1152556

research-article2023
CHL0010.1177/17475198231152556Journal of Chemical ResearchYe et al.

Research Paper

Journal of Chemical Research

Synthesis and enzymatic inhibition effects of January-February 1­–10

© The Author(s) 2023

thiazolidinedione 3C-like protease inhibitors

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DOI: 10.1177/17475198231152556
https://doi.org/10.1177/17475198231152556
journals.sagepub.com/home/chl

Xin Ye1, Yuhua Li2, Lina Guo2, Yiling Yao1, Rouyu Zhu1,
Shuang Wei1, Hua Diao2 and Zhiyu Shao1

Abstract
The 3C-like protease (also known as Mpro) plays a key role in SARS-CoV-2 replication and has similar substrates
across mutant coronaviruses, making it an ideal drug target. We synthesized 19 thiazolidinedione derivatives via the
Knoevenagel condensations and Mitsunobu reactions as potential 3C-like protease inhibitors. The activity of these
inhibitors is screened in vitro by employing the enzymatic screening model of 3C-like protease using fluorescence
resonance energy transfer. Dithiothreitol is included in the enzymatic reaction system to avoid non-specific enzymatic
inhibition. Active inhibitors with diverse activity are found in this series of compounds, and two representative inhibitors
with potent inhibitory activity are highlighted.

Keywords
3C-like protease inhibitor, anti-coronavirus compound, SARS-CoV-2, thiazolidinedione derivatives
Date received: 6 November 2022; accepted: 7 January 2023

R2
H H
O N O N O N In vitro tests of the inhibition
O O O
activity were carried out.
S S S (DTT was added)

R1 R1
O
O
N
O N
O
S O N
O
F
S

New thiazolidinedione derivatives were designed and synthesized. Two of these compounds were proved to have
potent inhibitory activity against SARS-CoV-2 Mpro.

1
 ollege of Chemistry and Chemical Engineering, Donghua University,
C Corresponding authors:
Shanghai, China Hua Diao, NHC Key Laboratory of Reproduction Regulation, Shanghai
2
NHC Key Laboratory of Reproduction Regulation, Shanghai Institute Institute for Biomedical and Pharmaceutical Technologies, School of
for Biomedical and Pharmaceutical Technologies, School of Basic Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Medical Sciences, Fudan University, Shanghai, China Email: diaohua@sibpt.com

