Design, synthesis, and biological evaluation of chalcone-linked thiazole-imidazopyridine derivatives as anticancer agents

Article abstract of DOI:10.1007/s00044-020-02590-9

A novel library of chalcone linked thiazole-imidazopyridine (12a–j) derivatives were designed, synthesized, and their structures were characterized by ¹H NMR, ¹³C NMR and mass spectral studies. Further, all compounds were tested for their anticancer effects on four human cancer cell lines including MCF-7 (breast carcinoma), A549 (lung carcinoma), DU-145 (prostate carcinoma) and MDA MB-231 (breast carcinoma) by employing MTT method, using etoposide as the positive control. Among them, compound 12b displayed more potent anticancer activity against four cancer cell lines when compared to the positive control.

Full text of DOI:10.1007/s00044-020-02590-9

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-020-02590-9
ORIGINAL RESEARCH
Design, synthesis, and biological evaluation of chalcone-linked
thiazole-imidazopyridine derivatives as anticancer agents
Vellanki Ragha Suma1,2 Reddymasu Sreenivasulu3 Mandava Venkata Basaveswara Rao4
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Madala Subramanyam5 Mohamed Jawed Ahsan6 Ramesh Alluri7 Kuppili Ram Mohan Rao1
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Received: 23 November 2019 / Accepted: 11 June 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
A novel library of chalcone linked thiazole-imidazopyridine (12a–j) derivatives were designed, synthesized, and their
structures were characterized by 1H NMR, 13C NMR and mass spectral studies. Further, all compounds were tested for their
anticancer effects on four human cancer cell lines including MCF-7 (breast carcinoma), A549 (lung carcinoma), DU-145
(prostate carcinoma) and MDA MB-231 (breast carcinoma) by employing MTT method, using etoposide as the positive
control. Among them, compound 12b displayed more potent anticancer activity against four cancer cell lines when
compared to the positive control.
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Keywords Imidazo[4,5-b]pyridine Zolpidine Licochalcone A Chalcone and anticancer activity
Introduction
2010; Meffert et al. 2003; Clemens 1991) and internal
factors (Mantovani et al. 2008; Clayton et al. 2011; Porta
et al. 2011). Cancer treatment has become an important and
challenging therapeutic task in medicinal chemistry. The
three main treatment strategies employed are surgery,
radiation therapy, and chemotherapy. Of these, chemother-
apy is one of the important therapy used for the treatment of
cancer, which employs chemotherapeutic agents. However,
this is associated with various side effects. Hence, the dis-
covery of potent anticancer agents without side effects is a
challenge in development of cancer chemotherapeutics for
the future generations.
Now days, cancer is the second leading cause of death after
heart disease in developed and undeveloped countries (John
and Ross 2010), which is initiated by external (Park et al.
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-020-02590-9) contains supplementary
material, which is available to authorized users.
* Kuppili Ram Mohan Rao
rammohanrao.k@gmail.com
Nitrogen-containing heterocyclic molecules has always
attracted significant interest in pharmaceutical industry
because of their biological applications. Nitrogen contain-
ing imidazo[4,5-b]pyridines are versatile nitrogenized fused
hetero-aromatic units that have exhibited potent anticancer
properties against a panel of cell lines (Agarwal et al. 2016;
Ahsan et al. 2015; Durgesh et al. 2018a, 2018b, 2018c;
Hatti et al. 2015a, 2015b; Madhavi et al. 2017b; Murthy
et al. 2019; Pragathi et al. 2019; Rao et al. 2019; Reddy
et al. 2016a, 2016b; Reddy et al. 2019; Shahinshavali et al.
2019; Spandana et al. 2018a, 2018b; Sreenivasulu et al.
