Novel coumarin-thiazolyl ester derivatives as potential DNA gyrase Inhibitors: Design, synthesis, and antibacterial activity

Article abstract of DOI:10.1016/j.bioorg.2020.103907

The design and synthesis of novel coumarin-thiazolyl ester derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8p exhibited excellent antibacterial activity against four bacteria strains with MIC values of 0.05, 0.05, 8, and 0.05 μg/mL, respectively. In vitro drug-resistant bacterial inhibition experiments indicated that compound 8p exhibited the best bacteriostatic effect in the selected compounds and four positive control drugs with MIC values of 4 μg/mL. In vitro enzyme inhibitory assay showed that compound 8p exhibited potent inhibition against DNA gyrase with IC₅₀ values of 0.13 μM. The molecular docking model indicated that compounds 8p can bind well to the DNA gyrase by interacting with amino acid residues. This study demonstrated that the compound 8p can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.

Full text of DOI:10.1016/j.bioorg.2020.103907

BioorganicChemistry100(2020)103907
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Novel coumarin-thiazolyl ester derivatives as potential DNA gyrase
Inhibitors: Design, synthesis, and antibacterial activity
⁎
Hao Liua, Dong-Guo Xiaa, Zhi-Wen Chua, Rui Hub, Xiang Chenga, Xian-Hai Lva,
a School of Science, Anhui Agricultural University, 230036 Hefei, People’s Republic of China
b Central Iron & Steel Research Institute, 100081 Beijing, People’s Republic of China
A R T I C L E I N F O
A B S T R A C T
Keywords:
The design and synthesis of novel coumarin-thiazolyl ester derivatives of potent DNA gyrase inhibitory activity
were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial
activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8p
exhibited excellent antibacterial activity against four bacteria strains with MIC values of 0.05, 0.05, 8, and
0.05 μg/mL, respectively. In vitro drug-resistant bacterial inhibition experiments indicated that compound 8p
exhibited the best bacteriostatic effect in the selected compounds and four positive control drugs with MIC
values of 4 μg/mL. In vitro enzyme inhibitory assay showed that compound 8p exhibited potent inhibition
against DNA gyrase with IC50 values of 0.13 μM. The molecular docking model indicated that compounds 8p can
bind well to the DNA gyrase by interacting with amino acid residues. This study demonstrated that the com-
pound 8p can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide
valuable information for the commercial DNA gyrase inhibiting bactericides.
DNA gyrase inhibitors
Coumarin
Thiazole
Molecular docking
Drug-resistant bacteria
Antibacterial activity
1. Introduction
structural features, is more conducive to the interaction of DNA, enzymes,
and receptors in various biological cations, anions, small molecules and
The spread of antibiotic-resistant bacteria poses a substantial threat
to morbidity and mortality worldwide [1]. Deaths caused by microbial
infections such as bacteria and fungi account for about one-fifth of the
world’s total deaths [2]. Regarding antibiotic-resistant bacteria, in the
past two decades, the US Food and Drug Administration and the Eur-
opean Medicines Agency have disclosed that only two new antibiotic
classes (lipopeptides and oxazolidinones) have been developed and
approved [3,4]. As the basic nuclear enzyme of cells, DNA topoisome-
rases (DNA Topo) are involved in life processes such as cell replication,
transcription, and mitosis [5]. The bacterial topoisomerases II (DNA
gyrase) is a validated target for the development of novel antibacterial
agents [6,7]. Since its discovery in 1962, the quinolones, one of the
DNA gyrase inhibitors [8,9], gradually became helpless for many drug-
resistant bacteria after extensive use and abuse [3]. In order to solve
this problem, an effective method is to retain the existing antibiotic core
scaffold and continuously modify the new compounds without reducing
its antibacterial activity [10]. Based on our previous work [8], we had
found that coumarin could be modified as a core scaffold to give
compounds excellent antibacterial activity.
biological systems with respect to other azoles [11,12]. Accordingly,
thiazole fragment has been widely used in the design of medicinal mole-
cules [13]. Especially with the success of a series of thiazole compounds
for clinical and agricultural production [14–17], such as the third cepha-
losporins, tigemonam, aztreonam, sulfathiazole and so on, had been widely
used to deal with various diseases. These drugs indicated that thiazole
derivatives had a large space for being developed as agents with excellent
antibacterial activity, low toxicity, and fewer side effects [11,18].
Human use of antibacterial agents continues to cause pollution and
residual toxicity in the natural environment [19,20]. In previous work
[21], we found that when an ester group is introduced into a com-
pound, it enhances the antibacterial activity of the compound and al-
lows it to bind more tightly to the target enzyme [22]. In this work, we
chose coumarin as a primer scaffold, introduced and bound the thia-
zolyl to coumarin with an ester group to generate target scaffold, there
are 23 novel coumarin-thiazolyl ester derivatives targeting DNA gyrase
designed and synthesized. All compounds were used to examined an-
tibacterial activity against four bacteria strains. Moreover, molecular
docking analysis and Lipinski’s parameters [23] were performed and
measured on all derivatives to fully discussed the structure-activity
relationships.
Azole compounds play an obvious and important role in combating
bacterial infections. Among them, thiazole, by virtue of its unique
⁎ Corresponding author at: School of Science, Anhui Agricultural University, 230036 Hefei, People’s Republic of China.
E-mail address: lvxianhai@ahau.edu.cn (X.-H. Lv).
https://doi.org/10.1016/j.bioorg.2020.103907
Received 17 February 2020; Received in revised form 22 April 2020; Accepted 30 April 2020
Availableonline04May2020
0045-2068/©2020ElsevierInc.Allrightsreserved.

