Design, synthesis and cytotoxic evaluation of a novel series of benzo[d]thiazole-2-carboxamide derivatives as potential EGFR inhibitors

Article abstract of DOI:10.1007/s00044-017-1925-7

A novel series of benzo[d]thiazole-2-carboxamide derivatives have been de novo designed based on virtual screening methods. The target compounds were synthesized and evaluated for the cytotoxicity against epidermal growth factor receptor high-expressed cancer cell lines (A549, HeLa, and SW480), epidermal growth factor receptor low-expressed cell line (HepG2) and human liver normal cell line (HL7702). Several target compounds have showed moderate to excellent potency against A549, HeLa, and SW480 and weak cytotoxic effects against HepG2, which implies they are probably epidermal growth factor receptor inhibitors. And scarcely did they exhibit any activities against HL7702, which signifies they are likely to overcome the nonspecific toxicity against normal cells. Especially, the compound 6-[2-(diethylamino)-2-oxoethoxy]-N-(furan-2-ylmethyl)benzo[d]thiazole-2-carboxamide (6i) was identified as a promising agent, exhibiting the most potent cytotoxic activities with IC₅₀ values of 4.05, 12.17, 6.76 μM against the A549, HeLa, and SW480 cell lines, respectively.

Full text of DOI:10.1007/s00044-017-1925-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1925-7
ORIGINAL RESEARCH
Design, synthesis and cytotoxic evaluation of a novel series of benzo
[d]thiazole-2-carboxamide derivatives as potential EGFR
inhibitors
Lan Zhang1 Xin-Shan Deng1 Chao Zhang1 Guang-Peng Meng1 Jiao-Feng Wu1
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Xue-Song Li1 Qing-Chun Zhao1,2 Chun Hu1
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Received: 24 February 2017 / Accepted: 18 May 2017
© Springer Science+Business Media New York 2017
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Abstract A novel series of benzo[d]thiazole-2-carbox-
amide derivatives have been de novo designed based on
virtual screening methods. The target compounds were
synthesized and evaluated for the cytotoxicity against epi-
dermal growth factor receptor high-expressed cancer cell
lines (A549, HeLa, and SW480), epidermal growth factor
receptor low-expressed cell line (HepG2) and human liver
normal cell line (HL7702). Several target compounds have
showed moderate to excellent potency against A549, HeLa,
and SW480 and weak cytotoxic effects against HepG2,
which implies they are probably epidermal growth factor
receptor inhibitors. And scarcely did they exhibit any
activities against HL7702, which signifies they are likely to
overcome the nonspecific toxicity against normal cells.
Especially, the compound 6-[2-(diethylamino)-2-oxoetho-
xy]-N-(furan-2-ylmethyl)benzo[d]thiazole-2-carboxamide (6i)
was identified as a promising agent, exhibiting the most
potent cytotoxic activities with IC50 values of 4.05, 12.17,
6.76 μM against the A549, HeLa, and SW480 cell lines,
respectively.
Keywords EGFR inhibitors Benzo[d]thiazole-2-
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●
carboxamide derivatives Synthesis Anticancer activities
Introduction
Investigations during the last few decades have established
the essential role of the epidermal growth factor receptor
(EGFR), which is a kind of tyrosine kinase reported in the
literature firstly (Slamon et al. 1987, 1989). As known,
EGFR family comprises four distinct members, including
EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3),
and ErbB4 (HER4) (Lichtenberger et al. 2010). Because of
its significant function in cells life and widely distribution in
cells, EGFR has already become one of the most promising
targets of antitumor drug research (Luo et al. 2011). In
addition, EGFR has proved to be related to the develop-
ment, progression, aggressiveness, and metastasis of many
solid tumors, such as head and neck cancers, non small cell
lung cancer and glioblastomas (Qian et al. 2010). Therefore
the inhibition of EGFR turns into a beneficial antitumor
therapeutic strategy. For instance, erlotinib, a widely used
small-molecule inhibitor of EGFR with better safety and
positive clinical activities, can inhibit EGFR which is
overexpressed, and as a consequence erlotinib is generally
recognized as an approved antitumor drug (Zhou et al.
2016a, b).
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-017-1925-7) contains supplementary material,
which is available to authorized users.
* Chun Hu
chunhu@syphu.edu.cn
Simple and small hetero-aromatic systems often have
surprisingly complex biological properties. Benzo[d]thia-
zole is widely found in both natural products and drugs
(Wang et al. 2013). The design and development of new
benzo[d]thiazole derivatives as the potential chemother-
apeutic agents against cancer had attracted the interest of
1
Key Laboratory of Structure-Based Drug Design & Discovery,
Ministry of Education, Shenyang Pharmaceutical University,
Shenyang 110016, China
2
Department of Pharmacy, General Hospital of Shenyang Military
Area Command, Shenyang 110016, China

Med Chem Res
Fig. 1 Structures of anticancer compounds with benzo[d]thiazole
moiety reported in recent years
medicinal chemists and several attempts were made to
modify the benzo[d]thiazole to improve their antitumor
activities (Al-Ghorbani et al. 2016). In the past few years, a
series of antitumor agents with benzo[d]thiazole moiety
(Fig. 1) have been designed and synthesized (Al-Ghorbani
et al. 2016; Lei et al. 2016; Ismail et al. 2013; Yang et al.
2015). Hence the compounds containing benzo[d]thiazole
scaffold provided the attractive possibilities for targeted
therapy in cancer treatments. All of the above-mentioned
facts encouraged us to design and synthesize novel benzo[d]
thiazole derivatives as the potential anticancer agents.