2017; 2018; 2019; 2020; Subramanyam et al. 2018; Suma
et al. 2019; Yakantham et al. 2019). It is a structural analog
of a purine base. Its derivatives easily interact with the
proteins of DNA and RNA. They also show a variety of
biological properties like antimitotic (Temple 1990),
1
Department of Chemistry, , GITAM Institute of Science Gandhi
Institute of Technology and Management (Deemed to be
University), Visakhapatnam, Andhra Pradesh 530045, India
2
Department of Chemistry, Government Degree and PG College,
Bhadrachalam, Telangana 507111, India
3
Department of Chemistry, University College of Engineering
(Autonomous), Jawaharlal Nehru Technological University,
Kakinada, Andhra Pradesh 533003, India
4
Department of Chemistry, Krishna University,
Machilipatnam, Andhra Pradesh 521001, India
5
Department of Chemistry, SR and BGNR Govt. Arts and Science
College (Autonomous), Khammam, Telangana 507002, India
6
Department of Pharmaceutical Chemistry, Maharishi Arvind
College of Pharmacy, Ambabari Circle, Jaipur, Rajasthan, India
7
Vishnu Institute of Pharmaceutical Education & Research
(VIPER), Narsapur, Medak, Telangana 502313, India

Medicinal Chemistry Research
N
N
cyclization reaction with 4-methyl cinnamaldehyde (4) in
the presence of CuBr in ethanol solvent at 60 °C for 8 h to
afford 2-p-tolylH-imidazo[1,2-a]pyridine-3-carbaldehyde
(5). This was then reacted with hydroxyl amine hydro-
chloride in DMSO solvent and reaction mixture was stirred
at 90 °C for 2 h to afford pure 2-p-tolylH-imidazo[1,2-a]
pyridine-3-carbonitrile (6). This intermediate 5 was con-
verted into thioamide group by reacting with NaSH,
MgCl2.6H2O in dry DMF and was stirred at 40 °C for
90 min to provide pure 2-p-tolylH-imidazo[1,2-a]pyridine-
3-carbothioamide (7). Compound 7 undergoes cyclization
with 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone (8) in
absolute ethanol at room temperature for 1 h, then stirred at
reflux for 20 min to give 3-(4-(3,4,5-trimethoxyphenyl)
thiazol-2-yl)-2-p-tolylH-imidazo[1,2-a]pyridine (9). Com-
pound 9 was reacted with selenium dioxide in ethanol and
reaction mixture was stirred at reflux for 24 h to afford 4-(3-
(4-(3,4,5-trimethoxyphenyl)thiazol-2-yl)H-imidazo[1,2-a]
pyridin-2-yl)benzaldehyde (10). Furthermore, aldehyde 9
undergoes to Claisen-schmidt condensation reaction with
substituted acetophenones (11a–j) in the presence of aq
KOH base in ethanol at room temperature for 12 h to pro-
vide pure chalcones 12a–j.
N
HO
MeO
OH
O
O
Licochalcone A (2)
Zolpidem (1)
Fig. 1 Structure of Zolpidem (1) and Licochalcone A (2)
anticancer (Byth et al. 2006; Kamal et al. 2015, 2010),
antifungal (Rival et al. 1991), antiviral (Gudmundsson et al.
2003; Gueiffier et al. 1998), anti-inflammatory (Lacerda
et al. 2009), antimicrobial (Al-Tel et al. 2011), antiulcer
(Starrett et al. 1989), anti tuberculotic (Bukowski and
Kaliszan 1991) and hypnotic (Kercher et al. 2007). Among
these, the drug candidate, Zolpidine (1, Fig. 1) contains
imidazo[4,5-b]pyridine core as a backbone of the structure
and is used for the treatment of anxiety (antianxiolytic)
(Harrison and Keating 2005; Lancel and Steiger 1999;
Langer et al. 1990).
On the other hand, chalcones are the unique class of α,
β-unsaturated ketones and are precursors of flavonoids and
isoflavonoids (Rozmer and Perjési 2016). The unsaturated
(–COCH=CH–) system is responsible for biological activ-
ity exhibited by this class of compounds. These derivativs
possess a broad spectrum of biological activities including
antimitotic (Ducki et al. 1998), anticancer (Modzelewska
et al. 2006), antimalarial (Larsen et al. 2005), antifungal
(Lahtchev et al. 2008), antioxidant (Nowakowska 2007),
antituberclosis (Lin et al. 2002), antioncogenic (Go et al.