H. Liu, et al.
BioorganicChemistry100(2020)103907
Table 1
recrystallization is needed in most cases. As shown in Fig. 1, the in-
termediates 7 were synthesized by stirring the mixture of 4,5-di-
methylthiazole and a series of substituted aldehyde in the ultra-dry THF
at −78 °C. Then the reaction was warmed to room temperature for 2 h,
quenched with water and extracted with ethyl acetate to give the crude
product. The crude product was purified by recrystallization (ethyl
acetate/hexanes). The target compounds were prepared by mixing in-
termediate 4 and intermediate 7 with DCC and DMAP at 0 °C. The
chemical structures of all synthesized compounds were determined by
1H NMR, 13C NMR, and MS. Compounds 8e and 8i have been char-
acterized by single crystal X-ray crystallography. The check-cif files for
compounds 8e and 8i are listed in Supporting Information, crystal data
are shown in Fig. 2 and Table S4. Crystallographic data (excluding
structure factors) for the structure were deposited with the Cambridge
Crystallographic Data Center (CCDC) as No. CCDC-1908526 (8e) and
No. CCDC-1908525 (8i).
MIC Values of Compounds 8a-8x against S. aureus, L. monocytogenes, E. coli and
Salmonella.
Compd.
R1
R2
R3
MIC (μg/mL)
S. aa
L.ma
E.ca
S. ea
8a
H
H
Phenyl
4
64
64
64
64
32
8
0.05
0.05
0.05
4
8b
8c
H
H
Para-chlorophenyl
Isobutyl
4
> 64
> 64
> 64
4
H
H
4
8d
8e
H
H
Naphthyl
4
H
H
Meta-chlorophenyl
Ortho-chlorophenyl
Meta-chlorophenyl
Para-methylphenyl
Phenyl
4
0.05
4
8f
H
H
0.05
32
8
8g
Me
Br
Br
Br
Br
Br
Br
NO2
Cl
Cl
Cl
Cl
H
H
0.05
0.05
> 64
0.05
> 64
0.05
4
4
4
8h
8i
H
4
4
> 64
0.05
4
H
0.05
4
8j
H
Para-chlorophenyl
Isobutyl
2
4
8k
8l
H
4
4
0.05
0.05
4
H
Naphthyl
2
4
8m
8n
8o
8p
8q
8r
H
Meta-chlorophenyl
Meta-chlorophenyl
Phenyl
4
> 64
32
0.05
4
2.3. Antibacterial activity and SAR discussion
H
8
64
H
4
32
4
32
H
Para-chlorophenyl
Naphthyl
0.05
0.05
> 64
> 64
64
8
0.05
> 64
> 64
> 64
> 64
> 64
> 64
> 64
0.05
0.25
0.5
The MIC values of the in vitro antibacterial activity screening of all
compounds are presented in Table 1. Most of the derivatives exhibited
moderate to potent antibacterial activities of four bacterial strains. For
two gram-positive bacteria, in these derivatives, five compounds (i.e.,
8f, 8g, 8i, 8p, and 8q) displayed significant antibacterial activity
against S. aureus compared with four positive control drugs
(MIC = 0.125–4 μg/mL), with MIC values equal to 0.05 μg/mL. Five
compounds (i.e., 8g, 8i, 8k, 8p, and 8x) exhibited excellent anti-
bacterial activity against L. monocytogenes compared with four positive
control drugs (MIC = 4–8 μg/mL), with MIC values equal to 0.05 μg/
mL. For two gram-negative bacteria, compound 8 m was found to show
improved antibacterial activity against E. coli compared with four po-
sitive control drugs (MIC = 0.125–8 μg/mL), with MIC values equal to
0.05 μg/mL. 9 compounds (i.e., 8a, 8b, 8c, 8e, 8i, 8k, 8l, 8p and 8x)
showed better antibacterial activity against Salmonella compared with
four positive control drugs (MIC = 0.25–4 μg/mL), with MIC values
equal to 0.05 μg/mL.
H
0.05
4
H
Meta-chlorophenyl
Para-methylphenyl
Phenyl
4
16
8
8s
N(Et2)
N(Et2)
N(Et2)
N(Et2)
N(Et2)
N(Et2)
–
4
8t
H
4
64
4
8u
8v
H
Naphthyl
4
> 64
32
4
H
Meta-chlorophenyl
Ortho-chlorophenyl
Para-chlorophenyl
–
2
4
8w
8x
H
8
64
4
H
4
0.05
4
4
CIPb
NBc
GATd
LVXe
–
0.125
2
0.5
4
–
–
–
6.25
4
–
–
–
0.5
4
8
4
–
–
–
4
0.125
0.25
a
Abbreviations: Staphylococcus aureus (ATCC-12600); Listeria monocytogenes
(ATCC-15313); Escherichia coli (ATCC-25922); Salmonella (ATCC-9184).
b
c
d
e
Ciprofloxacin.
Novobiocin.
Gatifloxacin.
Levofloxacin.
After analyzing biological activity data, we found that the anti-
bacterial activities of the compounds were enhanced when the target
compounds had a substituent on the coumarin core. Among them,
bromine and chlorine substituents have more significant effect. For S.
aureus, when the R1 position of compounds was substituted with bro-
mine or chlorine, its antibacterial activities were increased. When the
R2 position was substituted with diethylamino, only compound 8v
showed good antibacterial activity. For L. monocytogenes, compound 8v
exhibited excellent antibacterial activity, indicating that when both R1
and R3 were substituted by chlorine moiety, the enhancement of anti-
bacterial activity is beneficial. However, when R2 position was sub-
stituted with diethylamino, the antibacterial activity of the compound
is poor, the same as when both R1 and R2 position were hydrogen. For
E. coli, the overall antibacterial activities of compounds are not ideal
except 8x. For Salmonella, when R1 position was substituted with bro-
mine or chlorine, compounds 8m and 8p showed potent antibacterial
activity compared with novobiocin and gatifloxacin. In summary, the
results demonstrated that the improved antifungal activities of these
compounds may be attributed to the substitution at the coumarin core
and replacement of the phenyl in thiazolyl (Fig. 3).