Previous studies have been established that the quina-
zoline ring of marketed erlotinib can be replaced with benzo
[d]thiazole as the bioisosteres and mimic, which can com-
petitively bind the ATP binding regions of EGFR tyrosine
kinase, and the compound N-(2,6-dichlorophenyl)-
6-methylbenzo[d]thiazol-2-amine may be potent EGFR
inhibitor and has showed excellent antitumor activity
(Noolvi et al. 2012). Based on the above active compounds,
the carboxamide group was introduced to get benzo[d]
thiazole-2-carboxamide derivatives as the target compounds
(Fig. 2). Herein, the design, synthesis, biological activity
evaluation and structure–activity relationships (SARs) of a
novel series of benzo[d]thiazole-2-carboxamide derivatives
as the potent inhibitors of EGFR were described in the
paper.
Fig. 2 Rational design of target compounds based on known EGFR
inhibitors
A combination method of both rigid and flexible docking
procedure of Molegro Virtual Docker (MVD) software
(Thomsen and Christensen 2006) was used to analyze the
most accurate binding mode of ligands from multiple pre-
dictions generated from MVD runs. The binding mode of
the interactions between EGFR and small molecules were
visually revealed by PyMOL 1.7.
We explored the EGFR complex structures with the
known inhibitor erlotinib available in the Research Colla-
boratory for Structural Bioinformatics Protein Data Bank
[PDB ID code: 1M17 (Stamos et al. 2002)]. The crucial
information on the binding modes of the inhibitor was then
used as the docking protocol. The 3D structure of EGFR
was cited as the docking model. And a virtual compound
library including benzo[d]thiazole-2-carboxamide deriva-
tives was compiled and built up by ourselves. Similarly,
molecular docking simulation studies were carried out to
discover the binding modes of our virtual compounds with
the active sites of EGFR, and based of the obtained hits, the
benzo[d]thiazole-2-carboxamide derivatives were emerged
as promising candidates.
Results and discussion
Virtual screening
The docking procedure produces efficient model for
ligand–receptor interaction study and virtual screening in
rational drug design, especially when the crystal structure of
a receptor or enzyme is available.
The dynamic calculations of erlotinib and all target
compounds binding with EGFR have been presented
(Table 1). The results have showed that all the compounds

Med Chem Res
exhibit similar binding energy. Among them, the target
compound 6-[2-(diethylamino)-2-oxoethoxy]-N-(furan-2-
ylmethyl)benzo[d]thiazole-2-carboxamide (6i) has showed
a lower binding energy than erlotinib, which means the
compound 6i may exhibit more potent anticancer activities.
Based on the docking, the theoretical binding mode
between erlotinib and EGFR was shown in Fig. 3. The N
atom in 3-position of erlotinib formed a hydrogen bond with
residue GLN767, and the methoxy group in 7- position
formed a hydrogen bond with residue PRO770. There were
also hydrophobic effects between erlotinib and the residues,
such as LEU694, ALA719, LYS721, MET769, and
LEU820.
(Fig. 4). As shown, a hydrogen bond has been formed
between 2-carboxamide and residue PRO770, and the N
atom in 6-position formed a hydrogen bond with residue
ASP776. The binding modes have showed that 6i formed
relatively weak hydrophobic interactions with residues
LEU694, LYS704, LEU768, and CYS773. As described,
the binding mode of compound 6i is similar to that of
erlotinib.
Chemistry
With the aim of preparing a series of novel benzo[d]thia-
zole-2-carboxamide derivatives, the initial steps of the
synthesis of target compounds (6a–6l) from commercially
available L-cysteine (1) were carried out essentially as
described in Scheme 1 (Ciuffreda et al. 2013; Cheng et al.
2013). Reaction of compound 1 with ethanol and SOCl2
afforded the ester 2, which was converted to intermediate 4
with 1,4-benzoquinone followed by an oxidation-
cyclization step, and the intermediate 4 was purified by
column chromatography on silica gel. Reaction of 4 with
corresponding 2-chloroacetamide by using anhydrous
K2CO3 and KI gave the key intermediates 5a–5d. Treat-
ment of 5a–5d with benzylamine or 4-fluorobenzylamine or
2-furylmethylamine via ammonolysis yielded benzo[d]
thiazole-2-carboxamide derivatives as the target com-
pounds. The structures of the target compounds were
characterized by infrared (IR), electrospray ionization mass
As an example, the predicted docking interactions
between the target compound 6i and EGFR were performed
Table 1 Dynamic calculations of erlotinib and all the target
compounds binding with EGFR
Ligand
binding energy
RMSD
6a
−118.472
−106.173
−103.726
−109.986
−111.946
−113.075
−127.711
−124.758
−141.785
−116.327
−120.193
−109.462
−122.264
−4.347
−3.121
−1.873
−3.550
−5.183
−0.769
−2.623
−4.977
−3.511
−8.511
−6.153
−3.415
−1.810
6b
6c
6d
6e
6f
6g
6h
6i
1
spectra (ESI-MS), H nuclear magnetic resonance (NMR),
6j
13C NMR and high-resolution mass spectra (HRMS).
Furthermore, compound 6e as an example was taken to
explore the proton–proton correlations with the 1H–1H
COSY spectra. The spectra have revealed three separated
6k
6l
Erlotinib
Fig. 3 The binding mode of the erlotinib in the active site of EGFR: a 3D structure b 2D structure

Med Chem Res
Fig. 4 The binding mode of the compound 6i in the active site of EGFR: a 3D structure b 2D structure
Scheme 1 Synthetic route of the
target compounds 6a–6l.
Reagents and conditions: a
SOCl2, ethanol, reflux, 12 h; b
1,4-benzoquinone, methanol, rt,
3 h; c isopropanol, K3Fe(CN)6,
NaOH, rt, 14 h; d K2CO3, KI,
acetone, reflux, 16 h; e ethanol,
reflux, 3 h
spin–spin systems (H-4/H-5, H-2′/H-3′ and H-2″/H-3″) and
all the proton–proton correlations were denoted in Fig. 5.
our target compounds are likely to act as the potential
EGFR inhibitors with low nonspecific toxicity.
The SARs analyses have revealed as follows: (1) Com-
pared to compound 6a and 6e, compound 6i exhibit better
cytotoxic activities against A549, HeLa, and SW480 cells.