2005), antileishmanial (Nielsen et al. 1998), anti-
inflammatory (Rojas et al. 2003), antiviral (Cheenpracha
et al. 2006), antibacterial (Liaras et al. 2011) activities and
exhibit hyper glycaemic (Satyanarayana et al. 2004) cardi-
ovascular (Furman et al. 2001) properties, induce apoptosis,
are cytotoxic (Dimmock et al. 1998). Chalcone functionality
is also present in anticancer agents like Licochalcone A (2)
(2012), which is first isolated from the root of Glycyrrhiza
glabra (Yoon et al. 2007; Fu et al. 2004). It acts as a human
DNA topoisomerase-I inhibitor.
Biological evaluation
In vitro cytotoxicity
The developed compounds (12a–j) were screened for their
anticancer activity against four human cancer cell lines
viz, MCF-7 (breast carcinoma), A549 (lung carcinoma),
DU-145 (prostate carcinoma), and MDA MB-231 (breast
carcinoma) by using MTT method, and clinical drug eto-
poside was used as the positive control. Etoposide is
employed in chemotherapy medication for the treatment of
different types of cancers. Etoposide has 3,5-dimethoxy-4-
hydroxy phenyl active scaffold. In the present research, we
synthesized different derivatives by varying the sub-
stituents on the phenyl ring. Hence we selected Etoposide
as standard drug.
Previously reported chalcone derivatives showed
medium-to-less anticancer activities against a panel of
cancer cell lines (Madhavi et al. 2016, 2017a). But chalcone
linked thiazole-imidazopyridine derivatives exhibited potent
anticancer activities against four specified cancer cell lines.
It can be explained on the basis of insertion of active
scaffold “thiazole-imidazopyridine”. Among the ten
screened compounds, five compounds (12b, 12c, 12d, 12i
and 12j) have exhibited superior potency in anticancer
activity on four cell lines. Structure-activity relationship
studies indicated that the compound 12b with electron-rich
(3,4,5-trimethoxy) group on the phenyl ring displayed the
Based on the above information and our continuous
efforts, we have synthesized a new series of structurally
modified chalcone incorporated thiazole-imidazopyridine
(12a–j) derivatives and investigated their anticancer activ-
ities against a panel of four human cancer cell lines.
Results and discussion
Chemistry
The synthetic route for these compounds 12a–j is outlined
in Scheme 1. Compound pyridin-2-amine (3) undergoes

Medicinal Chemistry Research
CuBr, EtOH, 60 oC, 8h
CHO
N
Scheme 1 Synthesis chalcone
linked thiazole-imidazopyridine
derivatives
N
N
NH2
3
4
5
CHO
Br
NH2OH.HCl, DMSO
90 oC, 2h
O
N
N
NaSH, MgCl2.6H2O
DMF, 40 oC, 90 min
N
N
MeO
OMe
7
CN
6
S
OMe
8
H2N
CHO
Ethanol, rt, 1h
reflux, 20 min
MeO
MeO
S
OMe
N
EtOH, SeO2, reflux
24h
N
N
N
10
N
OMe
OMe
N
MeO
S
9
O
11a-j
EtOH, aq KOH
rt, 12h
R
11a; R = H
11b; R = 3,4,5-trimethoxy
11c; R = 3,5-dimethoxy
11d; R = 4-methoxy
11e; R = 4-chloro
N
R
N
11f; R = 4-bromo
11g; R = 4-nitro
11h; R = 3,5-dinitro
11i; R = 4-cyano
N
S
11j; R = 4-methyl
O
MeO
MeO
12a-j
OMe
12a; R = H
12b; R = 3,4,5-trimethoxy
12c; R = 3,5-dimethoxy
12d; R = 4-methoxy
12e; R = 4-chloro
12f; R = 4-bromo
12g; R = 4-nitro
12h; R = 3,5-dinitro
