylphenyl)acryloyl)phe-
nyl)amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIl).
1
Yield 57%, yellow solid, mp 154–156°C. H NMR
(DMSO-d6): 8.59–8.57 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.01–7.99 (d, J = 8.0 Hz, 2H, Ar-H), 7.87–7.83
(d, J = 16.0 Hz, 1H, –CO–HC=CH–), 7.78–7.76 (d,
J = 8.0 Hz, 2H, Ar-H), 7.64–7.61 (d, J = 16.0 Hz, 1H,
–CO–HC=CH–), 7.33–7.31 (d, J = 8.0 Hz, 2H, Ar-
H), 7.02 (s, 1H, Ar-NH), 6.67–6.65 (d, J = 8.0 Hz,
2H, Ar-H), 4.67–4.60 (dd, J = 20.0 Hz, J = 8.0 Hz,
1H, –O–CH2–), 4.37–4.33 (t, J = 8.0 Hz, 1H,
‒CH–NH), 4.25–4.19 (dd, J = 20.0 Hz, J = 8.0 Hz,
1H, –O–CH2–), 3.85–3.84 (d, J = 4.0 Hz, 2H,
‒O–CH2–CH2–CH). 13C NMR (DMSO-d6):
186.23, 175.62, 170.09, 153.45, 136.83, 134.52, 133.18,
131.48, 130.42, 128.88, 128.10, 126.29, 125.58, 112.05,
65.75, 48.40, 46.32, 31.17, 28.54. HR-MS (ESI)
Calcd. for C21H20ClN2O4 [M + H]+: 399.1112, found: ‒HN–CH2–), 2.42–2.36 (m, 1H, –O–CH2–CH2–
399.1114.
CH), 2.25–2.15 (m, 1H, –O–CH2–CH2–CH), 1.3
(s, 1H, –CH(CH3)2), 1.23–1.21 (d, J = 8.0 Hz, 6H,
(S)-2-((4-(3-(4-Fluorophenyl)acryloyl)phenyl)-
‒CH(CH3)2). 13C NMR (DMSO-d6): 186.61, 175.62,
170.18, 153.16, 151.26, 142.23, 133.27, 131.22, 129.16,
127.30, 126.71, 121.81, 112.01, 65.74, 48.39, 46.39,
33.86, 31.40, 31.15, 28.54, 24.12. HR-MS (ESI) Calcd.
for C24H27N2O4 [M + H]+: 407.1971, found: 407.1973.
amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide (VIj).
1
Yield 67%, brown solid, mp 177–179°C. H NMR
(DMSO-d6): 8.60–8.58 (d, J = 8.0 Hz, 1H, –CO–
NH), 8.02–8.00 (d, J = 8.0 Hz, 2H, Ar-H), 7.96–7.92
(d, J = 8.0 Hz, 2H, Ar-H), 7.90–7.86 (d, J = 16.0 Hz,
1H, –CO–HC=CH–), 7.66–7.62 (d, J = 16.0 Hz,
1H, –CO–HC=CH–), 7.31–7.26 (t, J = 8.0 Hz, 2H,
Ar-H), 7.04 (brs, 1H, Ar-NH), 6.66–6.64 (d, J = 8.0 Hz,
2H, Ar-H), 4.66–4.59 (dd, J = 20.0 Hz, J = 8.0 Hz,
1H, –O–CH2–), 4.37–4.32 (t, J = 8.0 Hz, 1H,
‒CH–NH), 4.25–4.18 (dd, J = 20.0 Hz, J = 8.0 Hz,
1H, –O–CH2–), 3.85 (s, 2H, –HN–CH2–), 2.42–
2.35 (m, 1H, –O–CH2–CH2–CH), 2.25–2.14 (m,
(S)-2-((4-(3-(4-(tert-Butyl)phenyl)acryloyl)phe-
nyl)amino)-N-(2-oxotetrahydrofuran-3-yl)acetamide
1
(VIm). Yield 54%, yellow solid, mp 147–149°C. H
NMR (DMSO-d6): 8.59–8.57 (d, J = 8.0 Hz, 1H,