These results suggest that the introduction of 2-
furylmethylamino in 2-position is beneficial for anticancer
activity than that of benzylamino and 4-fluorobenzylamino;
(2) By comparison, compounds 6a–6d have showed variant
activity. In general, the introduction of 2-(diethylamino)-
2-oxoethoxy into the 6-position has resulted in strong
cytotoxic activities. Furthermore, the presence of 2-
(morpholin-4-yl)-2-oxoethoxy plays no significant effect or
slight effect on the activity. In contrast, the presence of 2-
oxo-2-(piperidin-1-yl)ethoxy and 2-[2-(2-methoxyphenoxy)
ethyl]amino results in the decrease or loss of the activity.
These results have revealed that the introduction of a small
Evaluation of the bioactivity
Using erlotinib as a positive control, the target compounds
6a–6l were evaluated for the cytotoxic activities in vitro
against EGFR high-expressed cancer cell lines (A549,
HeLa, and SW480) (Zhou et al. 2016a, b; Chen et al. 2015),
EGFR low-expressed cell line (HepG2) (Lin and Kao 2014)
and human liver normal cell line (HL7702) by MTT cell
proliferation assay. The cytotoxicity assay results expressed
as IC50 values (Table 2) and demonstrated that several
target compounds have showed moderate to excellent
potency against A549, HeLa, and SW480 and weak cyto-
toxic effects on HepG2 and HL7702, which is indicated that

Med Chem Res
group in 6-position is advantageous for anticancer activity;
(3) The activity of compound 6b against SW480 is superior
to that of it against A549 and HeLa, and the activity of
compound 6l against HeLa is better than that of it against
A549 and SW480, the results demonstrate that the two
compounds exhibit excellently selective activity; (4) Com-
pound 6i (IC50 = 4.05, 12.17, and 6.76 μM, respectively)
exhibits strong cytotoxic activities against A549, HeLa and
SW480; (5) All the tested compounds exhibit weak cyto-
toxic activities against HepG2 and HL7702.
Conclusion
A novel series of benzo[d]thiazole-2-carboxamide deriva-
tives were designed and synthesized, and evaluated for the
cytotoxic activities against EGFR high-expressed cancer
cell lines (A549, HeLa, and SW480), EGFR low-expressed
cell line (HepG2) and human liver normal cell line
(HL7702). The cytotoxicity assay results have showed that
these target compounds exhibit moderate to excellent
potency against A549, HeLa, and SW480 and weak cyto-
toxic activities against HepG2 and HL7702, which implies a
supporting evidence for them as potent EGFR inhibitors
with low nonspecific toxicity. The preliminary SARs pro-
vided promising opportunities to guide further research on
benzo[d]thiazole-2-carboxamide derivatives as the novel
anticancer agents.
Experimental
Molecular docking
The complexes for the enzyme were those deposited in the
RCSB Protein Data Bank for the EGFR (PDB code: 1M17)
after eliminating the inhibitor (erlotinib) and water mole-
cules. The missing residues were built and the polar
hydrogen atoms acid residues were added. Molecular
docking was carried out using MVD. The docking was set
at 1500 maximum iterations with a simplex evolution
population size of 50 and a minimum of 10 runs. The
schematic diagrams of interactions between 1M17 and the
small molecules were analyzed by PyMOL 1.7.
1
Fig. 5 Key H–1H COSY correlations of compound 6e
Table 2 In vitro cytotoxicity of the target compounds 6a–6l
Compound
IC50 (μM)
A549
HeLa
SW480
HepG2
HL7702
Chemistry
6a
20.73
>100
49.28
>100
40.27
>100
41.40
>100
4.05
36.10
>100
46.11
>100
70.99
>100
95.89
>100
12.17
48.55
>100
1.13
31.19
9.31
>100
>100
>100
>100
95.34
>100
>100
>100
>100
>100
>100
86.37
(–)
>100
>100
>100
>100
>100
>100
99.17
>100
>100
>100
>100
>100
(–)
6b
6c
All the starting materials were commercially available and
directly used without further purification. All the reaction
progresses were monitored by thin layer chromatography
(TLC) analysis with the silica gel plates (Qingdao Jiyida
silica reagent factory, Qingdao, China). The melting points
were determined on a melting-point apparatus with micro-
scope (Zhengzhou Mingyi Instrument Equipment Co., Ltd.,
Zhengzhou, China), and were uncorrected. ESI mass spectra
were performed on a Waters spectrometer (Waters Cor-
poration, USA). The IR spectra were recorded on a Bruker
45.91
54.89
69.59
>100
>100
49.72
6.76
6d
6e
6f
6g
6h
6i
6j
49.44
33.21
>100
13.41
>100
47.89
41.47
16.72
6k
6l
IFS55 spectrometer utilizing KBr pellets. 1H NMR and 13
C
NMR spectra were recorded on a Bruker spectrometer
(Faellanden, Switzerland) with 400 MHz for proton NMR
Erlotinib
15.34

Med Chem Res
or 101 MHz NMR for carbon NMR respectively, and with
TMS as an internal standard and dimethyl sulfoxide
(DMSO)-d6 or CDCl3 as the solvent, chemical shifts (d
values) and coupling constants (J values) were respectively
given in ppm and Hz. HRMS were recorded on a Agilent
Technologies 6530 Accurate-Mass Q-TOF Mass Spectro-
meter (Agilent Technologies, USA).
General procedure for the preparation of intermediate
5a–5d
A solution of compound 4 (2.23 g, 0.010 mol), 2-
chloroacetamide (0.020 mol), anhydrous potassium carbo-
nate (13.81 g, 0.10 mol), and potassium iodide (0.16 g,
0.0010 mol) in acetone (100 mL) was stirred at reflux for 16 h.
The reaction is monitored by TLC and upon to completion
the solid was removed by filtration and the solution is
evaporated in vacuo. The residue was purified by recrys-
tallization using ethanol to afford product as a solid.