2. Results and discussion
2.1. Molecular design
In the beginning, we synthesized seven intermediates 7. After
measuring its MIC values against four bacteria (Table S1), we can see
that the antibacterial activity of the intermediates 7 is not ideal (Table
S2). So, we introduced the coumarin to get the target scaffold. The data
in Table 1 indicated that the introduction of thiazolyl groups with the
coumarin core greatly enhances the antibacterial activity of the com-
pounds, which demonstrated the rationality of our design strategy. The
compounds were designed based on Lipinski’s “Rule of 5″ properties
with computer aids [23]. The aim of computational analysis is to filter
the compounds considered unsuitable for screening purposes. These
parameters were calculated using Molinspiration software (https://
www.molinspiration.com/) and the results (Table S3) showed that the
compounds we designed and synthesized almost meet the requirements
of the above parameters, making them play an important role in drug
development.
2.2. Chemistry
2.4. Antibacterial effect of selected compounds on drug-resistant bacteria
The key reaction in the synthesis of this class of compounds was the
esterification reaction. The synthetic routes of the 8a–8x are outlined in
Fig. 1. Intermediate 4 was easily prepared by the reaction of 2-hydro-
xybenzaldehydes (1) and Meldrum's Acid (2) with a catalytic amount of
piperidinyl acetate refluxed in ethanol. This one-pot procedure is con-
venient and straightforward with simple product isolation. No
In order to further verify whether these compounds have inhibitory
effects on drug-resistant bacteria, we selected five compounds (8i, 8l,
8p, 8q, and 8v) to determine the minimum inhibitory concentration
values for MRSA and VRSA. In terms of two drug-resistant bacteria
strains, the selected compounds and the positive control drugs have a
better antibacterial effect on MRSA. As can be seen from the data in
2

H. Liu, et al.
BioorganicChemistry100(2020)103907
Fig. 1. Synthetic routes for intermediate 4, 7, and target compounds. Reagents and conditions: (a) Piperidine, acetic acid, EtOH, 25 °C; (b) reflux, 2 h; (c) n-BuLi, THF
(dry), −78 °C; (d) DCC, DMAP, DCM, 0 °C,10–15 h.
Fig. 2. The crystal structures of compound 8e and 8i.
Fig. 3. Summarized SARs of target compounds.
Table 2, compound 8p exhibited the best bacteriostatic effect in the
selected compounds and four positive control drugs. Based on the above
bioactivity experimental data, compound 8p can act as the most potent
DNA gyrase inhibitor in the reported series of compounds.
2.5. Enzyme inhibitory activity
From the results of the in vitro biological assay, compound 8p was
identified as the most promising candidate for further study, and it′s in
vitro enzyme inhibitory activity against DNA gyrase isolated from E. coli
was determined. As shown in Table 3, the inhibitory effect of compound
8p on DNA gyrase is better than that of four control drugs, with an IC50
value of 0.13 μM. These results further indicated that the practical
potential of this novel compound can put a great deal of pressure on the
survival of the bacteria.
Table 2
MIC Values of selected compounds against MRSA and VRSA.
Compd.
MIC (μg/mL)
a
MRSA
VRSAb
8i
8
> 64
16
4
2.6. Molecular docking analysis
8l
16
4
8p
In order to gain a deep understanding of the molecular docking re-
lationship between active and inactive compounds, the docking details of
compound 8p and 8a with DNA gyrase are shown in Fig. 4. For com-
pound 8p, as shown in Fig. 3(A), Arg1122(D) established cation-π in-
teraction with thiazolyl. In the coumarin core, Arg1122(B) formed a hy-
drogen bond (angle = 180°, distance = 2.29 Å) with chlorine substituent,
and Dc11(E) formed a hydrogen bond (angle = 180°, distance = 2.33 Å)
8q
4
8
8v
8
32
16
32
32
16
CIP
NB
GAT
LVX
4
16
8
32
a
b
Methicillin-resistant S. aureus (MRAS, N315).
Vancomycin-resistant S. aureus (VRSA, Mu50).
with
a carbonyl group. Another hydrogen bond (angle = 180°,
3

H. Liu, et al.
BioorganicChemistry100(2020)103907
Table 3
4. Materials and methods
Inhibitory effects of selected compounds against
DNA gyrase.
4.1. General methods
Compd.
IC50 (μM)
DNA gyrase
All chemicals and reagents used in this work were purchased from
Energy, Meryer. 1H NMR and 13C NMR spectra were collected on
Agilent DD2 600 Hz spectrometer with CDCl3 as the solvent, and the
chemical shifts (δ) were recorded in parts per million (ppm). ESI-MS
spectra were carried out on a Mariner System 5304 mass spectrometer.
Elemental analyses were performed on a CHN-O-Rapid instrument.
Crystal data were collected with a Bruker D8 Venture diffractometer.
8p
0.13
CIP
NB
0.75
0.82
GAT
LVX
10.66
22.14
distance = 2.44 Å) was formed between Ser1084(B) and chlorine sub-
stituent which attached to the benzene ring. For compound 8a, the ben-
zene ring established four π-π interactions with Dc11(E), Dc11(F),
Dg10(E) and Dg10(F) respectively. Besides, it does not interact with other
amino acid residues, which may account for its inactive in bioactivity.
Moreover, we have found that the introduction of halogen substituents
can form hydrogen bonds between compound and amino acid residues.
4.1.1. General procedure for the synthesis of coumarin-3-carboxylic acids
[24]
2-hydroxybenzaldehydes (1) (0.02 mol) and Meldrum's Acid (2)
(0.02 mol) were dissolved in ethanol, then hexahydropyridine and
acetic acid were added as catalyst refluxed in ethanol. The crude pro-
duct then crystallizes in the solvent. After filtration and washing with
ethanol, intermediate 4 was obtained in excellent yield and purity.
3. Conclusions
4.1.2. General procedure for the synthesis of thiazole derivatives [25]
A flame-dried round bottom flask under N2 was charged with 4,5-
dimethylthiazole (5) (1 mL, 9.45 mmol) and THF and the mixture was
cooled to −78 °C. Then n-Butyl lithium (1.9 M, 6 mL, 11.3 mmol) was
added dropwise to the flask. The mixture was stirred for 45 min at
−78 °C. The aldehyde (6) (28.4 mmol) was then added, and the re-
action was stirred for 1 h at −78 °C. After that, the reaction was
warmed to room temperature and reacted for 2 h. Finally, water was
added to quench the reaction. The reaction mixture was extracted with
ethyl acetate and water. The combined organic extracts were dried over
sodium sulfate, filtered, and concentrated in vacuo. The resulting re-
sidue was purified by recrystallization (ethyl acetate/hexanes).