‒CO–NH), 8.01–7.99 (d, J = 8.0 Hz, 2H, Ar-H),
7.87–7.83 (d, J = 16.0 Hz, 1H, –CO–HC=CH–),
7.78–7.76 (d, J = 8.0 Hz, 2H, Ar-H), 7.64–7.60 (d,
J = 16.0 Hz, 1H, –CO–HC=CH–), 7.47–7.45 (d,
1H, –O–CH2–CH2–CH). 13C NMR (DMSO-d6): J = 8.0 Hz, 1H, Ar-H), 7.33–7.31 (d, J = 8.0 Hz, 1H,
Ar-H), 7.04–7.01 (t, J = 4.0 Hz, 1H, Ar-NH), 6.67–
6.64 (d, J = 12.0 Hz, 2H, Ar-H), 4.67–4.60 (dd, J =
20.0 Hz, J = 8.0 Hz, 1H, –O–CH2–), 4.37–4.33 (t,
186.51, 175.63, 170.17, 164.79, 162.32, 153.23, 140.95,
132.25, 132.22, 131.36, 131.30, 131.28, 126.57, 122.67,
116.40, 116.19, 112.00, 65.76, 48.40, 46.36, 31.16,
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SYNTHESIS OF NOVEL CHALCONE-BASED L-HOMOSERINE LACTONES
145
J = 8.0 Hz, 1H, –CH–NH), 4.23–4.18 (dd, J = 20.0 Hz, 7.67–7.65 (d, J = 8.0 Hz, 2H, Ar-H), 7.57–7.53 (d,
J = 8.0 Hz, 1H, –O–CH2–), 3.85–3.84 (d, J = 4.0 Hz, J = 16.0 Hz, 1H, –HC=CH–), 7.44–7.42 (m, 3H,
Ar-H), 4.47–4.42 (td, 1H, –O–CH2–), 4.27–4.20
(td, 1H, –O–CH2–), 3.68–3.58 (m, 3H, –CH–NH
and –HN–CH2–), 2.66–2.59 (m, 1H, –O–CH2–
CH2–CH), 2.38 (brs, 1H, –NH–CH2), 2.18–2.13
2H, –HN–CH2–), 2.42–2.35 (m, 1H, –O–CH2–
CH2–CH), 2.25–2.14 (m, 1H, –O–CH2–CH2–
CH), 1.30 (s, 4H, –C(CH3)3), 1.23–1.21 (d, J = 8.0
Hz, 5H, –C(CH3)3). C NMR (DMSO-d6): 186.63,
175.62, 170.18, 153.16, 151.27, 142.24, 133.26, 132.86,
13
13
(m, 1H, –O–CH2–CH2–CH). C NMR (CDCl3):
131.22, 129.16, 128.88, 127.30, 126.71, 126.13, 121.81, 189.01, 176.96, 169.64, 144.56, 141.68, 134.91, 133.88,
112.01, 65.75, 48.39, 46.39, 35.06, 33.86, 31.40, 28.54, 130.53, 129.98, 128.98, 128.47, 121.76, 118.98, 119.00,
24.12. HR-MS (ESI) Calcd. for C25H29N2O4 [M + 65.52, 57.18, 51.74, 30.20. HR-MS (ESI) Calcd. for
C21H21N2O4 [M + H]+: 365.1501, found: 365.1503.
H]+: 421.2127, found: 421.2124.
(S)-N-(4-(3-(4-Bromophenyl)acryloyl)phenyl)-2-
Preparation of intermediates (VIIa)–(VIIm). Gen-
eral approach. To the mixture of corresponding amine
(0.89 mmol) and K2CO3 (148 mg, 1.07 mmol) in ace-
tone chloroacetyl chloride (81 μL, 1.07 mmol) was
dropped in. The reaction mixture was stirred at room
temperature for 3 h. After the reaction finished, the
mixture was poured into 15 mL of ice water. The pre-
cipitate formed was filtrated and washed with water.