Synthesis of L-cysteine ethyl ester hydrochloride (2)
The thionyl chloride (22 mL, 0.30 mol) was slowly added to
a solution of L-cysteine 1 (24.20 g, 0.20 mol) in ethanol
(300 mL) with stirring and cooling in an ice bath. After
stirring at reflux for 12 h, the solvent was evaporated under
vacuum to afford ester 2 as a white solid. The resulting
product was used directly in the following step without
further purification. Yield of compound 2: 36.42 g (98.1%).
Ethyl 6-[2-(diethylamino)-2-oxoethoxy]benzo[d]thiazole-2-
carboxylate (5a)
Yellow solid; yield: 93.6%; M.p.:139–140 °C; ESI-MS,
m/z: calcd. 336.11 (M+); found 337.1 ([M + H]+), 359.1
([M + Na]+); 1H NMR (400 MHz, DMSO-d6): δ 8.10 (d, J
= 9.1 Hz, 1H, benzo[d]thiazole-H4), 7.72 (d, J = 2.5 Hz,
1H, benzo[d]thiazole-H7), 7.25 (dd, J = 9.1, 2.5 Hz, 1H,
benzo[d]thiazole-H5), 4.93 (s, 2H, COCH2O), 4.42 (q, J =
7.1 Hz, 2H, OCH2), 3.30 (q, J = 7.0 Hz, 4H, NCH2), 1.36
(t, J = 7.1 Hz, 3H, CH3), 1.17 (t, J = 7.1 Hz, 3H, CH3), 1.11
(t, J = 7.1 Hz, 3H, CH3).
Synthesis of ethyl S-(2,5-dihydroxyphenyl)cysteinate (3)
A solution of 1,4-benzoquinone (6.48 g, 0.060 mol) in
methanol (150 mL) is added dropwise into a solution of L-
cysteine ethyl ester hydrochloride 2 (22.28 g, 0.12 mol) in
methanol (60 mL) with stirring at room temperature for 3 h.
The reaction is monitored by TLC and upon to completion
the solvent is evaporated in vacuo to afford crude product 3
without further purification. Yield of compound 3: 13.81 g
(89.6%).
Ethyl 6-[2-oxo-2-(piperidin-1-yl)ethoxy]benzo[d]thiazole-
2-carboxylate (5b)
Yellow solid; yield: 86.5%; M.p.:87–89 °C; ESI-MS, m/z:
calcd. 348.11 (M+); found 349.1 ([M + H]+), 371.1 ([M +
1
Synthesis of ethyl 6-hydroxybenzo[d]thiazole-2-
Na]+); H NMR (400 MHz, DMSO-d6): δ 8.11 (d, J = 9.1
carboxylate (4)
Hz, 1H, benzo[d]thiazole-H4), 7.44 (d, J = 2.5 Hz, 1H,
benzo[d]thiazole-H7), 7.22 (dd, J = 9.1, 2.5 Hz, 1H, benzo
[d]thiazole-H5), 4.79 (s, 2H, COCH2O), 4.53 (q, J = 7.1 Hz,
2H, OCH2), 3.56 (t, J = 5.1 Hz, 2H, NCH2), 3.54 (t, J = 5.1
Hz, 2H, NCH2), 1.65–1.61 (m, 6H, CH2), 1.47 (t, J = 7.1
Hz, 3H, CH3).
To a solution of the compound 3 (13.81 g, 0.054 mol) in
isopropanol (360 mL) an aqueous solution of 1M K3Fe
(CN)6 (300 mL) and 4M NaOH (20 mL) is added, respec-
tively. The mixture was stirred at room temperature for 14
h. At the end of the reaction with TLC monitoring, the solid
was removed by filtration and the solution extracted with
ethyl acetate. The combined organic phase was dried over
anhydrous sodium sulfate, and concentrated in vacuo. The
obtained product is purified by column chromatography on
silica gel using petroleum ether/ ethyl acetate (3/1, v/v) as
the eluent to afford compound 4: yellow solid; yield: 80.2%;
M.p.:176–177 °C (lit.(Meroni et al. 2010): 178–180 °C);
ESI-MS, m/z: calcd. 223.03(M+); found 224.1([M + H]+),
246.1([M + Na]+); 1H NMR (400 MHz, DMSO-d6): δ 7.98
(d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4), 7.39 (d, J = 2.3
Hz, 1H, benzo[d]thiazole-H7), 7.12 (dd, J = 9.0, 2.4 Hz,
1H, benzo[d]thiazole-H5), 4.46 (q, J = 7.0 Hz, 2H, CH2),
1.41 (t, J = 7.1 Hz, 3H, CH3).
Ethyl 6-[2-(morpholin-4-yl)-2-oxoethoxy]benzo[d]thiazole-
2-carboxylate (5c)
Yellow solid; yield: 98.8%; M.p.:181–183 °C; ESI-MS,
m/z: calcd. 350.09(M+); found 351.1([M + H]+), 373.1
([M + Na]+); 1H NMR (400 MHz, DMSO-d6): δ 8.10
(d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4), 7.43 (d, J = 2.3
Hz, 1H, benzo[d]thiazole-H7), 7.22 (dd, J = 9.1, 2.3 Hz,
1H, benzo[d]thiazole-H5), 4.64 (s, 2H, COCH2O), 4.57
(q, J = 7.0 Hz, 2H, OCH2), 3.68–3.59 (m, 8H, CH2), 1.47
(t, J = 7.1 Hz, 3H, CH3).