Zhiyu Shao, College of Chemistry and Chemical Engineering Donghua

University, Shanghai 201620, China.
Email: zyshao@dhu.edu.cn

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2 Journal of Chemical Research
O
N O
O S N
N N
O S
tideglusib TDZD-8
Figure 1. Novel 3CL protease inhibitors possessing a
thiadiazolidinedione structure.
Introduction
At the end of 2019, COVID-19, caused by SARS-CoV-2,
led to a global health crisis, with more than six hundred mil-
lion people cumulatively diagnosed with SARS-CoV-2 and
more than six and a half million deaths according to the
World Health Organization (WHO). SARS-CoV-2 is an
enveloped, positive single-stranded RNA virus belonging
to the subgenus Sarbecovirus of the genus Betacoronavirus,1
the genome of which consists of about 30,000 nucleotides.2
SARS-CoV-2 has high homology with SARS-CoV and
Middle East respiratory syndrome coronavirus (MERS-
CoV). After the infection of host cells by this virus, the
ORF1a/b of SARS-CoV-2 is first translated and expressed
with two polyprotein precursors (pp1a and pp1ab) with the
help of the host cell.3 The polyprotein precursors undergo
intramolecular cleavage by the action of the main protease
(Mpro for short). Mpro, a papain-like protease, is also known
as a 3C-like protease (3CLpro),4 because its cleavage site
specificity is similar to that of the 3C protease of picornavi-
rus, and both are referred to as Mpro/3CLpro. The non-struc-
tural proteins produced by the polyprotein precursors are
involved in the production of viral subgenomic RNA and
four structural proteins (envelope/E, membrane/M, spike/S,
and nucleocapsid/N), which, in turn, are responsible for the
reproduction and release of the offspring virus. Since the
Mpro protease plays a crucial role in the virus's life cycle
and there is no homologous protein in the human body, the
Mpro master protease is an ideal target for developing anti-
viral drugs.5
Since the SARS outbreak in 2003, several anti-SARS
drugs based on the Mpro structure have been investigated.
Anti-HIV drugs such as lopinavir and ritonavir also act on
similar protease targets and have been well-validated in
clinical practice.6 Meanwhile, the screened Mpro inhibitors
have a certain degree of broad-spectrum anti-coronavirus
ability and may even be used for the treatment of other ani-
mal diseases caused by coronaviruses (porcine coronavirus,
for example), because Mpro is highly conserved in beta cor-
onavirus.7 SARS-CoV-2 Mpro/3CLpro differs from SARS-
CoV Mpro/3CLpro by only 12 amino acids, and the homology
is greater than 96%.8 Also according to the Global Initiative
on Sharing Avian Influenza Data (GISAID), SARS-CoV-2
Mpro is highly conserved. The mutation rate of its binding
domain is less than 0.001.9 Therefore, mutations do not
broadly affect the efficacy of SARS-CoV-2 Mpro inhibitors.
Figure 2. Principle of FRET.
As its key roles are in mediating viral replication and tran-
scription, Mpro is viewed as an ideal drug target for viruses.10
Jin et al.11 screened about 10,000 compounds using fluo-
rescence resonance energy transfer (FRET) analysis and
selected seven compounds with IC50 values in the range of
0.67–21.4 µM, including tideglusib and TDZD-8 (Figure
1). Tideglusib and TDZD-8 are novel 3CL protease inhibi-
tors possessing a thiadiazolidinedione structure. However,
recent research results suggest that the thiadiazolidinedione
structure of tideglusib suffers from instability. Inhibition of
3CL protease activity by tideglusib is significantly reduced
when dithiothreitol (DTT) is added to the enzymatic assay
of cysteine protease. The results of this experiment show
that tideglusib is sensitive to DTT and is a non-specific
inhibitor of SARS-CoV-2 Mpro.12 We hypothesize that the
sulfur-nitrogen bond in the structure of the thiadiazolidine-
dione is a high-energy bond. The addition of DTT breaks
the sulfur-nitrogen bond leading to ring opening. Thus,
tideglusib has significant issues as a drug.
Computer simulations show that when tideglusib is
bound to the substrate protease, the two carbonyl groups of
the thiadiazolidinedione structure form hydrogen bonds
with the protease. Two side chains occupy the pocket to
dock COVID-19 virus Mpro.11 Thus, we designed their bio-
isostere structures. Thiazolidinediones also have two car-
bonyl groups and two side chains, and one of the nitrogen
atoms has been replaced with a methylene group to improve
structural stability. Thiazolidines can be used as dual inhib-
itors of aldose reductase and protein tyrosine phosphatase
1B, which are potential agents for the treatment of type 2
diabetes mellitus and its complications,13 as tyrosinase
inhibitors.14 It also has an inhibitory effect on RNA
viruses,15 so it was hypothesized that it might have an
inhibitory effect on 3CL protease.
The enzyme activity was measured by inhibition assays
using FRET (Figure 2). The MCA-AVLQSGFR-Lys(Dnp)-
Lys-NH2 substrate peptide was derived from residues
P4-P5’ of the SARS-CoV-2 Mpro N-terminal autoprocessing
site with the AVLQSGFRK sequence. The enzymatic cleav-
age between Q4 and S5 of AVLQSGFR-Lys(Dnp)-Lys-NH2
releases a highly fluorescent 7-methoxycoumarin (MCA)
Ye et al.
O H O H
N N
O O
S S
F O
F N
Intermediate 1 Intermediate 2
73% yield 62% yield
Figure 3. Structures of intermediates 1–5.
H H
N a O N
O R1 CHO
O +
S S
Scheme 1. Synthesis of intermediates 1–5 (a) Piperidine,
AcOH, EtOH, 90 °C, overnight.
H
O N a O
O + R2 OH
S S
R1
Scheme 2. Synthesis of Y-01–Y-19 (a) Triphenylphosphine,
diethyl azodicarboxylic acid. THF, ice bath, overnight.
moiety that is affected by the internal bursting agent of
2,4-dinitrophenol (DNP), resulting in a large increase in
fluorescence intensity. The substrate is cleaved by 3CL/
Mpro to produce MCA fluorescent group, which has a maxi-
mum excitation at 320 nm and a maximum emission wave-
length of 405 nm. The activity of 3CL Mpro is detected by
measuring the fluorescence intensity. A potent 3CL Mpro
inhibitor, GC376 serves as a positive control for the
experiments.16
Results and discussion
The intermediates 1–5 (Figure 3) were synthesized by the
Knoevenagel condensation of thiazolidinedione and five
different substituted benzaldehydes (Scheme 1). TZD has a
range of tautomers. The SN2 substitution reactions involv-
ing halogenated hydrocarbons under alkaline conditions
are likely to occur in both N and O. Therefore, a highly
selective Mitsunobu reaction (Scheme 2) was used to syn-
thesis 19 compounds Y-01–Y-19 (Table 1) by replacing the
hydrogen on the nitrogen atom with an alcohol.
In vitro tests of the inhibition activity were carried out on
the 19 compounds synthesized (final concentration of the
reaction system 50 µM) and the positive control GC376
(final concentration of the reaction system 0.2 μM). Of these,
3
O H H
O H N O
N N
O
O S O
S S
F HO
Intermediate 3 Intermediate 4 Intermediate 5
87% yield 79% yield 60% yield
64.2% inhibition was achieved for Y-10, 61.9% for Y-15,
and 41.2% for Y-06, while 17.2% inhibition was achieved
O
for Y-04% and 15.9% inhibition was achieved for Y-05 at
50 µM (Table 2). The most potent compounds, Y-10 and
R1 Y-15, were selected for further IC50 assay studies.
The IC50 values of the selected compounds inhibiting
SARS-CoV-2 3CL Mpro were calculated and plotted.
Reference group GC376 has an IC50 value of 60.04 nM.
Compound Y-10 has an IC50 value of 75 µM, and compound
Y-15 has an IC50 value of 58.61 µM (Figure 4). The remain-
ing compounds have IC50 values higher than 100 µM.
R2
N
O
Conclusion
All the 1,2,4-thiazolidine-3,5-dione derivatives synthesized
R1
demonstrated inhibitory effects against recombinant 3CL
Mpro. With the addition of DTT, Y-15 and Y-10 had the
most potent and specific enzyme inhibition activity against
the recombinant 3CL Mpro. The results of this study provide
novel and important reference to design SARS-CoV-2 Mpro
targeted inhibitors.
Experimental
Materials and reagents
All reagents used were analytically pure reagents from com-
mercially available companies such as Lakin, Adamas, and
Titan, and reactions were monitored by thin-layer chroma-
tography (silica gel HSGF254 from Yantai Jiangyou Silicone
Development Co., Ltd., China). Spots were observed by
ultraviolet (UV) irradiation (254 nm), and compounds were
purified by silica gel column chromatography (100–200
mesh). Melting points were determined on a melting point
determination apparatus RY-1 (Tianjin, China). 1H NMR,
13
C NMR, and 19F NMR spectra were recorded using a
Bruker 600 MHz NMR spectrometer with DMSO-d6
(D = 99.9% + TMS = 0.03%) as the solvent. Mass spectra
were obtained on an Agilent 6120 Ion Trap LC/MS 500
analysis system (Santa Clara, CA, USA). Elemental analy-
ses were obtained on an Elementar Vario EL III elemental
analyzer (Langenselbold, Germany).
MCA-AVLQSGFR-Lys (Dnp)-Lys-NH2 and SARS-
CoV-2 Main Protease Mpro were obtained from Beyotime
Biotechnology Inc. (China). GC376 was purchased from
TargetMol (Wellesley Hills, MA, USA). Costar® 96-well
4 Journal of Chemical Research

Table 1. Compounds Y-01–Y-19.