The product was dried under vacuum to obtain com-
pounds (VIIa)–(VIIm) as solids without any further
purification.
Preparation of analogues (VIIIa)–(VIIIm). General
approach. To a solution of corresponding chlorinated
compound (VIIa)–(VIIm) (0.45 mmol) and homoser-
ine lactone hydrochloride (62 mg, 0.45 mmol) dis-
solved in acetonitrile (10 mL), K2CO3 (187mg,
1.35 mmol) and KI (15 mg, 0.09 mmol) were added.
The reaction mixture was refluxed for 6 h. Upon com-
pletion (monitored by TLC), the precipitated solids
was filtered off. Removal of the solvent in vacuo gave a
residue that was purified with column chromatogra-
phy to afford analogues (VIIIa)–(VIIIm) as solids.
((2-oxotetrahydrofuran-3-yl)amino)acetamide (VIIIc).
1
Yield 74%, yellow solid, mp 164–166°C. H NMR
(DMSO-d6): 10.31 (s, 1H, Ar-NH), 8.19–8.17 (d, J =
8.0 Hz, 2H, Ar-H), 8.02–7.98 (d, J = 16.0 Hz, 1H,
‒HC=CH–), 7.88–7.86 (d, J = 8.0 Hz, 2H, Ar-H),
7.84–7.82 (d, J = 8.0 Hz, 2H, Ar-H), 7.72–7.66 (m,
3H, –HC=CH– and Ar-H), 4.34–4.32 (td, 1H, –O–
CH2–), 4.21–4.14 (td, 1H, –O–CH2–), 3.71–3.66 (t,
J = 8.0 Hz, 1H, –CH–NH), 3.52 (s, 2H, –HN–
CH2–), 2.96 (brs, 1H, –NH–CH2), 2.48–2.43 (m,
1H, –O–CH2–CH2–CH), 2.07–1.99 (m, 1H, –O–
CH2–CH2–CH). 13C NMR (DMSO-d6): 187.97,
177.97, 171.10, 143.64, 142.44, 134.41, 132.88, 130.40,
129.99, 129.51, 127.75, 127.21, 122.37, 119.03, 66.05,
55.96, 50.94, 29.98. HR-MS (ESI) Calcd. for
C21H20BrN2O4 [M + H]+: 443.0606, found: 443.0603.
(S)-N-(4-(3-([1,1'-Biphenyl]-4-yl)acryloyl)phe-
nyl)-2-((2-oxotetrahydrofuran-3-yl)amino)acetamide
1
(VIIId). Yield 55%, yellow solid, mp 182–184°C. H
NMR (CDCl3): 9.53 (s, 1H, Ar-NH), 8.09–8.07 (d,
J = 8.0 Hz, 2H, Ar-H), 7.90–7.78 (d, J = 16.0 Hz, 1H,
–HC=CH), 7.82–7.80 (d, J = 8.0 Hz, 2H, Ar-H),
7.76–7.74 (d, J = 8.0 Hz, 2H, Ar-H), 7.69–7.65 (m,
4H, Ar), 7.62–7.58 (d, J = 16.0 Hz, 1H, –HC=CH),
7.51–7.47 (t, J = 8.0 Hz, 2H, Ar-H), 7.42–7.41 (d, J =
8.0 Hz, 1H, Ar-H), 4.49–4.45 (td, 1H, –O–CH2–),
4.29–4.22 (td, 1H, –O–CH2–), 3.72–3.58 (m, 3H,
‒CH–NH and –HN–CH2–), 2.68–2.62 (m, 1H,
‒O–CH2–CH2–CH), 2.63 (brs, 1H, –NH–CH2),
(S)-N-(4-(3-(4-Chlorophenyl)acryloyl)phenyl)-2-
((2-oxotetrahydrofuran-3-yl)amino)acetamide (VIIIa).