Med Chem Res
Ethyl 6-{2-{[2-(2-methoxyphenoxy)ethyl]amino}-2-
oxoethoxy}benzo[d]thiazole-2-carboxylate (5d)
9.0 Hz, 1H, benzo[d]thiazole-H4), 7.45 (d, J = 2.5 Hz, 1H,
benzo[d]thiazole-H7), 7.40–7.34 (m, 5H, Ar–H), 7.21 (dd,
J = 9.0, 2.5 Hz, 1H, benzo[d]thiazole-H5), 4.78 (s, 2H,
OCH2), 4.68 (d, J = 6.0 Hz, 2H, NHCH2), 3.59–3.48 (m,
4H, NCH2), 1.68–1.55 (m, 6H, CH2); 13C NMR (101 MHz,
CDCl3): δ 165.66, 161.75, 160.01, 157.50, 148.02, 138.89,
137.60, 128.98, 128.91, 128.18, 128.08, 127.94, 125.17,
117.46, 105.53, 68.21, 46.56, 44.00, 43.45, 26.67, 25.67,
24.55; HRMS (ESI): calcd for C22H23N3O3S, [M]+ m/z,
409.1465; found, 410.1537([M + H]+), 432.1362([M +
Na]+).
Yellow solid; yield: 67.8%; M.p.:151–152 °C; ESI-MS, m/
1
z: calcd. 430.12 (M+); found 431.1 ([M + H]+); H NMR
(400 MHz, CDCl3): δ 7.34 (d, J = 9.0 Hz, 1H, benzo[d]
thiazole-H4), 6.96 (d, J = 2.7 Hz, 1H, benzo[d]thiazole-H7),
6.91 (dd, J = 9.0, 2.7 Hz, 1H, benzo[d]thiazole-H5),
6.91–6.82 (m, 4H, Ar–H), 4.43 (s, 2H, COCH2O), 4.12 (t, J
= 5.0 Hz, 2H, OCH2), 3.83 (s, 3H, OCH3), 3.75 (t, J = 5.4
Hz, 2H, OCH2), 3.48–3.41 (m, 2H, CH2), 1.72 (t, J = 7.2
Hz, 3H, CH3).
General procedure for the preparation of benzo[d]
thiazole-2-carboxamide derivatives 6a–6l
N-benzyl-6-[2-(morpholin-4-yl)-2-oxoethoxy]benzo[d]
thiazole-2-carboxamide (6c)
A solution of compound 5a–5d (0.0030 mol) and benzyla-
mine or 4-fluorobenzylamine or 2-furylmethylamine
(0.0090 mol) in ethanol (20 mL) was stirred at reflux for
12 h. After cooling to ambient temperature, the solution is
evaporated in vacuo. The residue was purified by column
chromatography on silica gel using petroleum ether/ ethyl
acetate(2/1, v/v) as the eluent to afford the corresponding
products (6a–6l).
Pink solid; yield: 51.1%; M.p.: 186–188 °C; IR: (KBr,
cm−1): υ 3421.4, 3277.0, 2923.5, 2845.7, 1666.0, 1637.9,
1496.5, 1436.6, 1359.1, 1253.8, 1210.2, 1114.7, 1001.5,
838.4, 827.6, 697.5; ESI-MS, m/z: calcd. 411.13 (M+);
1
found 412.1 ([M + H]+); H NMR (400 MHz, CDCl3): δ
7.92 (d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4), 7.45 (d, J =
2.3 Hz, 1H, benzo[d]thiazole-H7), 7.38–7.34 (m, 5H,
Ar–H), 7.19 (dd, J = 9.0, 2.4 Hz, 1H, benzo[d]thiazole-H5),
4.79 (s, 2H, OCH2), 4.68 (d, J = 6.0 Hz, 2H, NHCH2),
3.67–3.65 (m, 8H, CH2); 13C NMR (101 MHz, CDCl3): δ
166.15, 161.95, 159.96, 157.10, 148.19, 138.92, 137.52,
129.14, 128.98, 128.17, 127.95, 127.83, 125.31, 117.28,
105.56, 68.12, 66.95, 66.83, 46.04, 44.01, 42.63; HRMS
(ESI): calcd for C21H21N3O4S, [M]+ m/z, 411.1253; found,
434.1155([M + Na]+).
N-benzyl-6-[2-(diethylamino)-2-oxoethoxy]benzo[d]
thiazole-2-carboxamide (6a)
White solid; yield: 58.7%; M.p.: 146–148 °C; IR: (KBr,
cm−1): υ 3422.8, 3347.7, 2932.2, 1665.3, 1632.0, 1523.6,
1554.6, 1259.9, 1213.0, 1060.2, 1030.6, 945.7, 827.4,
699.0; ESI-MS, m/z: calcd. 397.15 (M+); found 398.1 ([M
+ H]+), 420.1 ([M + Na]+); 1H NMR (400 MHz, CDCl3): δ
7.90 (d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4), 7.39–7.35
(m, 5H, Ar–H), 7.32 (d, J = 2.0 Hz, 1H, benzo[d]thiazole-
H7), 7.21 (dd, J = 9.1, 2.1 Hz, 1H, benzo[d]thiazole-H5),
4.77 (s, 2H, OCH2), 4.68 (d, J = 5.8 Hz, 2H, NHCH2), 3.41
(q, J = 7.1 Hz, 4H, CH2), 1.24 (t, J = 7.0 Hz, 3H, CH3),
1.15 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (101 MHz,
CDCl3): δ 166.53, 161.69, 160.03, 157.58, 148.03, 138.87,
137.55, 129.05, 128.97, 128.16, 128.03, 127.92, 125.16,
117.53, 105.52, 68.07, 43.99, 41.71, 40.56, 14.53, 12.95;
HRMS (ESI): calcd for C21H23N3O3S, [M]+ m/z, 397.1461;
found, 398.1539([M + H]+), 420.1358([M + Na]+).