Compound R1 R2 Yield
Y-01 76%

Y-02 73%

Y-03 94%

Y-04 78%

Y-05 83%

Y-06 47%

Y-07 77%

Y-08 66%

Y-09 83%
Ye et al. 5

Table 1. (Continued)

Compound R1 R2 Yield
Y-10 84%

Y-11 85%

Y-12 62%

Y-13 50%

Y-14 72%

Y-15 48%

Y-16 42%

(Continued)
6 Journal of Chemical Research

Table 1. (Continued)
Compound R1 R2 Yield
Y-17 29%

Y-18 37%

Y-19 66%

Table 2. Inhibition rate relative to the negative control. assays. The IC50 values against 3CL Mpro were measured
with 9–11 concentration sets, and three independent experi-
Compound Concentration Time Inhibition rate
ments were performed. Data were analyzed with GraphPad
Y-10 50 µM 2–8 min 64.2% Prism software.
Y-15 50 µM 2–8 min 61.9%
Y-06 50 µM 2–8 min 41.2%
Intermediates 1–5 general procedure
Y-04 50 µM 2–8 min 17.2%
Y-05 50 µM 2–8 min 15.9% To a solution of 2,4-thiazolidinedione (20 mmol) and
3-fluorobenzaldehyde (20 mmol) in anhydrous ethanol
(20 mL), added dropwise piperidine (4 mL) and glacial ace-
assay plates (Cat no. 3925) was purchased from Coring Inc. tic acid (2 mL). The resulting mixture was heated to 110 °C
(Corning, NY, USA). for 3 h and stirred overnight at 90 °C. After cooling to room
temperature, the reaction mixture was poured into ice water
(100 mL), and a large amount of yellow solid precipitated.
Enzymatic activity assays
The crude product was filtered off, recrystallized from eth-
Briefly, the 3CL Mpro of 30 nM was mixed with serial dilu- anol, and dried in vacuo to afford intermediate 1 as a light
tions of each compound in reaction buffer (50 mM Tris- yellow solid.
HCl, pH 7.3, 1 mM ethylenediaminetetraacetic acid
(EDTA), 0.01% TritonX-100; 1 mM DTT), and incubated (Z)-5-(3-Fluorobenzylidene)thiazolidine-2,4-dione (inter-
at 37 °C for 10 min. Next, a final concentration of 20 μM mediate 1). Light yellow solid, 73% yield.17
fluorogenic substrate MCA-AVLQSGFR-Lys(Dnp)- (Z)-5-(2-Fluorobenzylidene)thiazolidine-2,4-dione (inter-
Lys-NH2 was added. The fluorescence intensity was imme- mediate 2). Light yellow solid, 62% yield.18
diately measured at the wavelengths of 320 nm (excitation) (Z)-5-(4-Fluorobenzylidene)thiazolidine-2,4-dione (inter-
and 405 nm (emission) every 3 min for 30 min using a mediate 3). Yellow solid, 87% yield.19
TECAN infinite 200PRO plate reader (Männedorf, (Z)-5-(4-(Dimethylamino)benzylidene)thiazolidine-2,4-
Switzerland). GC376 (100 nM) was used as a positive dione (intermediate 4). Orange solid, 79% yield.20
control. (Z)-5-(4-Hydroxy-3-methoxybenzylidene)thiazoli-
The compounds with potent inhibition observed in pre- dine-2,4-dione (intermediate 5). Yellow solid, 60%
liminary inhibition assays were selected for further IC50 yield.21
Ye et al.
Figure 4. IC50 values of compounds Y-10 and Y-15.
Compounds Y-01–Y-06
To a stirred mixture of intermediate 1 (2 mmol) and 2-phe-
noxyethanol (2.4 mmol) in tetrahydrofuran (THF) (12 mL),
added triphenylphosphine (4 mmol). When the triphe-
nylphosphine had dissolved completely, diethyl azodicar-
boxylate (DEAD) (4 mmol) was added dropwise at ice bath
temperature. After stirring for 10 min, the ice bath was
removed, and the mixture was stirred for a further 12 h at
room temperature. The solvent was removed under vacuum
after thin layer chromatography (TLC) showed complete
consumption of intermediate 1 (PE/EA = 9:1). The crude
product was purified by column chromatography on silica
gel eluting with PE/EA = 9:1 to give compound Y-01.
Products Y-02–Y-06 were prepared in a similar manner.
(Z)-5-(3-Fluorobenzylidene)-3-(2-phenoxyethyl)thiazoli-
dine-2,4-dione (Y-01): Light yellow solid, 76% yield. m.p.
102 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.95 (s, 1H),
7.59 (dd, J = 14.2, 8.0 Hz, 1H), 7.48 (d, J = 10.0 Hz, 1H),
7.45 (d, J = 7.9 Hz, 1H), 7.34 (td, J = 8.4, 2.3 Hz, 1H), 7.27