1
Yield 66%, yellow solid, mp 181–183°C. H NMR
(DMSO-d6): 10.31 (s, 1H, Ar-NH), 8.19–8.17 (d, J =
8.0 Hz, 2H, Ar-H), 8.01–7.97 (d, J = 16.0 Hz, 1H,
‒HC=CH–), 7.95–7.93 (d, J = 8.0 Hz, 2H, Ar-H),
7.85–7.82 (d, J = 12.0 Hz, 2H, Ar-H), 7.74–7.70 (d,
J = 16.0 Hz, 1H, –HC=CH–), 7.54–7.52 (d, J = 8.0
Hz, 2H, Ar-H), 4.37–4.32 (td, 1H, –O–CH2–),
4.21–4.16 (td, 1H, –O–CH2–), 3.71–3.66 (t, 1H,
‒CH–NH), 3.53 (s, 2H, –HN–CH2–), 2.96 (brs,
1H, –NH–CH2), 2.48–2.43 (m, 1H, –O–CH2–
CH2–CH), 2.10–2.00 (m, 1H, –O–CH2–CH2–
13
2.18–2.12 (m, 1H, –O–CH2–CH2–CH). C NMR
(CDCl3): 188.01, 172.16, 143.53, 143.35, 142.43,
139.71, 134.42, 132.96, 130.26, 129.99, 129.51, 129.36,
129.31, 128.46, 127.54, 127.21, 127.02, 126.88, 122.39,
119.40, 62.49. HR-MS (ESI) Calcd. for C27H25N2O4
13
[M + H]+: 441.1814, found: 441.1817.
CH). C NMR (DMSO-d6): 187.88, 177.97, 171.08,
143.67, 142.36, 135.43, 134.23, 132.73, 130.97, 130.45,
129.40, 123.71, 119.00, 66.04, 56.98, 50.94, 29.97.
HR-MS (ESI) Calcd. for C21H20ClN2O4 [M + H]+:
399.1112, found: 399.1114.
(S)-N-(4-(3-(3,5-Dichlorophenyl)acryloyl)phe-
nyl)-2-((2-oxotetrahydrofuran-3-yl)amino)acetamide
1
(VIIIe). Yield 64%, yellow solid, mp 155–157°C. H
NMR (CDCl3): 9.57 (s, 1H, Ar-NH), 8.20–8.16 (d,
J = 16.0 Hz, 1H, –HC=CH-), 8.04–8.02 (d, J = 8.0
Hz, 2H, Ar-H), 7.80–7.78 (d, J = 8.0 Hz, 2H, Ar-H),
(S)-N-(4-Cinnamoylphenyl)-2-((2-oxotetrahydro-
furan-3-yl)amino)acetamide (VIIIb). Yield 61%, yellow
1
solid, mp 152–154°C. H NMR spectrum(CDCl3): 7.52–7.48 (d, J = 16.0 Hz, 1H, –HC=CH–),7.46–
7.43 (m, 1H, Ar-H), 7.35–7.32 (m, 2H, Ar-H), 4.47–
4.43 (td, 1H, –O–CH2–), 4.26–4.21 (td, 1H, –O–
9.54 (s, 1H, Ar-NH), 8.05–8.03 (d, J = 8.0 Hz, 2H,
Ar-H), 7.83–7.77 (m, 3H, –HC=CH– and Ar-H),
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CHUNYING LUO et al.
CH2–), 3.70–3.49 (3H, –CH–NH and –HN–CH2–), CH), 2.29 (brs, 1H, –NH–CH2), 2.14–2.08 (m, 1H,
–O–CH2–CH2–CH). 13C NMR (CDCl3): 189.00,
2.67–2.20 (brs, 1H, –NH–CH2), 2.19–2.18 (m, 2H,
–O–CH2–CH2–CH). 13C NMR (101 MHz, CDCl3): 177.12, 169.81, 159.92, 144.45, 141.79, 136.26, 133.75,
129.96, 122.03, 121.10, 118.99, 116.29, 113.45, 65.58,
57.11, 55.37, 51.65, 30.14. HR-MS (ESI) Calcd. for
188.85, 177.00, 169.68, 141.83, 140.28, 135.45, 133.57,
133.25, 131.19, 130.29, 130.11, 127.81, 127.13, 124.47,
118.98, 65.54, 57.20, 51.74, 30.20. HR-MS (ESI) C22H23N2O5 [M + H]+: 395.1607, found: 395.1604.