All the new coumarin-thiazolyl ester derivatives were synthesized
and evaluated for their antibacterial activity against four bacteria
strains. The experimental results indicated that most of the synthesized
compounds showed moderate to potent antibacterial activities. Most
surprisingly, compound 8p exhibited excellent antibacterial activity
against four bacteria strains with MIC values of 0.05, 0.05, 8 and
0.05 μg/mL, respectively. Among these compounds, 8i and 8v exhibited
the best antibacterial activity against S. aureus, 8x displayed the best
antibacterial activity against L. monocytogenes. SAR and molecular
docking analysis revealed that the promising antibacterial efficacy can
be attributed to the substitution of chlorine on the benzene and mod-
ification of the coumarin core. Moreover, the rationality of the deri-
vatives we designed was fully confirmed in experiments. The results of
the present work showed that coumarin-thiazolyl ester derivatives can
be potential bactericides for the discovery of DNA gyrase inhibitors and
worth further study.
4.1.3. General procedure for the synthesis of coumarin-thiazolyl ester
derivatives
Intermediate 4 (1 mmol) and the intermediate 7 (1 mmol) were
dissolved in dichloromethane to the glass flask, then DCC and DMAP
Fig. 4. Binding models of compound 8p(A&B) and 8a(C&D) with DNA gyrase (3D&2D diagram).
4

H. Liu, et al.
BioorganicChemistry100(2020)103907
are added as a condensing agent reacted at 0 °C for 10–15 h. After the
thin layer chromatography (TLC) monitoring reaction was completed,
the mixture was vacuum filtered and concentrated. Finally, the above
crude product can be isolated and purified by column chromatography
(Hexane/EtOAc = 4:1) to obtain target compounds 8.
4.1.9. (2-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl
2-oxo-2H-
chromene-3-carboxylate(8f)
1H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 7.80 (d, J = 6.8 Hz, 1H),
7.66–7.59 (m, 2H), 7.56 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.31 (dt,
J = 23.3, 7.8 Hz, 4H), 2.30 (d, J = 4.5 Hz, 6H). 13C NMR (150 MHz,
CDCl3) δ 161.62, 161.50, 156.23, 155.33, 149.47, 135.59, 133.16,
129.94, 129.68, 128.77, 128.13, 127.27, 118.02, 117.78, 117.54,
116.78, 72.27, 14.74, 11.25. MS (ESI): 426.05(C22H16ClNO4S, [M
+H]+). Anal. Calcd for C22H16ClNO4S: C, 62.05; H, 3.79; Cl, 8.32; N,
3.29; O, 15.03; S, 7.53; Found: C, 62.03; H, 3.78; Cl, 8.30; N, 3.28; O,
15.04; S, 7.55.
4.1.4. (4,5-dimethylthiazol-2-yl)(phenyl)methyl
2-oxo-2H-chromene-3-
carboxylate(8a)
1H NMR (600 MHz, CDCl3) δ 8.48 (s, 1H), 7.62–7.54 (m, 3H), 7.42
(d, J = 7.4 Hz, 2H), 7.28 (dd, J = 11.3, 5.7 Hz, 4H), 7.23 (t,
J = 7.3 Hz, 1H), 2.22 (dd, J = 30.7, 16.9 Hz, 6H). 13C NMR (150 MHz,
CDCl3) δ 170, 162.96, 156.71, 155.03, 148.62, 134.35, 129.54, 128.71,
128.42, 127.98, 127.20, 126.45, 124.86, 118.09, 117.79, 116.67,
116.64, 61.92, 14.20, 11.24. MS (ESI): 392.09(C22H17NO4S, [M+H]+).
Anal. Calcd for C22H17NO4S: C, 67.50; H, 4.38; N, 3.58; O, 16.35; S,
8.19; Found: C, 67.48; H, 4.39; N, 3.57; O, 16.33; S, 8.20.
4.1.10. (3-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 6-methyl-2-oxo-
2H-chromene-3-carboxylate(8g)
1H NMR (600 MHz, CDCl3) δ 8.55 (s, 1H), 7.79 (dd, J = 7.7, 1.4 Hz,
1H), 7.55 (s, 1H), 7.43 (dd, J = 8.5, 1.3 Hz, 1H), 7.38 (d, J = 7.7 Hz,
2H), 7.30 (ddt, J = 9.0, 7.5, 4.0 Hz, 2H), 7.22 (d, J = 8.5 Hz, 1H), 2.39
(s, 3H), 2.30 (d, J = 5.0 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 161.69,
161.59, 156.52, 153.49, 149.54, 148.91, 135.83, 134.71, 129.93,
129.69, 129.29, 128.77, 127.28, 117.53, 117.24, 116.48, 72.21, 20.63,
14.75, 11.27. MS (ESI): 440.06(C23H18ClNO4S, [M+H]+). Anal. Calcd
for C23H18ClNO4S: C, 62.80; H, 4.12; Cl, 8.06; N, 3.18; O, 14.55; S,
7.29; Found: C, 62.81; H, 4.13; Cl, 8.04; N, 3.17; O, 14.53; S, 7.28.