12i; R = 4-cyano
12j; R = 4-methyl
highest anticancer activity amongst all the compounds
screened, with IC50 values MCF-7 = 0.18 0.094 µM,
A549 = 0.66 0.071 µM, DU-145 = 1.03 0.45 µM and
MDA MB-231 = 0.065 0.0082 µM. Compound 12c with
3,5-dimethoxy group exhibited slightly lower activity
(MCF-7 = 0.44 0.018 µM, A549 = 1.23 0.37 µM, DU-
145 = 1.12 0.25 µM and MDA MB-231 = 0.95
0.066 µM) compared to compound 12b. Similarly, com-
pound 12d having only one methoxy substituent (4-meth-
oxy) also showed decreased activity on four cell lines
(MCF-7 = 1.98 0.52 µM, A549 = 2.10 1.66 µM, DU-
145 = 2.44 1.32 µM and MDA MB-231 = 1.81
0.84 µM) than 12b and 12c.Replacement of 4-methoxy
substituent with electron-withdrawing substituent’s 4-chloro
(12e), 4-bromo (12 f), 4-nitro (12 g) and 3,5-dinitro (12 h)
declined the biological activity further. Interestingly, com-
pound 12i with 4-cyano group on the phenyl ring has shown
considerable anticancer activity (MCF-7 = 2.33 1.73 µM,
A549 = 2.17 1.50 µM, DU-145 = 1.90 0.88 µM and
MDA MB-231 = 2.02 0.99 µM) than 12e–h. Whereas,
compound 12j having weaker electron-rich group has
demonstrated improved anticancer activity on three cell
lines like MCF-7 = 1.73 0.11 µM, A549 = 1.69
0.32 µM, DU-145 = 1.33 0.45 µM. compound 12a which
has no substituent, exhibited lesser activity.
From the SAR studies, it could be concluded that the
presence of three electron donating –OCH3 group at 3,4,5
positions on phenyl ring displayed excellent potent antic-
ancer activities against four specified cancer cell lines.
Decrease the number of electron donating –OCH3 groups
on phenyl ring would decreases the activity against all
specified cancer cell lines. The presence of strong with-
drawing group –NO2 at 3, 5 positions on phenyl ring dis-
played very less anticancer activity against specified cancer
cell lines. Consequently, weak electron-withdrawing groups
like bromo and chloro on phenyl ring showed low

Medicinal Chemistry Research
Table 1 In vitro cytotoxicity of
newly synthesized compounds
12a-j with IC50 in µMa
Compound
bMCF-7
cA549
dDU-145
eMDA MB-231
12a
3.29 2.66
0.18 0.094
0.44 0.018
1.98 0.52
4.25 2.11
6.36 3.56
14.85 5.98
17.68 6.32
2.33 1.73
1.73 0.11
2.11 0.024
4.88 2.87
0.66 0.071
1.23 0.37
2.10 1.66
ND
7.13 3.14
1.03 0.45
1.12 0.25
2.44 1.32
5.89 3.23
6.68 3.11
ND
3.86 2.10
0.065 0.0082
0.95 0.066
1.81 0.84
3.57 2.59
ND
12b
12c
12d
12e
12f
10.33 5.48
16.03 6.19
11.55 5.42
2.17 1.50
1.69 0.32
3.08 0.135
12g
ND
12h
12i
9.42 4.62
1.90 0.88
1.33 0.45
1.97 0.45
15.61 5.22
2.02 0.99
3.22 2.48
1.91 0.84
12j
Etoposide
ND not determined
aEach data is represented as mean SD values from three different experiments performed in triplicates.
bMCF-7: human breast cancer cell line
cA549: human lung cancer cell line
dDU-145: human prostate cancer cell line
eMDA MB-231: human breast cancer cell line
Table 2 Molecular docking studies of the title compounds, 12a-j
against protein kinase, CLK1
anticancer activities. In this series of derivatives, cytotoxi-
city effect decreases as the electron donating group is
replaced with electron-withdrawing groups Table 1.