Calcd. for C21H19Cl2N2O4 [M + H]+: 433.0722, found:
(S)-N-(4-(3-(2-Chlorophenyl)acryloyl)phenyl)-2-
433.0726.
((2-oxotetrahydrofuran-3-yl)amino)acetamide (VIIIi).
1
(S)-N-(4-(3-(4-Bromo-2-fluorophenyl)acryloyl)-
Yield 54%, yellow solid, mp 185–187°C. H NMR
phenyl)-2-((2-oxotetrahydrofuran-3-yl)amino)acet-
(CDCl3): 9.58 (s, 1H, Ar-NH), 8.05–8.03 (d, J =
amide (VIIIf). Yield 57%, yellow solid, mp 178–
8.0 Hz, 2H, Ar-H), 7.81–7.78 (d, J = 12.0 Hz, 2H, Ar-
1
180°C. H NMR (CDCl3): 9.56 (s, 1H, Ar-NH),
8.05–8.02 (d, J = 12.0 Hz, 2H, Ar-H), 7.84–7.78 (3H,
–HC=CH– and Ar-H), 7.66–7.63 (d, J = 12.0 Hz,
2H, –HC=CH–),7.55–7.51 (t, J = 8.0 Hz, 1H, Ar-
H), 7.37–7.33 (t, J = 8.0 Hz, 2H, Ar-H), 4.48–4.44
(td, 1H, –O–CH2–), 4.28–4.22 (td, 1H, –O–CH2–),
3.71–3.54 (m, 3H, –CH–NH and –HN–CH2–),
2.68–2.61 (m, 1H, –O–CH2–CH2–CH), 2.36 (brs,
1H, –NH–CH2), 2.19–2.13 (m, 1H, –O–CH2–
H), 7.68–7.64 (d, J = 12.0 Hz, 1H, –HC=CH–),
7.56–7.51 (3H, –HC=CH– and Ar-H), 7.39 (1H, Ar-
H), 4.49–4.44 (td, 1H, –O–CH2–), 4.28–4.22 (td,
1H, –O–CH2–), 3.71–3.66 (m, 1H, –CH–NH) 3.50
(s, 2H, –HN–CH2–), 2.68–2.61 (m, 1H, –O–CH2–
CH2–CH), 2.34 (brs, 1H, –NH–CH2), 2.17–2.14
13
(m, 1H, –O–CH2–CH2–CH). C NMR (CDCl3):
188.07, 176.96, 169.66, 142.03, 141.22, 137.94, 135.59,
133.30, 130.09, 129.94, 126.51, 124.04, 119.03, 65.52,
57.23, 51.77, 50.85, 30.23. HR-MS (ESI) Calcd. for
C21H20ClN2O4 [M + H]+: 399.1112, found: 399.1116.
CH2–CH). 13C NMR (CDCl3): 188.57, 176.92,
169.59, 162.55, 159.98, 141.87, 135.98, 133.51, 130.61,
130.58, 130.07, 128.05, 128.01, 124.69, 124.61, 124.49,
122.27, 122.15, 120.14, 119.89, 118.99, 65.50, 57.23,
51.78, 30.23. HR-MS (ESI) Calcd. for
C21H19BrFN2O4 [M + H]+: 461.0512, found: 461.0516.
(S)-N-(4-(3-(4-Fluorophenyl)acryloyl)phenyl)-2-
((2-oxotetrahydrofuran-3-yl)amino)acetamide (VIIIj).