4.1.5. (4-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl
2-oxo-2H-
chromene-3-carboxylate(8b)
1H NMR (600 MHz, CDCl3) δ 8.58 (s, 1H), 7.66–7.58 (m, 2H), 7.53
(d, J = 8.4 Hz, 2H), 7.40–7.26 (m, 4H), 7.15 (s, 1H), 2.27 (dd,
J = 19.4, 11.3 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 162.95, 161.71,
155.40, 153.17, 149.54, 136.31, 134.67, 129.66, 128.92, 128.67,
127.90, 127.74, 124.84, 117.78, 117.56, 116.85, 116.05, 75.32, 14.66,
11.22. MS (ESI): 426.05(C22H16ClNO4S, [M+H]+). Anal. Calcd for
4.1.11. (4,5-dimethylthiazol-2-yl)(p-tolyl)methyl
6-bromo-2-oxo-2H-
chromene-3-carboxylate(8h)
1H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H), 7.75 (d, J = 2.2 Hz, 1H),
7.72 (dd, J = 8.8, 2.3 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.25 (d,
J = 8.9 Hz, 1H), 7.21–7.15 (m, 3H), 2.34 (s, 3H), 2.30 (d, J = 10.5 Hz,
6H). 13C NMR (150 MHz, CDCl3) δ 163.53, 161.18, 155.50, 154.12,
148.57, 147.69, 138.80, 137.14, 134.73, 131.65, 129.43, 127.26,
126.49, 119.26, 118.54, 117.33, 76.12, 21.19, 14.68, 11.22. MS (ESI):
484.01(C23H18BrNO4S, [M+H]+). Anal. Calcd for C23H18BrNO4S: C,
57.03; H, 3.75; Br, 16.50; N, 2.89; O, 13.21; S, 6.62; Found: C, 57.01; H,
3.76; Br, 16.51; N, 2.88; O, 13.20; S, 6.63.
C
22H16ClNO4S: C, 62.05; H, 3.79; Cl, 8.32; N, 3.29; O, 15.03; S, 7.53;
Found: C, 62.04; H, 3.80; Cl, 8.31; N, 3.28; O, 15.01; S, 7.51.
4.1.6. 1-(4,5-dimethylthiazol-2-yl)-2-methylpropyl 2-oxo-2H-chromene-3-
carboxylate(8c)
1H NMR (600 MHz, CDCl3) δ 8.53 (s, 1H), 7.61 (dd, J = 15.8,
7.6 Hz, 2H), 7.34–7.28 (m, 2H), 5.95 (d, J = 6.6 Hz, 1H), 2.28 (d,
J = 2.8 Hz, 6H), 2.25 (s, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.93 (dd,
J = 20.5, 6.8 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.26, 163.24,
162.06, 156.22, 155.25, 148.80, 134.43, 129.59, 126.48, 125.82,
124.77, 117.80, 116.73, 79.04, 33.33, 18.64, 14.63, 11.16. MS (ESI):
358.10(C19H19NO4S, [M+H]+). Anal. Calcd for C19H19NO4S: C, 63.85;
H, 5.36; N, 3.92; O, 17.90; S, 8.97; Found: C, 63.83; H, 5.37; N, 3.91; O,
17.91; S, 8.99.
4.1.12. (4,5-dimethylthiazol-2-yl)(phenyl)methyl
6-bromo-2-oxo-2H-
chromene-3-carboxylate(8i)
1H NMR (600 MHz, CDCl3) δ 8.50 (s, 1H), 7.79–7.67 (m, 2H), 7.58
(d, J = 7.3 Hz, 2H), 7.35 (dt, J = 28.0, 7.0 Hz, 3H), 7.24–7.17 (m, 2H),
2.29 (d, J = 8.7 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 163.28, 161.27,
155.50, 154.09, 148.57, 147.85, 137.62, 137.19, 131.68, 128.82,
128.73, 127.22, 119.23, 118.75, 118.52, 117.34, 76.14, 14.68, 11.23.
MS (ESI): 470.00(C22H16BrNO4S, [M+H]+). Anal. Calcd for
4.1.7. (4,5-dimethylthiazol-2-yl)(naphthalen-1-yl)methyl
2-oxo-2H-
chromene-3-carboxylate(8d)
C
22H16BrNO4S: C, 56.18; H, 3.43; Br, 16.99; N, 2.98; O, 13.61; S, 6.82;
1H NMR (600 MHz, CDCl3) δ 8.62 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H),
7.98–7.90 (m, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.67–7.61 (m, 1H), 7.60
(d, J = 7.7 Hz, 1H), 7.56–7.46 (m, 3H), 7.38–7.29 (m, 2H), 2.29 (d,
J = 16.4 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 163.37, 161.73,
156.27, 155.37, 149.48, 148.50, 134.53, 133.83, 133.57, 130.48,
129.64, 129.58, 128.77, 128.15, 126.67, 125.89, 125.39, 125.37,
124.76, 123.72, 117.83, 116.79, 73.43, 14.70, 11.25. MS (ESI):
442.10(C26H19NO4S, [M+H]+). Anal. Calcd for C26H19NO4S: C, 70.73;
H, 4.34; N, 3.17; O, 14.50; S, 7.26; Found: C, 70.72; H, 4.32; N, 3.18; O,
14.51; S, 7.25.
Found: C, 56.17; H, 3.42; Br, 16.97; N, 2.96; O, 13.60; S, 6.83.
4.1.13. (4-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 6-bromo-2-oxo-
2H-chromene-3-carboxylate(8j)
1H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H), 7.77–7.71 (m, 2H), 7.54
(d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.27 (s, 1H), 7.25 (s, 1H),
7.16 (s, 1H), 2.31 (d, J = 13.6 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ
162.69, 161.27, 155.49, 154.14, 148.75, 148.04, 137.32, 136.12,
134.82, 131.69, 128.97, 128.67, 119.18, 118.64, 118.56, 117.42,
75.50, 14.68, 11.24. MS (ESI): 503.96(C22H15BrClNO4S, [M+H]+).
Anal. Calcd for C22H15BrClNO4S: C, 52.35; H, 3.00; Br, 15.83; Cl, 7.02;
N, 2.77; O, 12.68; S, 6.35; Found: C, 52.36; H, 3.02; Br, 15.84; Cl, 7.03;
N, 2.78; O, 12.67; S, 6.33.
4.1.8. (3-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl
2-oxo-2H-
chromene-3-carboxylate(8e)
1H NMR (600 MHz, CDCl3) δ 8.61 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H),
7.67–7.59 (m, 2H), 7.57 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.38–7.28
(m, 4H), 2.31 (d, J = 4.2 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ
161.63, 161.52, 156.23, 155.35, 149.46, 148.94, 133.18, 129.94,
129.71, 129.66, 128.78, 127.27, 124.81, 117.80, 117.59, 116.81,
72.29, 14.75, 11.26. MS (ESI): 426.05(C22H16ClNO4S, [M+H]+). Anal.