S. No.
Compounds
Molecular docking studies
D Score
Emodel
Molecular docking studies
1
2
3
4
5
6
7
8
9
10
12a
12b
12c
12d
12e
12f
12g
12h
12i
−8.795
−9.264
−9.115
−8.548
−8.885
−9.017
−8.619
−9.705
−8.955
−8.794
−105.360
−115.063
−111.646
−109.363
−106.392
−107.381
−111.476
−122.674
−108.793
−105.595
The docking studies of all the imidazopyridine analogs
(12a–j) were carried against three potential targets, protein
kinases CLK1 (5X8I), EGFR (2J5F) and tubulin (1SA0) to
know the putative mechanism of actions of these new
analogs. The docking studies showed the docking scores
were found to be comparatively more against the CLK1.
The results of molecular docking studies are shown in
Table 2. The docking score of compounds 12c and 12d
were found to be −9.264 and −9.115 respectively showed
significant in vitro cytotoxicity. The comparative docking
results against the protein kinases, CLK1, EGFR and
tubulin are given in Table 1S (Supplementary information).
The imidazopyridine analogs were also reported as protein
kinases CLK1 inhibitor (Patent WO2017222285A1). The
imidazopyridine analogs were well accommodated in the
active site of protein kinase CLK1. The binding mode of all
the imidazopyridine analogs against the protein kinase
CLK1 is shown in Fig. 2. All the analogs bind in a similar
ways (Fig. 3a) except compound, 12g, which is shown in
Figs. 2 and 3b with specific saffron color. The carbonyl
functions of ligands, 12b, 12c, 12f, and 12i showed H-
bonding with residues Lys191. The carbonyl function of
ligand, 12h showed H-bonding with the residue Lys191
and nitro function showed slat bridges with the residues
Asp288, Asp325, and Lys290. The respective carbonyl and
methoxy functions of ligands, 12a, 12e, and 12j, showed
12j
H-bonding with the residue Lys191 and Lys290, respec-
tively. However the carbonyl function of ligand, 12g,
showed H-bonding with the residue Lys290. The methoxy
function of ligand, 12d showed H-bonding with the residue
Lys290. The imidazopyridine fragments of analogs, 12a–f
lies in the hydrophobic cavity of protein kinase
CLK1 surrounded by the residues, Phe326, Val324, Phe241,
Leu243, Leu244. The compounds 12b and 12c showed
significant in vitro cytotoxicity and their binding mode
against the active site of protein kinase CLK1 is shown in
Figs. 4 and 5. They showed similar type of binding in the
active site of CLK1. The binding modes of imidazopyridine
analogs, 12a, and 12d–f are shown in Fig. 1S, while the
binding modes of imidazopyridine analogs, 12g–j are shown
in Fig. 2S (Supplementary information).

Medicinal Chemistry Research
Experimental section
All chemicals and reagents were obtained from Aldrich
(Sigma-Aldrich, St. Louis, MO, USA), Lancaster (Alfa
Aesar, Johnson Matthey Company, Ward Hill, MA, USA)
and were used without further purification. Reactions were
monitored by TLC, performed on silica gel glass plates
containing 60 F-254, and visualization on TLC was
achieved by UV light or iodine indicator. 1H and 13C NMR
spectra were recorded on Gemini Varian-VXR-unity
(400 MHz, 300 MHz) instrument. Chemical shifts (δ) are
reported in ppm downfield from internal TMS standard. ESI
spectra were recorded on Micro mass, Quattro LC using
ESI + software with capillary voltage 3.98 kV and ESI
mode positive ion trap detector. Melting points were
determined with an electro thermal melting point apparatus,
and are uncorrected.