(dd, J = 8.6, 7.4 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 6.90 (d,
J = 7.8 Hz, 2H), 4.21 (t, J = 5.7 Hz, 2H), 4.04 (t, J = 5.7 Hz,
2H). 13C NMR (151 MHz, DMSO-d6): δ 167.4 (s), 165.9
(s), 162.7 (d, J = 245.0 Hz), 158.4 (s), 135.7 (d, J = 8.2 Hz),
132.2 (d, J = 2.6 Hz), 131.9 (d, J = 8.5 Hz), 130.0 (s), 126.1
(d, J = 2.7 Hz), 123.2 (s), 121.4 (s), 117.9 (d, J = 21.2 Hz),
117.4 (d, J = 22.5 Hz), 115.0 (s), 64.1 (s), 41.4 (s). 19F NMR
(565 MHz, DMSO-d6): δ −111.7 (s). ESIMS: m/z (relative
intensity) 366.0 [M + Na]+ (100). Anal. calcd for
C18H14FNO3S: C, 62.96%; H, 4.11%; N, 4.08%; found: C,
63.16%; H, 4.09%; N, 3.98%.
(Z)-5-(3-Fluorobenzylidene)-3-(2-(pyridin-2-yl)ethyl)thia-
zolidine-2,4-dione (Y-02): White solid, 73% yield. m.p.
112 °C. 1H NMR (600 MHz, DMSO-d6): δ 8.46 (d,
J = 4.6 Hz, 1H), 7.90 (s, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.59
(dd, J = 14.9, 7.2 Hz, 1H), 7.48 (d, J = 10.1 Hz, 1H), 7.44 (d,
J = 7.7 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.29 (d, J = 7.7 Hz,
1H), 7.22 (t, 1H), 4.00 (t, J = 7.3 Hz, 2H), 3.05 (t, J = 7.3 Hz,
2H). 13C NMR (151 MHz, DMSO-d6): δ 167.3 (s), 165.8
(s), 162.7 (d, J = 245.1 Hz), 158.2 (s), 149.6 (s), 137.2 (s),
135.8 (d, J = = 8.2 Hz), 131.9 (d, J = 8.4 Hz), 131.8 (d,
J = 2.5 Hz), 126.1 (d, J = 2.6 Hz), 123.8 (s), 123.4 (s), 122.3
(s), 117.9 (d, J = 21.2 Hz), 117.4 (d, J = 22.5 Hz), 41.9 (s),
35.2 (s). 19F NMR (565 MHz, DMSO-d6): δ −111.7 (s).
7
ESIMS: m/z (relative intensity) 329.0 [M + H]+ (100).
Anal. calcd for C17H13FN2O2S: C, 62.18%; H, 3.99%; N,
8.53%; found: C, 62.42%; H, 3.95%; N, 8.40%.
(Z)-5-(3-Fluorobenzylidene)-3-(pyridin-3-ylmethyl)thia-
zolidine-2,4-dione (Y-03): White solid, 94% yield. m.p.
128 °C. 1H NMR (600 MHz, DMSO-d6): δ 8.58 (d,
J = 1.8 Hz, 1H), 8.51 (dd, J = 4.7, 1.2 Hz, 1H), 7.96 (s, 1H),
7.73 (d, J = 7.9 Hz, 1H), 7.58 (dd, J = 14.6, 7.5 Hz, 1H), 7.48
(d, J = 9.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.8,
4.8 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 4.88 (s, 2H). 13C NMR
(151 MHz, DMSO-d6): δ 167.6 (s), 165.8 (s), 162.7 (d,
J = 245.2 Hz), 149.7 (s), 149.5 (s), 136.1 (s), 135.7 (d,
J = 8.2 Hz), 132.5 (d, J = 2.6 Hz), 131.9 (d, J = 8.5 Hz), 131.6
(s), 126.1 (d, J = 2.6 Hz), 124.2 (s), 123.3 (s), 117.9 (d,
J = 21.2 Hz), 117.4 (d, J = 22.4 Hz), 42.9 (s). 19F NMR
(565 MHz, DMSO-d6): δ −111.6 (s). ESIMS: m/z (relative
intensity) 315.0 [M + H]+ (100). Anal. calcd for
C16H11FN2O2S: C, 61.14%; H, 3.53%; N, 8.91%; found: C,
61.26%; H, 3.63%; N, 9.25%.
(Z)-5-(3-Fluorobenzylidene)-3-(2-methoxyethyl)thiazoli-
dine-2,4-dione (Y-04): Light yellow solid, 78% yield. m.p.
71.2 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.93 (s, 1H),
7.59 (td, J = 8.0, 6.3 Hz, 1H), 7.48 (dd, J = 10.1, 1.9 Hz, 1H),
7.44 (d, J = 7.9 Hz, 1H), 7.35 (td, J = 8.5, 2.3 Hz, 1H), 3.83
(t, J = 5.6 Hz, 2H), 3.54 (t, J = 5.6 Hz, 2H), 3.23 (s, 3H). 13C
NMR (151 MHz, DMSO-d6): δ 167.3 (s), 165.8 (s), 162.7
(d, J = 245.2 Hz), 135.7 (d, J = 8.2 Hz), 132.1 (d, J = 2.6 Hz),
131.9 (d, J = 8.4 Hz), 126.1 (d, J = 2.7 Hz), 123.2 (s), 117.9
(d, J = 21.2 Hz), 117.3 (d, J = 22.4 Hz), 68.2 (s), 58.3 (s),
41.4 (s). 19F NMR (565 MHz, DMSO-d6): δ −111.7 (s).
ESIMS: m/z (relative intensity) 304.0 [M + Na]+ (100).
Anal. calcd for C13H12FNO3S: C, 55.51%; H, 4.30%; N,
4.98%; found: C, 55.68%; H, 4.28%; N, 4.88%.
(Z)-3-(2-Ethoxyethyl)-5-(3-fluorobenzylidene)thiazoli-
dine-2,4-dione (Y-05): Yellow solid, 83% yield. m.p.
78.1 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.91 (s, 1H),
7.58 (dd, J = 14.9, 7.1 Hz, 1H), 7.50-7.41 (m, 2H), 7.33 (t,
J = 8.5 Hz, 1H), 3.82 (t, J = 5.8 Hz, 2H), 3.57 (t, J = 5.8 Hz,
2H), 3.43 (q, J = 7.0 Hz, 2H), 1.05 (t, J = 7.0 Hz, 3H). 13C
NMR (151 MHz, DMSO-d6): δ 167.3 (s), 165.8 (s), 162.7
(d, J = 245.1 Hz), 135.7 (d, J = 8.0 Hz), 132.0 (d, J = 2.4 Hz),