Calcd for C22H16ClNO4S: C, 62.05; H, 3.79; Cl, 8.32; N, 3.29; O, 15.03;
S, 7.53; Found: C, 62.03; H, 3.77; Cl, 8.31; N, 3.30; O, 15.05; S, 7.51.
4.1.14. 1-(4,5-dimethylthiazol-2-yl)-2-methylpropyl 6-bromo-2-oxo-2H-
chromene-3-carboxylate(8k)
1H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H), 7.76 (d, J = 2.1 Hz, 1H),
7.72 (dd, J = 8.8, 2.2 Hz, 1H), 7.24 (s, 1H), 5.96 (d, J = 6.6 Hz, 1H),
2.44 (dq, J = 13.5, 6.7 Hz, 1H), 2.31 (d, J = 4.1 Hz, 6H), 1.09 (d,
J = 6.7 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
162.97, 161.68, 155.56, 154.04, 148.14, 147.29, 137.07, 131.61,
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BioorganicChemistry100(2020)103907
126.57, 119.26, 118.53, 117.32, 79.33, 33.35, 18.66, 14.70, 11.23. MS
4.1.20. (4,5-dimethylthiazol-2-yl)(naphthalen-1-yl)methyl 6-chloro-2-oxo-
(ESI):
436.01(C19H18BrNO4S,
[M+H]+).
Anal.
Calcd
for
2H-chromene-3-carboxylate(8q)
C
19H18BrNO4S: C, 52.30; H, 4.16; Br, 18.31; N, 3.21; O, 14.67; S, 7.35;
1H NMR (600 MHz, CDCl3) δ 8.52 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H),
8.12 (s, 1H), 7.94 (s, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 7.9 Hz,
3H), 7.72 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.9 Hz, 2H), 2.30 (s, 3H),
2.28 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 163.06, 162.66, 158.44,
153.48, 153.09, 152.11, 146.95, 139.44, 134.06, 132.71, 130.45,
128.38, 127.85, 119.08, 118.24, 118.18, 108.68, 62.17, 14.15, 14.05.
MS (ESI): 476.06(C26H18ClNO4S, [M+H]+). Anal. Calcd for
Found: C, 52.31; H, 4.15; Br, 18.30; N, 3.22; O, 14.65; S, 7.34.
4.1.15. (4,5-dimethylthiazol-2-yl)(naphthalen-1-yl)methyl
6-bromo-2-
oxo-2H-chromene-3-carboxylate(8l)
1H NMR (600 MHz, CDCl3) δ 8.52 (s, 1H), 8.23 (d, J = 8.5 Hz, 1H),
7.94 (s, 1H), 7.89 (dd, J = 17.6, 7.6 Hz, 3H), 7.73 (dd, J = 4.8, 2.0 Hz,
1H), 7.71 (d, J = 4.2 Hz, 1H), 7.69–7.65 (m, 1H), 7.57–7.47 (m, 3H),
2.29 (d, J = 17.3 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 163.13,
161.30, 155.58, 154.11, 148.59, 147.95, 137.17, 133.82, 133.38,
131.66, 130.90, 130.43, 129.68, 128.81, 128.25, 126.73, 125.94,
125.36, 123.64, 119.25, 118.83, 118.52, 117.34, 73.64, 14.72, 11.27.
MS (ESI): 520.01(C26H18BrNO4S, [M+H]+). Anal. Calcd for
C
26H18ClNO4S: C, 65.61; H, 3.81; Cl, 7.45; N, 2.94; O, 13.45; S, 6.74;
Found: C, 65.60; H, 3.80; Cl, 7.46; N, 2.96; O, 13.43; S, 6.75.
4.1.21. (3-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 6-chloro-2-oxo-
2H-chromene-3-carboxylate(8r)
1H NMR (600 MHz, CDCl3) δ 8.43 (s, 1H), 7.72 (s, 1H), 7.58 (d,
J = 7.9 Hz, 2H), 7.55–7.50 (m, 2H), 7.32 (s, 1H), 7.30 (s, 1H), 1.94 (d,
J = 11.5 Hz, 3H), 1.83 (d, J = 12.7 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 163.30, 162.65, 158.45, 156.12, 154.48, 153.09, 152.10,
146.98, 139.45, 134.07, 132.72, 130.45, 128.38, 127.85, 119.07,
118.24, 118.19, 62.18, 14.15, 14.06. MS (ESI): 460.01(C22H15Cl2NO4S,
[M+H]+). Anal. Calcd for C22H15Cl2NO4S: C, 57.40; H, 3.28; Cl, 15.40;
N, 3.04; O, 13.90; S, 6.96; Found: C, 57.41; H, 3.27; Cl, 15.41; N, 3.03;
O, 13.92; S, 6.95.
C
26H18BrNO4S: C, 60.01; H, 3.49; Br, 15.35; N, 2.69; O, 12.30; S, 6.16;
Found: C, 60.02; H, 3.47; Br, 15.36; N, 2.68; O, 12.31; S, 6.15.
4.1.16. (3-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 6-bromo-2-oxo-
2H-chromene-3-carboxylate(8m)
1H NMR (600 MHz, CDCl3) δ 8.51 (s, 1H), 7.79–7.69 (m, 3H), 7.55
(s, 1H), 7.40 (dd, J = 7.6, 1.0 Hz, 1H), 7.36–7.28 (m, 2H), 7.24 (d,
J = 8.8 Hz, 1H), 2.31 (d, J = 5.3 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ
161.39, 161.09, 155.54, 154.09, 149.01, 147.94, 137.21, 131.68,
130.03, 129.74, 128.74, 127.29, 119.22, 118.68, 118.53, 117.37,
72.47, 14.76, 11.28. MS (ESI): 503.96(C22H15BrClNO4S, [M+H]+).
Anal. Calcd for C22H15BrClNO4S: C, 52.35; H, 3.00; Br, 15.83; Cl, 7.02;
N, 2.77; O, 12.68; S, 6.35; Found: C, 52.36; H, 3.02; Br, 15.82; Cl, 7.01;
N, 2.75; O, 12.67; S, 6.37.