Fig. 2 The binding mode of all the imidazopyridine analogs (12a-j)
against the active site
Fig. 3 a Binding mode of imidazopyridine analogs 12a–j except 12g. b. Binding mode of imidazopyridine analogs 12a–j including 12g
Fig. 4 Binding mode of ligand 12b and 12c against the active site of protein kinase CLK1

Medicinal Chemistry Research
Fig. 5 Binding mode of ligand
12b and 12c against the active
site of protein kinase CLK1

Medicinal Chemistry Research
2-p-TolylH-imidazo[1,2-a]pyridine-3-carbaldehyde (5)
washed with water to afford pure compound 7 as half white
color solid, in 12.9 g with 76% yield. mp: 211–214 °C, H
1
To the mixture of 2-amino pyridine (3)(13 g, 0.138 mmol)
and (E)-3-p-tolylacrylaldehyde (4) (24. 2 g, 0.166 mmol)
taken in ethanol, 10 mol% CuBr (1.98 g, 0.0138 mmol) was
added and the reaction mixture was stirred at 60 °C for 8 h.
After completion of the reaction (monitored by TLC), the
reaction mixture was filtered using the Whatman paper. The
filtrate was dried on rotavapor and was then extracted with
water and ethyl acetate. Ethyl acetate layer was dried over
anhydrous sodiumsulfate and evaporated on vacuum rota-
vapor to give crude product. The crude product was purified
by column chromatography using n-hexane and ethyl
acetateto provide pure colorless product 5 as yellow color
NMR (300 MHz, DMSO-d6):δ 2.47 (s, 3H), 7.11 (d, 2H,
J = 8.3 Hz), 7.16 (t, 1H), 7.58 (t, 1H), 7.84 (d, 2H, J =
8.3 Hz), 7.86 (d, 1H, J = 8.1 Hz), 9.33 (s, 2H), 9.66 (d, 1H,
J = 8.1 Hz); 13C NMR (75 MHz, DMSO-d6): δ 21.3, 113.4,
114.6, 116.3, 121.2, 125.6, 130.8, 132.0, 138.9, 140.2,
148.6, 178.3; MS (ESI): m/z 268 [M + H]+; Anal. Calcd for
C15H13N3S: C, 67.39; H, 4.90; N, 15.72. Found: C, 67.22;
H, 4.78; N, 15.55.
3-(4-(3,4,5-Trimethoxyphenyl)thiazol-2-yl)-2-p-
tolylH-imidazo[1,2-a]pyridine (9):
1
solid, in 23.8 g with 61% yield. mp: 168–169 °C; H NMR
The compounds 2-bromo-1-(3,4,5-trimethoxyphenyl)etha-
none (8) (13 g, 0.045 mmol) and 2-p-tolylH-imidazo[1,2-a]
pyridine-3-carbothioamide (7) (12 g, 0.045 mmol) were
dissolved in absolute ethanol and reaction mixture was
stirred at room temperature for 1 h and then refluxed for
20 min. After cooling, the precipitate obtained was filtered
and neutralized with sodium acetate base, recovered from
the HBr salts. The crude product was recrystallized twice
from ethanol solvent to afford pure compound 9 as half
white color solid, 14.3 g with 70% yield. mp: 201–203 °C;
1H NMR (300 MHz, DMSO-d6):δ 2.47 (s, 3H), 3.87 (s, 6H),
3.90 (s, 3H), 7.13 (d, 2H, J = 8.4 Hz), 7.17 (t, 1H), 7.38 (s,
2H), 7.59 (t, 1H), 7.85 (d, 2H, J = 8.5 Hz), 7.88 (d, 1H, J =
8.2 Hz), 8.23 (s, 1H), 9.69 (d, 1H, J = 8.2 Hz); 13C NMR
(75 MHz, DMSO-d6): δ 21.6, 56.3, 61.1, 103.6, 108.9,
114.6, 120.1, 127.6, 128.0, 130.1, 131.1, 131.8, 132.5,
135.3, 139.1, 140.6, 145.9, 149.0, 154.1, 159.1; MS (ESI):
m/z 458 [M + H]+; Anal. Calcd for C26H23N3O3S: C, 68.25;
H, 5.07; N, 9.18. Found: C, 68.42; H, 4.91; N, 9.36.