N-benzyl-6-{2-{[2-(2-methoxyphenoxy)ethyl]amino}-2-
oxoethoxy}benzo[d]thiazole-2-carboxamide (6d)
White solid; yield: 38.6%; M.p.: 139–141 °C; IR: (KBr,
cm−1): υ 3438.8, 2920.5, 1651.4, 1548.3, 1508.0, 1384.2,
1254.4, 1227.3, 1124.3, 1071.8, 1022.1, 824.6, 735.9,
698.6; ESI-MS, m/z: calcd. 491.15 (M+); found 492.2 ([M
+ H]+), 514.2 ([M + Na]+); 1H NMR (400 MHz, CDCl3): δ
7.92 (d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4), 7.40 (d, J =
2.5 Hz, 1H, benzo[d]thiazole-H7), 7.39–7.35 (m, 5H,
Ar–H), 7.17 (dd, J = 9.0, 2.6 Hz, 1H, benzo[d]thiazole-H5),
6.89–6.86 (m, 4H, Ar–H), 4.69 (d, J = 6.0 Hz, 2H,
NHCH2), 4.60 (s, 2H, OCH2CO), 4.13 (t, J = 5.0 Hz, 2H,
OCH2), 3.82 (s, 3H, OCH3), 3.78–3.73 (m, 2H, CH2); 13C
NMR (101 MHz, CDCl3): δ 167.92, 162.30, 159.86,
156.54, 149.99, 148.36, 147.79, 139.05, 137.52, 129.15,
129.01, 128.18, 127.98, 127.84, 125.37, 122.49, 121.22,
117.10, 115.22, 112.15, 105.98, 68.73, 68.19, 55.95, 44.03,
38.79; HRMS (ESI): calcd for C26H25N3O5S, [M]+ m/z,
491.1515; found, 514.1414 ([M + Na]+).
N-benzyl-6-[2-oxo-2-(piperidin-1-yl)ethoxy]benzo[d]
thiazole-2-carboxamide (6b)
Pink solid; yield: 54.4%; M.p.: 198–199 °C; IR: (KBr,
cm−1): υ 3429.8, 2921.8, 2852.9, 1649.8, 1521.6, 1495.8,
1384.4, 1249.8, 1216.9, 1122.7, 1085.8, 956.0, 829.1,
730.0, 694.4; ESI-MS, m/z: calcd. 409.15(M+); found 410.1
1
([M + H]+); H NMR (400 MHz, CDCl3): δ 7.91 (d, J =

Med Chem Res
6-[2-(Diethylamino)-2-oxoethoxy]-N-(4-fluorobenzyl)benzo
[d]thiazole-2-carboxamide (6e)
H5), 7.03 (t, J = 8.6 Hz, 2H, Ar–H), 4.79 (s, 2H, OCH2),
4.63 (d, J = 6.1 Hz, 2H, NHCH2), 3.69–3.60 (m, 8 H, CH2);
13C NMR (101 MHz, CDCl3): δ 166.08, 163.69, 161.81,
161.24, 157.14, 148.11, 138.89, 133.38, 129.88, 129.80,
125.27, 117.32, 115.90, 115.69, 105.54, 68.08, 66.92,
66.80, 46.00, 43.23, 42.60; HRMS (ESI): calcd for
C21H20FN3O4S, [M]+ m/z, 429.1159; found, 452.1059 ([M
+ Na]+).
White solid; yield: 39.2%; M.p.: 152–153 °C; IR: (KBr,
cm−1): υ 3425.9, 3349.2, 2935.9, 1665.7, 1630.7, 1511.6,
1437.9, 1384.3, 1259.4, 1211.8, 1162.2, 1059.4, 1035.2,
947.4, 829.1, 765.7, 645.5; ESI-MS, m/z: calcd. 415.14
(M+); found 416.1 ([M + H]+); 1H NMR (400 MHz,
CDCl3): δ 7.90 (d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4),
7.43 (d, J = 1.7 Hz, 1H, benzo[d]thiazole-H7), 7.35 (dd, J
= 8.6, 5.4 Hz, 2H, Ar–H), 7.21 (dd, J = 9.1, 1.8 Hz, 1H,
benzo[d]thiazole-H5), 7.04 (t, J = 8.0 Hz, 2H, Ar–H), 4.77
(s, 2H, OCH2), 4.64 (d, J = 5.9 Hz, 2H, NHCH2), 3.42 (q, J
= 7.2 Hz, 4H, CH2), 1.24 (t, J = 6.7 Hz, 3H, CH3), 1.15 (t,
J = 7.1 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3): δ
166.50, 163.72, 161.53, 161.27, 157.63, 147.99, 138.88,
133.47, 129.91, 129.83, 125.15, 117.59, 115.92, 115.71,
105.51, 68.01, 43.24, 41.71, 40.56, 14.53, 12.94; HRMS
(ESI): calcd for C21H22FN3O3S, [M]+ m/z, 415.1366;
found, 416.1441 ([M + H]+), 438.1266 ([M + Na]+).
N-(4-fluorobenzyl)-6-{2-{[2-(2-methoxyphenoxy)ethyl]
amino}-2-oxoethoxy}benzo[d]thiazole-2-carboxamide (6h)
Pink solid; yield: 43.1%; M.p.: 144–146 °C; IR: (KBr,
cm−1): υ 3422.7, 2921.1, 1651.1, 1509.7, 1384.3, 1254.8,
1225.5, 1124.0, 1072.0, 1024.0, 825.6, 735.7, 699.8; ESI-
MS, m/z: calcd. 509.14 (M+); found 510.1 ([M + H]+),
532.1 ([M + Na]+); 1H NMR (400 MHz, CDCl3): δ 7.92 (d,
J = 9.0 Hz, 1H, benzo[d]thiazole-H4), 7.41 (d, J = 2.1 Hz,
1H, benzo[d]thiazole-H7), 7.36 (dd, J = 8.6, 5.4 Hz, 2H,
Ar–H), 7.18 (dd, J = 9.0, 2.2 Hz, 1H, benzo[d]thiazole-H5),
7.05 (t, J = 8.6 Hz, 2H, Ar–H), 6.91–6.85 (m, 4H, Ar–H),
4.65 (d, J = 6.0 Hz, 2H, NHCH2), 4.60 (s, 2H, OCH2CO),
4.13 (t, J = 4.9 Hz, 2H, OCH2), 3.82 (s, 3H, OCH3),
3.78–3.76 (m, 2H, CH2); 13C NMR (101 MHz, CDCl3): δ
167.84, 167.07, 162.10, 161.31, 156.59, 150.00, 148.33,
146.61, 138.97, 133.63, 129.93, 129.85, 125.38, 122.50,
121.23, 117.17, 115.97, 115.76, 115.23, 112.15, 105.98,
68.74, 68.17, 55.95, 43.28, 38.79; HRMS (ESI): calcd for
C26H24FN3O5S, [M]+ m/z, 509.1421; found, 532.1327 ([M
+ Na]+).