1
Yield 62%, brown solid, mp 167–169°C. H NMR
(DMSO-d6): 10.34 (s, 1H, Ar-NH), 8.18–8.16 (d, J =
8.0 Hz, 2H, Ar-H), 8.00–7.96 (dd, J = 8.0 Hz, J =
4.0 Hz, 2H, Ar-H), 7.95–7.91 (d, J = 16.0 Hz, 1H,
‒HC=CH–), 7.85–7.83 (d, J = 8.0 Hz, 2H, Ar-H),
7.75–7.71 (d, J = 16.0 Hz, 1H, –HC=CH–), 7.33–
7.29 (t, J = 8.0 Hz, 2H, Ar-H), 4.34–4.32 (td, 1H,
–O–CH2–), 4.21–4.15 (td, 1H, –O–CH2–), 3.71–
3.64 (m, 1H, –CH–NH), 3.53 (s, 2H, –HN–CH2–),
2.96 (brs, 1H, –NH–CH2), 2.49–2.43 (m, 1H, –O–
CH2–CH2–CH), 2.08–2.00 (m, 1H, –O–CH2–
(S)-N-(4-(3-(3,4-Dichlorophenyl)acryloyl)phe-
nyl)-2-((2-oxotetrahydrofuran-3-yl)amino)acetamide
1
(VIIIg). Yield 62%, brown solid, mp 157–159°C. H
NMR (DMSO-d6): 10.42 (s, 1H, Ar-NH), 8.29 (1H,
Ar-H), 8.21–8.19 (d, J = 8.0 Hz, 2H, Ar-H), 8.09–
8.05 (d, J = 16.0 Hz, 1H, –HC=CH), 7.89–7.84 (3H,
Ar-H), 7.73–7.71 (d, J = 8.0 Hz, 1H, Ar-H), 7.71–
7.67 (d, J = 16.0 Hz, 1H, –HC=CH–), 4.34–4.32 (td,
1H, –O–CH2–), 4.21–4.14 (td, 1H, –O–CH2–),
3.70–3.66 (t, J = 8.0 Hz, 1H, –CH–NH), 3.53 (s,
2H, –HN–CH2–), 2.96 (brs, 1H, –NH–CH2),
2.48–2.45 (m, 1H, –O–CH2–CH2–CH), 2.10–2.02
CH2–CH). 13C NMR (DMSO-d6): 187.91, 177.96,
171.09, 165.05, 162.58, 143.64, 142.60, 132.80, 131.97,
131.93, 131.67, 131.59, 130.40, 122.34, 118.99, 116.49,
116.28, 66.04, 55.96, 50.94, 29.98. HR-MS (ESI)
Calcd. for C21H20FN2O4 [M + H]+: 383.1407, found:
383.1404.
13
(m, 1H, –O–CH2–CH2–CH). C NMR (DMSO-
d6): 187.75, 177.95, 171.14, 143.87, 141.01, 136.18,
133.04, 132.55, 132.28, 131.44, 130.55, 129.58, 124.52,
118.99, 66.04, 55.94, 50.94, 29.99. HR-MS (ESI)
Calcd. for C21H19Cl2N2O4 [M + H]+: 433.0722, found:
433.0725.
(S)-N-(4-(3-(2-Bromophenyl)acryloyl)phenyl)-2-
((2-oxotetrahydrofuran-3-yl)amino)acetamide (VIIIk).
1
Yield 56%, yellow solid, mp 174–176°C. H NMR
(S)-N-(4-(3-(3-Methoxyphenyl)acryloyl)phenyl)-
(CDCl3): 9.54 (s, 1H, Ar-NH), 8.06–8.03 (dd, J =
8.0 Hz, 2H, Ar-H), 7.80–7.71 (m, 4H, –HC=CH–
and Ar-H), 7.57–7.52 (m, 3H, Ar-H and –HC=CH–),
7.33–7.28 (t, J = 8.0 Hz, 1H, Ar-H), 4.48–4.44 (td,
1H, –O–CH2–), 4.28–4.22 (td, 1H, –O–CH2–),
3.71–3.55 (m, 3H, –CH–NH and –HN–CH2–),
2.68–2.61 (m, 1H, –O–CH2–CH2–CH), 2.36 (brs,
2-((2-oxotetrahydrofuran-3-yl)amino)acetamide (VIIIh).