(300 MHz, CDCl3): δ 2.47 (s, 3H), 7.08 (d, 2H, J = 8.1 Hz),
7.13 (t, 1H), 7.56 (t, 1H), 7.81 (d, 2H, J = 8.1 Hz), 7.85 (d,
1H, J = 8.0 Hz), 9.68 (d, 1H, J = 8.0 Hz), 10.12 (s, 1H); 13
C
NMR (75 MHz, CDCl3): δ 21.7, 115.3, 117.8, 120.3, 128.8,
129.5, 130.1, 130.8, 141.0, 147.9, 158.9, 179.6; MS (ESI):
m/z 237 [M + H]+; Anal. Calcd for C15H12N2O: C, 76.25;
H, 5.12; N, 11.86. Found: C, 76.03; H, 4.99; N, 11.71.
2-p-TolylH-imidazo[1,2-a]pyridine-3-carbonitrile (6)
A mixture of 2-p-tolylH-imidazo [1,2-a]pyridine-3-carbal-
dehyde (5) (23 g, 0.097 mmol) and NH2OH·HCl (7.45 g,
0.107 mmol) in DMSO (50 ml) was stirred at 90 °C for 2 h.
After completion of the reaction as confirmed by TLC (20%
EtOAc in hexane), the mixture was cooled and diluted with
H2O. The solid precipitated was collected by filtration,
washed with H2O and dried under suction to afford pure
nitrile compound 6 as half white color solid, in 16.2 g with
1
71% yield. mp: 160–162 °C. H NMR (300 MHz, DMSO-
d6): δ 2.47 (s, 3H), 7.10 (d, 2H, J = 8.2 Hz), 7.15 (t, 1H),
7.57 (t, 1H), 7.83 (d, 2H, J = 8.2 Hz), 7.85 (d, 1H, J =
8.0 Hz), 9.68 (d, 1H, J = 8.0 Hz); 13C NMR (75 MHz,
CDCl3): δ 21.6, 93.3, 113.2, 114.8, 118.6, 125.9, 127.5,
128.2, 129.10129.8, 140.6, 146.9, 153.6; MS (ESI): m/z
236 [M + H]+; Anal. Calcd for C15H11N3: C, 77.23; H,
4.75; N, 18.01. Found: C, 77.06; H, 4.63; N, 17.85.
4-(3-(4-(3,4,5-Trimethoxyphenyl)thiazol-2-yl)H-
imidazo[1,2-a]pyridin-2-yl)benzaldehyde (10)
A mixture of compound (9) (13 g, 0.0284 mmol), SeO2
(15.8 g, 0.142 mmol) and 70 ml ethanol was stirred at reflux
for 24 h. After completion of the reaction, the mixture was
cooled to room temperature and filtered through a celite pad.