N-(4-fluorobenzyl)-6-[2-oxo-2-(piperidin-1-yl)ethoxy]benzo
[d]thiazole-2-carboxamide (6f)
White solid; yield: 47.4%; M.p.: 151–153 °C; IR: (KBr,
cm−1): υ 3422.8, 3333.9, 2919.3, 2850.6, 1656.0, 1508.8,
1431.0, 1250.9, 1215.5, 1085.2, 1006.0, 847.0, 825.1,
753.5, 673.2; ESI-MS, m/z: calcd. 427.14 (M+); found
1
428.1 ([M + H]+); H NMR (400 MHz, CDCl3): δ 7.91 (d,
J = 9.0 Hz, 1H, benzo[d]thiazole-H4), 7.45 (d, J = 2.5 Hz,
1H, benzo[d]thiazole-H7), 7.36 (dd, J = 8.6, 5.4 Hz, 2H,
Ar–H), 7.21 (dd, J = 9.1, 2.5 Hz, 1H, benzo[d]thiazole-H5),
7.04 (t, J = 8.7 Hz, 2H, Ar–H), 4.78 (s, 2H, OCH2), 4.64 (d,
J = 6.0 Hz, 2H, NHCH2), 3.59–3.48 (m, 4H, NCH2),
1.60–1.55 (m, 6H, CH2); 13C NMR (101 MHz, CDCl3): δ
165.64, 161.58, 161.29, 160.06, 157.55, 148.02, 138.92,
133.44, 129.92, 129.84, 125.12, 117.51, 115.94, 115.73,
105.53, 68.19, 46.55, 43.45, 43.25, 26.67, 25.66, 24.55;
HRMS (ESI): calcd for C22H22FN3O3S, [M]+ m/z,
427.1366; found, 428.1442 ([M + H]+), 450.1272 ([M +
Na]+).
6-[2-(Diethylamino)-2-oxoethoxy]-N-(furan-2-ylmethyl)
benzo[d]thiazole-2-carboxamide (6i)
Yellow solid; yield: 35.3%; M.p.: 144–146 °C; IR: (KBr,
cm−1): υ 3381.3, 2919.1, 1677.9, 1660.8, 1535.7, 1490.4,
1223.9, 1076.7, 1010.9, 967.0, 940.8, 837.4, 816.4, 738.8,
618.8; ESI-MS, m/z: calcd. 387.13(M+); found 388.1([M +
1
H]+); H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.8 Hz,
1H, benzo[d]thiazole-H4), 7.64 (d, J = 2.3 Hz, 1H, benzo[d]
thiazole-H7), 7.39 (d, J = 8.7 Hz, 1H, furan-H5), 7.21 (dd, J
= 8.9, 2.4 Hz, 1H, benzo[d]thiazole-H5), 6.36–6.30 (m, 2H,
furan-H3/H4), 4.77 (s, 2H, OCH2), 4.67 (d, J = 5.1 Hz, 2H,
NHCH2), 3.41 (q, J = 7.1 Hz, 4H, CH2), 1.23 (t, J = 7.0 Hz,
3H, CH3), 1.14 (t, J = 6.7 Hz, 3H, CH3); 13C NMR (101
MHz, CDCl3): δ 166.51, 161.41, 159.89, 157.60, 150.57,
147.99, 142.66, 138.85, 125.18, 117.55, 110.65, 108.19,
105.48, 68.00, 41.70, 40.55, 36.78, 14.52, 12.93; HRMS
(ESI): calcd for C19H21N3O4S, [M]+ m/z, 387.1253; found,
388.1335 ([M + H]+), 410.1146 ([M + Na]+).
N-(4-fluorobenzyl)-6-[2-(morpholin-4-yl)-2-oxoethoxy]
benzo[d]thiazole-2-carboxamide (6g)
Yellow solid; yield: 41.1%; M.p.: 184–185 °C; IR: (KBr,
cm−1): υ 3422.6, 2928.2, 2851.6, 1671.2, 1635.5, 1509.9,
1440.0, 1384.4, 1227.2, 1206.4, 1117.5, 1001.0, 951.5,
825.0, 767.0, 708.8; ESI-MS, m/z: calcd. 429.12 (M+);
1
found 430.1 ([M + H]+); H NMR (400 MHz, CDCl3): δ
7.91 (d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4), 7.45 (d, J =
2.4 Hz, 1H, benzo[d]thiazole-H7), 7.35 (dd, J = 8.5, 5.4 Hz,
2H, Ar–H), 7.18 (dd, J = 9.0, 2.4 Hz, 1H, benzo[d]thiazole-

Med Chem Res
N-(Furan-2-ylmethyl)-6-[2-oxo-2-(piperidin-1-yl)ethoxy]
benzo[d]thiazole-2-carboxamide (6j)
CH2); 13C NMR (101 MHz, CDCl3): δ 167.88, 161.99,
159.74, 156.55, 150.51, 149.93, 148.31, 147.83, 142.72,
138.95, 125.39, 122.45, 121.21, 117.14, 115.11, 112.10,
110.69, 108.25, 105.92, 68.68, 68.16, 55.92, 38.77, 36.80;
HRMS (ESI): calcd for C24H23N3O6S, [M]+ m/z, 481.1308;
found, 504.1206([M + Na]+).