1
Yield 48%, brown solid, mp 154–156°C. H NMR
(CDCl3): 9.58 (s, 1H, Ar-NH), 8.29 (1H, Ar-H),
8.02–8.00 (d, J = 8.0 Hz, 2H, Ar-H), 7.78–7.73 (3H,
–HC=CH and Ar-H), 7.53–7.49 (d, J = 16.0 Hz, 1H,
–HC=CH), 7.35–7.28 (1H, Ar-H), 7.24–7.22 (d, J =
8.0 Hz, 1H, Ar-H) 7.15 (1H, Ar-H), 6.97–6.94 (dd,
J = 8 Hz, J = 4 Hz, 1H, Ar-H), 4.43–4.39 (td, 1H, 1H, –NH–CH2), 2.22–2.14 (m, 1H, –O–CH2–
CH2–CH). 13C NMR (CDCl3): 188.46, 176.87,
169.56, 142.65, 141.84, 137.08, 133.60, 133.19, 132.20,
130.85, 130.48, 130.04, 129.81, 127.24, 123.08, 122.96,
–O–CH2–), 4.24–4.18 (td, 1H, –O–CH2–), 3.85 (s,
3H, –OCH3), 3.66–3.56 (m, 3H, –CH–NH and
–HN–CH2–), 2.63–2.57 (m, 1H, –O–CH2–CH2–
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SYNTHESIS OF NOVEL CHALCONE-BASED L-HOMOSERINE LACTONES
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118.99, 65.48, 57.23, 51.79, 30.23. HR-MS (ESI) compound 30 (C30) shows good inhibitory activity on
Calcd. for C21H20BrN2O4 [M + H]+: 443.0606, found:
443.0604.
QS [19, 20], thus, C30 was taken as the positive con-
trol to calibrate the screening system.
Preparation of QSIS-lasI plates. LB agar (20 g/L;
15 mL) was melted and cooled to 50°C. Gentamicin,
C12-HSL, and TTC (2,3,5-triphenyltetrazolium
chloride) were added at 80 mg/mL, 20 nM, and
0.25 mg/mL, respectively. After mixing, the QSIS-
lasI overnight culture in LB medium (10 g NaCl/L,
10 g polypepton/L, 5 g yeast extract/L, and pH 7.0.)
was added to approximately 2 × 107 colony-forming
units/mL. Agar plates were subsequently prepared by
pouring 15 mL of the mixture into Petri dishes. The
medium was allowed to solidify, and then wells were
made. A total of 5 μL of test substance was added to
each well, after which they were incubated overnight at
37°C. The appearance of a red circular growth zone
around the reservoir indicated the presence of QSI
compounds in the sample.
(S)-N-(4-(3-(4-Isopropylphenyl)acryloyl)phenyl)-
2-((2-oxotetrahydrofuran-3-yl)amino)acetamide (VIIIl).
1
Yield 63%, yellow solid, mp 163–165°C. H NMR
(CDCl3): 9.52 (s, 1H, Ar-NH), 8.06–8.03 (d, J =
12.0 Hz, 2H, Ar-H), 7.83–7.77 (m, 3H, –HC=CH–
and Ar-H), 7.61–7.59 (d, J = 8.0 Hz, 2H, Ar-H),
7.54–7.50 (d, J = 16.0 Hz, 1H, –HC=CH–), 7.31–
7.29 (d, J = 8.0 Hz, 2H, Ar-H), 4.47–4.43 (td, 1H,
‒O–CH2–), 4.25–4.21 (td, 1H, –O–CH2–), 3.70–
3.58 (m, 3H, –CH–NH and –HN–CH2–), 2.99–
2.93 (m, 1H, –O–CH2–CH2–CH), 2.66–2.60 (m,
1H, –CH(CH3)2), 2.37 (brs, 1H, –NH–CH2), 2.22–
2.07 (m, 1H, –O–CH2–CH2–CH), 1.30–1.28 (d, J =
8.0 Hz, 6H, –CH(CH3)2). 13C NMR (CDCl3): 189.13,
176.90, 169.56, 151.96, 144.68, 141.54, 134.07, 132.57,
129.94, 128.62, 127.11, 120.86, 118.95, 65.50, 57.20,
51.76, 34.14, 30.22, 23.79. HR-MS (ESI) Calcd. for
C24H27N2O4 [M + H]+: 407.1971, found: 407.1974.