131.9 (d, J = 8.3 Hz), 126.1 (d, J = 2.6 Hz), 123.2 (s), 117.8
8 Journal of Chemical Research
(d, J = 21.3 Hz), 117.3 (d, J = 22.5 Hz), 66.0 (s), 65.7 (s),
41.6 (s), 15.4 (s). 19F NMR (565 MHz, DMSO-d6): δ −111.7
(s). ESIMS: m/z (relative intensity) 318.0 [M + Na]+ (100).
Anal. calcd for C14H14FNO3S: C, 56.94%; H, 4.78%; N,
4.74%; found: C, 57.14%; H, 4.74%; N, 4.66%.
(Z)-3-(2-(2-Ethoxyethoxy)ethyl)-5-(3-fluorobenzylidene)
thiazolidine-2,4-dione (Y-06): White solid, 47.1% yield.
m.p. 97 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.93 (s, 1H),
7.58 (dd, J = 14.2, 7.9 Hz, 1H), 7.47 (d, J = 9.9 Hz, 1H), 7.44
(d, J = 7.8 Hz, 1H), 7.34 (td, J = 8.5, 2.0 Hz, 1H), 3.83 (t,
J = 5.7 Hz, 2H), 3.62 (t, J = 5.7 Hz, 2H), 3.50 (t, 2H), 3.41 (t,
2H), 3.37 (q, J = 7.0 Hz, 2H), 1.04 (t, J = 7.0 Hz, 3H). 13C
NMR (151 MHz, DMSO-d6): δ 167.3 (s), 165.8 (s), 162.7
(d, J = 245.1 Hz), 135.7 (d, J = 8.1 Hz), 132.0 (d, J = 2.3 Hz),
131.9 (d, J = 8.4 Hz), 126.1 (d, J = 2.5 Hz), 123.3 (s), 117.9
(d, J = 21.2 Hz), 117.3 (d, J = 22.4 Hz), 70.0 (s), 69.6 (s),
66.6 (s), 66.0 (s), 41.6 (s), 15.5 (s). 19F NMR (565 MHz,
DMSO-d6): δ −111.7 (s). ESIMS: m/z (relative intensity)
362.0 [M + Na]+ (100), 340.0 [M + H]+ (80). Anal. calcd
for C16H18FNO4S: C, 56.63%; H, 5.35%; N, 4.13%; found:
C, 56.48%; H, 5.30%; N, 3.97%.
Compounds Y-07–Y-13
To a stirred mixture of /intermediate 2 (2 mmol) and 2-phe-
noxyethanol (2.4 mmol) in THF (12 mL), added triphe-
nylphosphine (4 mmol). When the triphenylphosphine had
dissolved completely, DEAD (4 mmol) was added drop-
wise at ice bath temperature. After stirring for 10 min, the
ice bath was removed, and the mixture was stirred for a
further 12 h at room temperature. The solvent was removed
under vacuum after TLC showed complete consumption of
intermediate 2 (PE/EA = 9:1). The crude product was puri-
fied by column chromatography on silica gel eluting with
PE/EA = 9:1 to give compound Y-07. Products Y-08–Y-13
were prepared in a similar manner.
(Z)-5-(2-Fluorobenzylidene)-3-(2-phenoxyethyl)thiazoli-
dine-2,4-dione (Y-07): White solid, 77% yield. m.p. 105 °C.
1
H NMR (600 MHz, DMSO-d6): δ 7.92 (s, 1H), 7.57 (td,
J = 7.7, 1.8 Hz, 2H), 7.40 (t, J = 13.0, 5.2 Hz, 2H), 7.27 (t,
J = 8.6, 7.4 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H), 6.90 (d,
J = 7.9 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 4.04 (t, J = 5.7 Hz,
2H). 13C NMR (151 MHz, DMSO-d6): δ 167.4 (s), 165.8
(s), 161.0 (d, J = 252.3 Hz), 158.4 (s), 133.5 (d, J = 8.9 Hz),
130.0 (s), 129.5 (s), 125.9 (d, J = 3.3 Hz), 124.6 (d,
J = 6.1 Hz), 124.4 (s), 121.5 (s), 121.3 (d, J = 12.0 Hz), 116.8
(d, J = 21.3 Hz), 115.0 (s), 64.1 (s), 41.5 (s). 19F NMR
(565 MHz, DMSO-d6): δ −113.9 (s). ESIMS: m/z (relative
intensity) 366.0 [M + Na]+ (100). Anal. calcd for
C18H14FNO3S: C, 62.96%; H, 4.11%; N, 4.08%; found: C,
63.26%; H, 4.11%; N, 3.77%.
(Z)-5-(2-Fluorobenzylidene)-3-(2-(pyridin-2-yl)ethyl)thia-
zolidine-2,4-dione (Y-08): White solid, 66% yield. m.p.
114 °C. 1H NMR (600 MHz, DMSO-d6): δ 8.46 (d,
J = 4.7 Hz, 1H), 7.86 (s, 1H), 7.70 (t, J = 8.4, 6.9 Hz, 1H),
7.60-7.50 (m, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.29 (d,
J = 7.7 Hz, 1H), 7.25-7.19 (m, 1H), 4.00 (t, J = 7.3 Hz, 2H),
3.05 (t, J = 7.3 Hz, 2H). 13C NMR (151 MHz, DMSO-d6): δ
167.2 (s), 165.7 (s), 161.0 (d, J = 252.2 Hz), 158.1 (s), 149.6
(s), 137.1 (s), 133.4 (d, J = 8.8 Hz), 129.4 (s), 125.9 (s),
124.5 (s), 124.2 (d, J = 6.1 Hz), 123.8 (s), 122.3 (s), 121.3
(d, J = 11.7 Hz), 116.7 (d, J = 21.4 Hz), 41.9 (s), 35.2 (s). 19F
NMR (565 MHz, DMSO-d6): δ −114.0 (s). ESIMS: m/z
(relative intensity) 329.0 [M + H]+ (100). Anal. calcd for
C17H13FN2O2S: C, 62.18%; H, 3.99%; N, 8.53%; found: C,
62.36%; H, 3.96%; N, 8.26%.
(Z)-5-(2-Fluorobenzylidene)-3-(pyridin-3-ylmethyl)thia-
zolidine-2,4-dione (Y-09): White solid, 83% yield. m.p.