White solid; yield: 48.1%; M.p.: 196–198 °C; IR: (KBr,
cm−1): υ 3426.6, 2927.1, 2853.3, 1653.1, 1529.7, 1498.4,
1384.4, 1251.5, 1221.3, 1127.3, 1084.8, 1008.4, 962.8,
829.1, 753.0; ESI-MS, m/z: calcd. 399.13 (M+); found
400.1 ([M + H]+), 422.1 ([M + Na]+); 1H NMR (400 MHz,
CDCl3): δ 7.93 (d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4),
7.44 (d, J = 2.5 Hz, 1H, benzo[d]thiazole-H7), 7.39 (d, J =
8.7 Hz, 1H, furan-H5), 7.21 (dd, J = 9.0, 2.6 Hz, 1H, benzo
[d]thiazole-H5), 6.35–6.33 (m, 2H, furan-H3/H4), 4.78 (s,
2H, OCH2), 4.67 (d, J = 5.9 Hz, 2H, NHCH2), 3.59–3.48
(m, 4H, NCH2), 1.67–1.59 (m, 6H, CH2); 13C NMR (101
MHz, CDCl3): δ 165.66, 161.47, 159.89, 157.52, 150.58,
148.03, 142.69, 138.90, 125.22, 117.52, 110.67, 108.21,
105.51, 68.19, 46.56, 43.45, 36.80, 26.67, 25.66, 24.55;
HRMS (ESI): calcd for C20H21N3O4S, [M]+ m/z, 399.1253;
found, 400.1338 ([M + H]+), 422.1153 ([M + Na]+).
Biological assay
In order to determine the anticancer activity of our target
compounds in vitro, the 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl tetrazolium bromide (MTT) assay was used. A549
cells, Hela cells, SW480 cells, HepG2 cells, and HL7702
cells were harvested in the logarithmic growth phase and
seeded in 96-well plates at a density of 8000 cells per well,
and cultured at 37 °C in humidified atmosphere containing
5% CO2 in Dulbecco’s modified Eagle’s medium (DMEM
or RPMI-1640) with 10% fetal bovine serum for 24 h before
any treatments. Tested compounds were dissolved in
DMSO and diluted in the culture fluid to get various con-
centrations. The cells were treated with target compounds
subsequently and incubated overnight. Then 20 μL of MTT
(5 mg/mL) was added in each well and after 4 h incubation,
the medium was removed immediately and MTT formazan
was solubilized in 150 μL DMSO. The optical densities
were measured with a microplate reader (Bio-Tek instru-
ments, INC. USA) at 490 nm. Inhibitory effects were
determined as IC50 value.
N-(Furan-2-ylmethyl)-6-[2-(morpholin-4-yl)-2-oxoethoxy]
benzo[d]thiazole-2-carboxamide (6k)
Pink solid; yield: 37.6%; M.p.: 188–190 °C; IR: (KBr,
cm−1): υ 3422.6, 2919.0, 2850.2, 1640.8, 1497.3, 1384.1,
1255.3, 1208.7, 1112.1, 1000.6, 828.3, 745.0; ESI-MS, m/z:
calcd. 401.10 (M+); found 402.1 ([M + H]+), 424.1 ([M +
1
Na]+); H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 9.0 Hz,
1H, benzo[d]thiazole-H4), 7.45 (d, J = 2.5 Hz, 1H, benzo[d]
thiazole-H7), 7.39 (d, J = 8.5 Hz, 1H, furan-H5), 7.19 (dd, J
= 9.1, 2.6 Hz, 1H, benzo[d]thiazole-H5), 6.35–6.33 (m, 2H,
furan-H3/H4), 4.79 (s, 2H, OCH2), 4.67 (d, J = 5.9 Hz, 2H,
NHCH2), 3.69–3.65 (m, 8H, CH2); 13C NMR (101 MHz,
CDCl3): δ 166.13, 161.73, 159.82, 157.14, 150.54, 148.20,
142.70, 138.94, 125.35, 117.31, 110.68, 108.23, 105.55,
68.14, 66.95, 66.83, 46.04, 42.63, 36.81; HRMS (ESI):
calcd for C19H19N3O5S, [M]+ m/z, 401.1045; found,
424.0951([M + Na]+).
Acknowledgements This work was supported by the National Sci-
ence Foundation of China (NSFC) for the grant No. 21342006 and the
Program for Innovative Research Team of the Ministry of Education of
China for the grant No. IRT_14R36. The authors would like to thank
Molegro ApS for kindly providing a free evaluation copy of their
software package and Schrödinger, LLC for allowing the use of
PyMOL Molecular Graphics System.
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interests.
N-(Furan-2-ylmethyl)-6-{2-{[2-(2-methoxyphenoxy)ethyl]
amino}-2-oxoethoxy}benzo[d]thiazole-2-carboxamide (6l)
Ethical approval This article does not contain any studies with
animals performed by any of the authors.
White solid; yield: 38.9%; M.p.: 144–146 °C; IR: (KBr,
cm−1): υ 3444.9, 2921.7, 1664.9, 1646.6, 1527.5, 1509.1,
1384.4, 1257.4, 1225.5, 1122.7, 1070.7, 1018.2, 847.2,
821.9, 742.5; ESI-MS, m/z: calcd. 481.13 (M+); found
482.2 ([M + H]+), 504.1 ([M + Na]+); 1H NMR (400 MHz,
CDCl3): δ 7.93 (d, J = 9.0 Hz, 1H, benzo[d]thiazole-H4),
7.40–7.39 (m, 2H, benzo[d]thiazole-H7/furan-H5), 7.18 (dd,
J = 9.0, 2.6 Hz, 1H, benzo[d]thiazole-H5), 6.89–6.85 (m,
4H, Ar–H), 6.36–6.34 (m, 2H, furan-H3/H4), 4.68 (d, J =
5.9 Hz, 2H, NHCH2), 4.60 (s, 2H, OCH2CO), 4.12 (t, J =
5.0 Hz, 2H, OCH2), 3.82 (s, 3H, OCH3), 3.79–3.75 (m, 2H,
Informed consent Informed consent was obtained from all indivi-
dual participants included in the study.
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