ACKNOWLEDGMENTS
We would like to thank Qian-Hong Gong of School of
Medicine and Pharmacy in Ocean University of China, for
providing us tested strains. We also gratefully acknowledge
Hong-Min Liu of this university for his assistance in acqui-
sition of mass spectrometric data, and New Drug Research
and Development Centre of Zhengzhou University for
facilities and funding supporting this work.
(S)-N-(4-(3-(4-(tert-Butyl)phenyl)acryloyl)phe-
nyl)-2-((2-oxotetrahydrofuran-3-yl)amino)acetamide
(VIIIm). Yield 64%, yellow solid, mp 154–156°C.
1H NMR (CDCl3): 9.56 (s, 1H, Ar-NH), 8.04–8.02
(d, J = 8.0 Hz, 2H, Ar-H), 7.82–7.77 (m, 3H,
‒HC=CH– and Ar-H), 7.61–7.59 (d, J = 8.0 Hz, 2H,
Ar-H), 7.54–7.50 (d, J = 16.0 Hz, 1H, –HC=CH–),
7.46–7.44 (m, 2H, Ar-H), 4.45–4.41 (td, 1H, –O–
CH2–), 4.23–4.19 (td, 1H, –O–CH2–), 3.69–3.49
(m, 3H, –CH–NH and –HN–CH2–), 2.64–2.58
(m, 1H, –O–CH2–CH2–CH), 2.31 (brs, 1H, –NH–
CH2), 2.20–2.12 (m, 1H, –O–CH2–CH2–CH), 1.35
FUNDING
This work was supported by National Key Technologies
R & D Program of China (Grant no. 2017YFD0501401).
(s, 9H, –C(CH3)3). 13C NMR (CDCl3): 189.16,
177.02, 169.69, 154.20, 144.57, 141.63, 134.02, 132.16,
129.92, 128.36, 125.96, 120.99, 118.98, 65.54, 57.14,
51.71, 34.95, 31.16, 30.17. HR-MS (ESI) Calcd. for
C25H29N2O4 [M + H]+: 421.2127, found: 421.2125.
COMPLIANCE WITH ETHICAL STANDARDS
This article does not contain any studies involving ani-
mals or human participants performed by any of the
authors.
Construction of P. aeruginosa QSIS-lasI. To con-
struct an effective screening system, the lasI promoter
(about 300-bp) was amplified by PCR and fused to the
levansucrase-encoding gene, sacB, which leads to cell
death in the presence of C12-HSL and sucrose. The
resultant plasmid pMHLASI harboring the lasI–sacB
fusion was transformed into a P. aeruginosa lasI rhlI
double mutant PAO-MW1 to create the QSIS-lasI
selector. The concentration of C12-HSL could be eas-
ily controlled using mutant strains. When the QS
inhibitory (QSI) compound was presented, majority
of the cells survived and grew at the position where the
action of the C12-HSL and the QSI compound coun-
terbalanced each other. The growth of QSIS-lasI was
manifested as a red zone because the colorless dye
TTC in the media was reduced to the red triphenyl for-
mazan by bacteria [25]. QSIS-lasI was applied to the
QSIS-lasI agar well for diffusion assay. Furanone
Conflict of Interests
The authors declare that they have no conflict of interests.
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