130.2 °C. 1H NMR (600 MHz, DMSO-d6): δ 8.58 (d,
J = 2.0 Hz, 1H), 8.52 (dd, J = 4.8, 1.5 Hz, 1H), 7.93 (s, 1H),
7.74 (d, J = 7.9 Hz, 1H), 7.59-7.54 (m, 2H), 7.41-7.36 (m,
3H), 4.88 (s, 2H). 13C NMR (151 MHz, DMSO-d6): δ 167.6
(s), 165.7 (s), 161.0 (d, J = 252.3 Hz), 149.7 (s), 149.5 (s),
136.2 (s), 133.5 (d, J = 8.9 Hz), 131.5 (s), 129.5 (s), 125.9
(d, J = 3.4 Hz), 124.9 (d, J = 6.1 Hz), 124.5 (s), 124.2 (s),
121.3 (d, J = 12.0 Hz), 116.8 (d, J = 21.4 Hz), 43.0 (s). 19F
NMR (565 MHz, DMSO-d6): δ −113.8 (s). ESIMS: m/z
(relative intensity) 315.0 [M + H]+ (100). Anal. calcd for
C16H11FN2O2S: C, 61.14%; H, 3.53%; N, 8.91%; found: C,
61.09%; H, 3.80%; N, 8.90%.
(Z)-5-(2-Fluorobenzylidene)-3-(2-methoxyethyl)thiazoli-
dine-2,4-dione (Y-10): White solid, 84% yield. m.p.
73.5 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.89 (s, 1H),
7.60-7.51 (m, 2H), 7.38 (t, J = 8.1 Hz, 2H), 3.83 (t, J = 5.6 Hz,
2H), 3.54 (t, J = 5.6 Hz, 2H), 3.24 (s, 3H). 13C NMR
(151 MHz, DMSO-d6): δ 167.3 (s), 165.7 (s), 161.0 (d,
J = 252.3 Hz), 133.4 (d, J = 8.9 Hz), 129.4 (s), 125.9 (d,
J = 3.3 Hz), 124.5 (d, J = 6.2 Hz), 124.3 (s), 121.3 (d,
J = 11.8 Hz), 116.7 (d, J = 21.4 Hz), 68.2 (s), 58.3 (s), 41.4
(s). 19F NMR (565 MHz, DMSO-d6): δ −113.9 (s). ESIMS:
m/z (relative intensity) 304.0 [M + Na]+ (100). Anal. calcd
for C13H12FNO3S: C, 55.51%; H, 4.30%; N, 4.98%; found:
C, 55.73%; H, 4.23%; N, 5.02%.
(Z)-3-(2-Ethoxyethyl)-5-(2-fluorobenzylidene)thiazoli-
dine-2,4-dione (Y-11): White solid, 85% yield. m.p.
80.5 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.89 (s, 1H),
7.59-7.53 (m, 2H), 7.38 (t, J = 8.1 Hz, 2H), 3.82 (t, J = 5.8 Hz,
2H), 3.57 (t, J = 5.8 Hz, 2H), 3.43 (q, J = 7.0 Hz, 2H), 1.05
(t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO-d6): δ 167.3
(s), 165.7 (s), 161.0 (d, J = 252.3 Hz), 133.4 (d, J = 8.9 Hz),
129.4 (s), 125.9 (d, J = 3.5 Hz), 124.5 (d, J = 6.2 Hz), 124.3
(s), 121.3 (d, J = 11.8 Hz), 116.7 (d, J = 21.4 Hz), 66.0 (s),
65.7 (s), 41.6 (s), 15.4 (s). 19F NMR (565 MHz, DMSO-d6):
δ −113.9 (s). ESIMS: m/z (relative intensity) 318.1
[M + Na]+ (100), 296.0 [M + H]+ (60). Anal. calcd for
C14H14FNO3S: C, 56.94%; H, 4.78%; N, 4.74%; found: C,
57.12%; H, 4.75%; N, 4.72%.
(Z)-5-(2-Fluorobenzylidene)-3-(2-morpholinoethyl)thia-
zolidine-2,4-dione (Y-12): White solid, 62% yield. m.p.
124 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.91 (s, 1H),
7.61-7.54 (m, 2H), 7.39 (t, J = 7.9 Hz, 2H), 3.78 (t,
J = 6.4 Hz, 2H), 3.55-3.46 (m, 4H), 2.52 (t, J = 6.4 Hz, 2H),
2.40 (s, 4H). 13C NMR (151 MHz, DMSO-d6): δ 167.4 (s),
Ye et al.
165.8 (s), 161.0 (d, J = 252.1 Hz), 133.5 (d, J = 8.9 Hz),
129.5 (s), 125.9 (d, J = 3.5 Hz), 124.4 (d, J = 5.6 Hz), 124.4
(s), 121.3 (d, J = 11.9 Hz), 116.8 (d, J = 21.4 Hz), 66.7 (s),
55.1 (s), 53.6 (s), 39.2 (s). 19F NMR (565 MHz, DMSO-d6):
δ −114.0 (s). ESIMS: m/z (relative intensity) 337.0
[M + H]+ (100). Anal. calcd for C16H17FN2O3S: C,
57.13%; H, 5.09%; N, 8.33%; found: C, 57.26%; H,
5.09%; N, 8.25%.
(Z)-3-(2-(2-Ethoxyethoxy)ethyl)-5-(2-fluorobenzylidene)
thiazolidine-2,4-dione (Y-13): White solid, 50% yield. m.p.
95 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.88 (s, 1H),
7.58-7.51 (m, 2H), 7.40-7.34 (m, 2H), 3.83 (t, J = 5.7 Hz,
2H), 3.63 (t, J = 5.7 Hz, 2H), 3.51 (t, J = 5.7, 3.8 Hz, 2H),
3.41 (t, J = 5.7, 3.9 Hz, 2H), 3.37 (q, J = 7.0 Hz, 2H), 1.04 (t,
J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO-d6): δ 167.3
(s), 165.7 (s), 161.0 (d, J = 252.2 Hz), 133.4 (d, J = 8.9 Hz),
129.4 (s), 125.9 (d, J = 3.5 Hz), 124.4 (s), 124.3 (d,
J = 3.4 Hz), 121.2 (d, J = 11.9 Hz), 116.7 (d, J = 21.4 Hz),
70.0 (s), 69.6 (s), 66.6 (s), 66.0 (s), 41.6 (s), 15.5 (s). 19F
NMR (565 MHz, DMSO-d6): δ −114.0 (s). ESIMS: m/z
(relative intensity) 340.0 [M + H]+ (100), 362.0 [M + Na]+
(70). Anal. calcd for C16H18FNO4S: C, 56.63%; H, 5.35%;