4.1.22. (4,5-dimethylthiazol-2-yl)(p-tolyl)methyl 7-(diethylamino)-2-oxo-
2H-chromene-3-carboxylate(8s)
1H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H), 7.66 (s, 1H), 7.35 (d,
J = 8.9 Hz, 1H), 7.28 (s, 1H), 6.59 (d, J = 8.8 Hz, 2H), 6.47 (d,
J = 5.6 Hz, 2H), 6.42 (s, 1H), 3.51 (s, 4H), 2.41(s, 3H), 2.31–2.30(d,
J = 6 Hz, 6H), 1.25–1.22(t, J = 6 Hz, 6H). 13C NMR (150 MHz, CDCl3)
δ 165.13, 164.23, 160.17, 158.45, 158.19, 156.89, 153.62, 152.83,
151.62, 149.09, 142.03, 130.94, 129.88, 117.96, 109.45, 109.14,
107.69, 107.33, 97.05, 96.76, 61.10, 14.33, 12.40, 12.38. MS (ESI):
477.18(C27H28N2O4S, [M+H]+). Anal. Calcd for C27H28N2O4S: C,
68.05; H, 5.92; N, 5.88; O, 13.43; S, 6.73; Found: C, 68.04; H, 5.91; N,
5.87; O, 13.41; S, 6.74.
4.1.17. (3-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 6-nitro-2-oxo-
2H-chromene-3-carboxylate(8n)
1H NMR (600 MHz, CDCl3) δ 10.56 (s, 1H), 8.71 (d, J = 2.7 Hz,
1H), 8.34 (dd, J = 9.2, 2.8 Hz, 1H), 7.63–7.60 (m, 1H), 7.47 (dd,
J = 5.2, 3.9 Hz, 1H), 7.37–7.34 (m, 2H), 7.22 (d, J = 9.2 Hz, 1H), 7.07
(s, 1H), 2.34 (s, 6H). 13C NMR (150 MHz, CDCl3) δ 187.26, 163.13,
161.17, 149.21, 142.25, 133.10, 130.63, 130.47, 130.13, 127.90,
127.77, 124.67, 114.98, 77.15, 14.75, 11.38. MS (ESI):
471.03(C22H15ClN2O6S, [M+H]+). Anal. Calcd for C22H15ClN2O6S: C,
56.12; H, 3.21; Cl, 7.53; N, 5.95; O, 20.39; S, 6.81; Found: C, 56.10; H,
3.20; Cl, 7.52; N, 5.93; O, 20.38; S, 6.82.
4.1.23. (4,5-dimethylthiazol-2-yl)(phenyl)methyl 7-(diethylamino)-2-oxo-
2H-chromene-3-carboxylate(8t)
1H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H), 7.67 (s, 1H), 7.35 (d,
J = 12.1 Hz, 1H), 7.29–7.27 (m, 1H), 7.25 (s, 1H), 6.60 (s, 2H), 6.47 (s,
2H), 6.43 (s, 1H), 3.48–3.44(m, 4H), 2.41–2.39(t, J = 6 Hz, 6H),
1.25–1.22(m, 6H). 13C NMR (150 MHz, CDCl3) δ 165.03, 162.10,
156.15, 153.32, 150.75, 147.43, 141.68, 128.59, 128.28, 126.52,
124.60, 123.79, 119.07, 115.79, 108.04, 105.46, 92.07, 73.65, 49.16,
14.53, 14.06, 11.26. MS (ESI): 463.16(C26H26N2O4S, [M+H]+). Anal.
Calcd for C26H26N2O4S: C, 67.51; H, 5.67; N, 6.06; O, 13.84; S, 6.93;
Found: C, 67.50; H, 5.66; N, 6.05; O, 13.85; S, 6.94.
4.1.18. (4,5-dimethylthiazol-2-yl)(phenyl)methyl
6-chloro-2-oxo-2H-
chromene-3-carboxylate(8o)
1H NMR (600 MHz, CDCl3) δ 8.51 (s, 1H), 7.59 (dd, J = 9.7, 4.3 Hz,
4H), 7.38 (t, J = 7.4 Hz, 2H), 7.36–7.28 (m, 2H), 7.20 (s, 1H), 2.30 (d,
J = 8.8 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 163.29, 161.21, 155.64,
153.63, 148.58, 148.03, 137.59, 134.45, 130.19, 128.86, 128.77,
128.61, 127.23, 118.69, 118.30, 76.15, 14.72, 11.28. MS (ESI):
426.05(C22H16ClNO4S, [M+H]+). Anal. Calcd for C22H16ClNO4S: C,
62.05; H, 3.79; Cl, 8.32; N, 3.29; O, 15.03; S, 7.53; Found: C, 62.04; H,
3.78; Cl, 8.31; N, 3.28; O, 15.04; S, 7.55.
4.1.24. (4,5-dimethylthiazol-2-yl)(naphthalen-1-yl)methyl 7-(diethylamino)-
2-oxo-2H-chromene-3-carboxylate(8u)
1H NMR (600 MHz, CDCl3) δ 8.48 (d, J = 7.8 Hz, 1H), 8.29 (t,
J = 8.1 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.90 (t, J = 7.3 Hz, 1H),
7.86–7.82 (m, 2H), 7.53–7.45 (m, 3H), 7.32 (t, J = 8.4 Hz, 1H), 6.57
(d, J = 14.6 Hz, 1H), 6.43 (d, J = 7.7 Hz, 1H), 3.46–3.39 (m, 4H), 2.27
(t, J = 8.0 Hz, 6H), 1.25–1.19 (m, 6H). 13C NMR (150 MHz, CDCl3) δ
164.20, 162.28, 158.67, 157.82, 153.09, 149.73, 148.33, 133.81,
131.22, 130.62, 128.64, 126.52, 125.75, 125.45, 125.37, 123.95,
109.50, 108.14, 107.73, 96.73, 72.59, 45.06, 14.69, 12.40, 11.23. MS
(ESI): 513.18(C30H28N2O4S, [M+H]+). Anal. Calcd for C30H28N2O4S:
C, 70.29; H, 5.51; N, 5.46; O, 12.48; S, 6.25; Found: C, 70.28; H, 5.50;
N, 5.48; O, 12.46; S, 6.24.
4.1.19. (4-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 6-chloro-2-oxo-
2H-chromene-3-carboxylate(8p)
1H NMR (600 MHz, CDCl3) δ 8.51 (s, 1H), 7.62–7.58 (m, 2H), 7.53
(d, J = 8.4 Hz, 2H), 7.34 (dd, J = 20.7, 8.5 Hz, 3H), 7.16 (s, 1H), 2.31
(d, J = 14.0 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 162.71, 161.30,
155.53, 153.68, 148.72, 148.11, 136.13, 134.81, 134.50, 130.24,
128.96, 128.67, 124.33, 123.42, 118.71, 118.68, 118.29, 75.49, 14.66,
11.23. MS (ESI): 460.01(C22H15Cl2NO4S, [M+H]+). Anal. Calcd for
4.1.25. (3-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 7-(diethylamino)-
2-oxo-2H-chromene-3-carboxylate(8v)
C
22H15Cl2NO4S: C, 57.40; H, 3.28; Cl, 15.40; N, 3.04; O, 13.90; S, 6.96;
Found: C, 57.41; H, 3.29; Cl, 15.41; N, 3.03; O, 13.91; S, 6.97.
1H NMR (600 MHz, CDCl3) δ 8.48 (s, 1H), 7.58 (s, 1H), 7.50 (d,
6

H. Liu, et al.
BioorganicChemistry100(2020)103907
J = 7.0 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.31–7.28 (m, 2H), 7.15 (s,
1H), 6.60 (d, J = 8.9 Hz, 1H), 6.45 (s, 1H), 3.45 (q, J = 7.1 Hz, 4H),
2.31 (s, 3H), 2.29 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 163.59, 162.54,
158.74, 157.75, 153.22, 149.77, 148.53, 140.34, 134.46, 131.30,
129.88, 128.61, 128.37, 127.41, 127.33, 125.51, 124.69, 109.59,
107.72, 96.75, 74.41, 45.10, 14.67, 12.41, 11.21. MS (ESI):
497.12(C26H25ClN2O4S, [M+H]+). Anal. Calcd for C26H25ClN2O4S: C,
62.83; H, 5.07; Cl, 7.13; N, 5.64; O, 12.88; S, 6.45; Found: C, 62.81; H,
5.06; Cl, 7.11; N, 5.65; O, 12.89; S, 6.44.
4.4. Molecular docking
The crystal structure of DNA gyrase (PDB ID:2xcs) was downloaded
from the RCSB Protein Data Bank (https://www.rcsb.org/). The mole-
cular docking procedures were performed by the literature [30]. First,
we clean the receptor protein, such as water removal and hydrogena-
tion. Second, we define the active site with the position of GSK299423
and a radius of 9.0. All target compounds are then given a force field as
prepared small ligands. Finally, the docking work can be carried out by
using DS_CDOCKER protocol for receptor–ligand interactions section of
Discovery Studio 3.5. All compounds generated a total of 960 docking
poses with the target protein.
4.1.26. (2-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 7-(diethylamino)-
2-oxo-2H-chromene-3-carboxylate(8w)
1H NMR (600 MHz, CDCl3) δ 8.48 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H),
7.54 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.32 (d,
J = 7.6 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 6.59 (dd, J = 8.9, 2.1 Hz,
1H), 6.44 (s, 1H), 3.44 (q, J = 7.1 Hz, 4H), 2.30 (d, J = 6.2 Hz, 6H).
13C NMR (150 MHz, CDCl3) δ 162.51, 162.47, 158.68, 157.80, 153.12,
149.74, 148.72, 136.20, 133.17, 131.23, 129.62, 129.60, 128.88,
128.18, 127.73, 127.16, 109.53, 107.73, 96.74, 71.56, 45.07, 14.73,
12.41, 11.23. MS (ESI): 497.12(C26H25ClN2O4S, [M+H]+). Anal. Calcd
for C26H25ClN2O4S: C, 62.83; H, 5.07; Cl, 7.13; N, 5.64; O, 12.88; S,
6.45; Found: C, 62.84; H, 5.09; Cl, 7.11; N, 5.65; O, 12.90; S, 6.44.
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.
Acknowledgement
This work was financially supported by the Anhui Agricultural
University Graduate Innovation Fund (2019ysj-71). We are grateful to
Prof. Hai-Liang Zhu (State Key Laboratory of Pharmaceutical
Biotechnology, Nanjing University, Nanjing) for computational mole-
cular docking assistance. This work has been checked by Dr. Deepak
Kumar.
4.1.27. (4-chlorophenyl)(4,5-dimethylthiazol-2-yl)methyl 7-(diethylamino)-
2-oxo-2H-chromene-3-carboxylate(8x)
1H NMR (600 MHz, CDCl3) δ 8.46 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H),
7.33 (dd, J = 14.3, 8.7 Hz, 3H), 7.14 (s, 1H), 6.59 (dd, J = 8.9, 2.2 Hz,
1H), 6.43 (d, J = 1.8 Hz, 1H), 3.44–3.40 (m, 4H), 2.30–2.27 (m, 6H),
1.22 (t, J = 6 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 163.87, 162.66,
158.71, 156.87, 153.20, 149.79, 148.48, 136.94, 134.34, 131.31,
129.91, 128.79, 128.69, 127.33, 109.62, 107.67, 96.67, 74.49, 45.11,
14.70, 12.41, 10.93. MS (ESI): 497.12(C26H25ClN2O4S, [M+H]+).
Anal. Calcd for C26H25ClN2O4S: C, 62.83; H, 5.07; Cl, 7.13; N, 5.64; O,
12.88; S, 6.45; Found: C, 62.85; H, 5.06; Cl, 7.12; N, 5.65; O, 12.89; S,
6.46.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bioorg.2020.103907.
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