N, 4.13%; found: C, 56.61%; H, 5.25%; N, 4.01%.
Compounds Y-14–Y-16
To a stirred mixture of intermediate 3 (2 mmol) and 2-pyr-
idineethanol (2.4 mmol) in THF (12 mL), added triphe-
nylphosphine (4 mmol). When the triphenylphosphine had
dissolved completely, DEAD (4 mmol) was added drop-
wise at ice bath temperature. After stirring for 10 min, the
ice bath was removed, and the mixture was stirred for a
further 12 h at room temperature. The solvent was removed
under vacuum after TLC showed complete consumption
of intermediate 3 (PE/EA = 7:3). The crude product was
purified by column chromatography on silica gel eluting
with PE/EA = 8:2 to give compound Y-14. Products Y-15
and Y-16 were prepared in a similar manner.
(Z)-5-(4-Fluorobenzylidene)-3-(2-(pyridin-2-yl)ethyl)thia-
zolidine-2,4-dione (Y-14): Yellow solid, 72% yield. m.p.
132 °C. 1H NMR (600 MHz, DMSO-d6): δ 8.45 (dd, J = 4.8,
0.8 Hz, 1H), 7.90 (s, 1H), 7.74-7.66 (m, 3H), 7.38 (t,
J = 8.7 Hz, 2H), 7.28 (d, J = 7.7 Hz, 1H), 7.22 (t, J = 7.3,
5.0 Hz, 1H), 4.00 (t, J = 7.3 Hz, 2H), 3.04 (t, J = 7.3 Hz, 2H).
13
C NMR (151 MHz, DMSO-d6): δ 167.40 (s), 165.9 (s),
163.4 (d, J = 251.0 Hz), 158.2 (s), 149.6 (s), 137.1 (s), 133.1
(d, J = 8.9 Hz), 132.1 (s), 130.1 (d, J = 3.1 Hz), 123.8 (s),
122.3 (s), 121.4 (d, J = 2.3 Hz), 117.0 (d, J = 22.0 Hz), 41.8
(s), 35.2 (s). 19F NMR (565 MHz, DMSO-d6): δ −108.5 (s).
ESIMS: m/z (relative intensity) 329.0 [M + H]+ (100).
Anal. calcd for C17H13FN2O2S: C, 62.18%; H, 3.99%; N,
8.53%; found: C, 62.41%; H, 3.94%; N, 8.62%.
(Z)-5-(4-Fluorobenzylidene)-3-(2-morpholinoethyl)thiazo-
lidine-2,4-dione (Y-15): Yellow solid, 48% yield. m.p.
143 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.94 (s, 1H), 7.69
(dd, J = 8.5, 5.5 Hz, 2H), 7.39 (t, J = 8.7 Hz, 2H), 3.77 (t,
J = 6.4 Hz, 2H), 3.50 (s, 4H), 2.52 (t, J = 6.5 Hz, 2H), 2.40 (s,
4H). 13C NMR (151 MHz, DMSO-d6): δ 167.5 (s), 166.0 (s),
9
163.4 (d, J = 251.0 Hz), 133.1 (d, J = 8.9 Hz), 132.3 (s), 130.1
(d, J = 3.0 Hz), 121.3 (s), 117.0 (d, J = 22.0 Hz), 66.7 (s), 55.2
(s), 53.6 (s), 39.1 (s). 19F NMR (565 MHz, DMSO-d6): δ
−108.5 (s). ESIMS: m/z (relative intensity) 337.1 [M + H]+
(100). Anal. calcd for C16H17FN2O3S: C, 57.13%; H, 5.09%;
N, 8.33%; found: C, 57.25%; H, 5.09%; N, 8.60%.
(Z)-5-(4-Fluorobenzylidene)-3-(2-(pyrrolidin-1-yl)ethyl)
thiazolidine-2,4-dione (Y-16): Yellow solid, 42% yield.
m.p. 107 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.95 (s,
1H), 7.73-7.67 (m, 2H), 7.44-7.36 (m, 2H), 3.76 (t,
J = 6.5 Hz, 2H), 2.63 (t, J = 6.5 Hz, 2H), 2.47 (s, 4H), 1.64
(dt, J = 6.4, 3.0 Hz, 4H). 13C NMR (151 MHz, DMSO-d6): δ
167.5 (s), 166.0 (s), 163.4 (d, J = 250.8 Hz), 133.1 (d,
J = 8.9 Hz), 132.4 (s), 130.1 (d, J = 3.1 Hz), 121.4 (s), 117.0
(d, J = 22.0 Hz), 54.0 (s), 52.8 (s), 41.2 (s), 23.7 (s). 19F
NMR (565 MHz, DMSO-d6): δ −108.5 (s). ESIMS: m/z
(relative intensity) 321.1 [M + H]+ (100). Anal. calcd for
C16H17FN2O2S: C, 59.98%; H, 5.35%; N, 8.74%; found: C,
59.77%; H, 5.32%; N, 8.55%.
Compound Y-17
To a stirred mixture of intermediate 4 (2 mmol) and 2-phe-
noxyethanol (2.4 mmol) in THF (12 mL), added triphe-
nylphosphine (4 mmol). When the triphenylphosphine had
dissolved completely, DEAD (4 mmol) was added drop-
wise at ice bath temperature. After stirring for 10 min, the
ice bath was removed, and the mixture was stirred for a
further 12 h at room temperature. The solvent was removed
under vacuum after TLC showed complete consumption of
intermediate 4 (PE/EA = 7:3). The crude product was puri-
fied by column chromatography on silica gel eluting with
PE/EA = 9:1 to give compound Y-17.
(Z)-5-(4-(Dimethylamino)benzylidene)-3-(2-phenoxye-
thyl)thiazolidine-2,4-dione (Y-17): Yellow solid, 29%
yield. m.p. 112 °C. 1H NMR (600 MHz, DMSO-d6): δ 7.80
(s, 1H), 7.44 (d, J = 9.0 Hz, 2H), 7.30-7.22 (m, 2H), 6.92 (t,
J = 7.3 Hz, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 9.0 Hz,
2H), 4.19 (t, J = 5.7 Hz, 2H), 4.01 (t, J = 5.7 Hz, 2H), 3.00 (s,
6H). 13C NMR (151 MHz, DMSO-d6): δ 167.9 (s), 166.2
(s), 158.4 (s), 152.1 (s), 134.7 (s), 132.9 (s), 130.0 (s), 121.4
(s), 120.2 (s), 115.0 (s), 113.4 (s), 112.5 (s), 64.2 (s), 41.0
(s), 40.0 (s). ESIMS: m/z (relative intensity) 369.0 [M + H]+
(100). Anal. calcd for C20H20N2O3S: C, 65.20%; H, 5.47%;
N, 7.60%; found: C, 65.32%; H, 5.40%; N, 7.49%.
Compound Y-18
To a mixture of intermediate 4 (2 mmol) and 2-pyri-
dineethanol (2.4 mmol) in THF (12 mL), added triphe-
nylphosphine (4 mmol). When the triphenylphosphine
had dissolved completely, DEAD (4 mmol) was added
dropwise at ice bath temperature. After stirring for
10 min, the ice bath was removed, and the mixture was
stirred for a further 12 h at room temperature. The solvent
was removed under vacuum after TLC showed complete
consumption of intermediate 4 (PE/EA = 7:3). The crude
product was recrystallized from acetone, filtered off, and
dried in vacuo to afford compound Y-18.
10
(Z)-5-(4-(Dimethylamino)benzylidene)-3-(2-(pyridin-2-yl)
ethyl)thiazolidine-2,4-dione (Y-18): Yellow solid, 37%
yield. m.p. 118 °C. 1H NMR (600 MHz, DMSO-d6): δ 8.46
(d, J = 4.1 Hz, 1H), 7.76 (s, 1H), 7.70 (td, J = 7.6, 1.7 Hz,
1H), 7.45 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 7.7 Hz, 1H), 7.22
(dd, J = 7.0, 5.2 Hz, 1H), 6.82 (d, J = 8.9 Hz, 2H), 3.98 (t,
J = 7.3 Hz, 2H), 3.04 (d, J = 7.4 Hz, 2H), 3.02 (s, 6H). 13C
NMR (151 MHz, DMSO-d6): δ 167.8 (s), 166.1 (s), 158.3
(s), 152.1 (s), 149.6 (s), 137.1 (s), 134.3 (s), 132.8 (s), 123.7
(s), 122.3 (s), 120.2 (s), 113.7 (s), 112.5 (s), 41.6 (s), 40.1
(s), 35.4 (s). ESIMS: m/z (relative intensity) 354.1 [M + H]+
(100). Anal. calcd for C19H19N3O2S: C, 64.57%; H, 5.42%;
N, 11.89%; found: C, 64.89%; H, 5.38%; N, 11.77%.
Compound Y-19
To a stirred mixture of intermediate 5 (2 mmol) and 2-pyri-
dineethanol (2.4 mmol) in THF (12 mL), added triphe-
nylphosphine (4 mmol). When the triphenylphosphine had
dissolved completely, DEAD (4 mmol) was added drop-
wise at ice bath temperature. After stirring for 10 min, the
ice bath was removed, and the mixture was stirred for a
further 12 h at room temperature. The solvent was removed
under vacuum after TLC showed complete consumption of
intermediate 5 (PE/EA = 6:4). The crude product was puri-
fied by column chromatography on silica gel eluting with
PE/EA = 7:3 to give compound Y-19.
(Z)-5-(4-Hydroxy-3-methoxybenzylidene)-3-(2-(pyridin-
2-yl)ethyl)thiazolidine-2,4-dione (Y-19): Yellow solid,
66% yield. m.p. 134 °C. 1H NMR (600 MHz, DMSO-d6): δ
10.01 (s, 1H), 8.46 (d, J = 4.1 Hz, 1H), 7.79 (s, 1H), 7.69 (td,
J = 7.6, 1.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.22 (dd,
J = 6.9, 5.1 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 7.08 (dd,
J = 8.3, 1.9 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 3.98 (t,
J = 7.3 Hz, 2H), 3.82 (s, 3H), 3.03 (t, J = 7.3 Hz, 2H). 13C
NMR (151 MHz, DMSO-d6): δ 167.7 (s), 166.1 (s), 158.2
(s), 150.1 (s), 149.6 (s), 148.5 (s), 137.1 (s), 134.0 (s), 124.8
(s), 124.7 (s), 123.7 (s), 122.3 (s), 117.3 (s), 116.7 (s), 114.8
(s), 56.1 (s), 41.7 (s), 35.3 (s). ESIMS: m/z (relative inten-
sity) 357.0 [M + H]+ (100). Anal. calcd for C18H16N2O4S:
C, 60.66%; H, 4.53%; N, 7.86%; found: C, 60.68%; H,
4.51%; N, 7.66%.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Journal of Chemical Research
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was supported by the Science and Technology Commission
of Shanghai Municipality (grant no. 22S11901000).
ORCID iD
Zhiyu Shao https://orcid.org/0000-0002-2520-8188
Supplemental material
Supplemental material for this article is available online.
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