The filtrate was evaporated by vacuum and diluted with
50 ml water and extracted with 150 ml of CH2Cl2. The
CH2Cl2 layer was washed with saturated NaHCO3 solution,
dried over anhydrous sodium sulfate. The crude product was
purified by column chromatography by using hexane:ethyl
acetate (4:6) as eluent to afford pure aldehyde 10, as half
white color solid, in 10.8 g with 81% yield. mp: 224
2-p-TolylH-imidazo[1,2-a]pyridine-3-carbothioamide (7)
To a slurry of 70% sodium hydrosulfide hydrate (7 g,
0.125 mmol) and magnesium chloride hexahydrate
(12.97 g, 0.0638 mmol) in 45 ml of DMF, 2-p-tolylH-imi-
dazo[1,2-a]pyridine-3-carbonitrile (6) (15 g, 0.0638 mmol)
was added in one portion, and the mixture was stirred at
room temperature for 90 min. The resulting green slurry was
poured into 100 ml of water, and the precipitates obtained
were collected by filtration. The crude product was sus-
pended in 1 N HCl and stirred for 20 min, then filtered and
1
−226 °C. H NMR (300 MHz, DMSO-d6):δ 3.87 (s, 6H),
3.90 (s, 3H), 7.18 (d, 2H, J = 8.5 Hz), 7.20 (t, 1H), 7.38 (s,
2H), 7.60 (t, 1H), 7.86 (d, 2H, J = 8.5 Hz), 7.89 (d, 1H, J =
8.2 Hz), 8.24 (s, 1H), 9.69 (d, 1H, J = 8.2 Hz), 10.35 (s, 1H);
13C NMR (75 MHz, DMSO-d6): δ 56.1, 60.9, 103.4, 108.6,

Medicinal Chemistry Research
109.8, 114.6, 120.1, 126.9, 128.0, 130.3, 131.1, 132.6, 138.1,
138.9, 139.3, 145.7, 148.3, 154.1, 158.9, 191.4; MS (ESI):
m/z 472 [M + H]+; Anal. Calcd for C26H21N3O4S: C, 66.23;
H, 4.49; N, 8.91. Found: C, 66.06; H, 4.36; N, 8.78.
(2E)-1-(3,5-Dimethoxyphenyl)-3-(4-(3-(4-(3,4,5-
trimethoxyphenyl)thiazol-2-yl)H-imidazo[1,2-a]
pyridin-2-yl)phenyl)prop-2-en-1-one (12c)
This compound 12c was prepared following the method
described for the preparation of the compound 12a,
employing 10 (500 mg, 0.001 mmol) with 1-(3,5-dime-
thoxyphenyl)ethanone(11c) (180 mg, 0.001 mmol) and
crude product was purified by column chromatography
(ethyl acetate/hexane: 8:2) to afford pure compound 12c as
half white color solid, 248.7 mg with 37% yield. mp:
267–269 °C,1H NMR (300 MHz, DMSO-d6):δ 3.69 (s, 6H),
3.87 (s, 6H), 3.90 (s, 3H), 6.88 (s, 1H), 7.11 (d, 1H, J =
15.6 Hz), 7.18 (d, 2H, J = 8.4 Hz), 7.19 (t, 1H), 7.34 (s,
2H), 7.38 (s, 2H), 7.60 (t, 1H), 7.88–7.97 (m, 4H), 8.25 (s,
1H), 9.69 (d, 1H, J = 8.2 Hz); 13C NMR (75 MHz, DMSO-
d6):δ 56.4, 57.5, 61.5, 104.5, 109.4, 110.5, 112.4, 115.6,
120.6, 124.7, 127.5, 127.9, 128.5, 128.8, 131.5, 131.7,
134.6, 134.8, 135.7, 139.5, 144.5, 145.8, 146.3, 149.6,
154.2, 159.3, 160.5, 171.4; MS (ESI): m/z634 [M + H]+;
Anal. Calcd for C36H31N3O6S: C, 68.23; H, 4.93; N, 6.63.
Found: C, 68.06; H, 4.81; N, 6.49.
(2E)-3-(4-(3-(4-(3,4,5-Trimethoxyphenyl)thiazol-2-yl)
H-imidazo[1,2-a]pyridin-2-yl)phenyl)-1-phenylprop-
2-en-1-one (12a)
A mixture of acetophenone (11a) (0.13 ml,0.001 mmol) and
4-(3-(4-(3,4,5-trimethoxyphenyl)thiazol-2-yl)H-imidazo
[1,2-a]pyridin-2-yl)benzaldehyde (10)(500 mg, 0.001 mmol)
was dissolved in 20 ml ethanol. To this mixture, potassium
hydroxide (40%, 1 ml) was added at 0–5 °C. The reaction
mixture was stirred at room temperature for 12 h. The
reaction mixture was poured over crushed ice and acidified
with dil HCl. The light yellow solid thus obtained was fil-
tered, washed with water and dried. The residue was purified
on column chromatography by using ethyl acetate/hexane
(7:3) to afford compound 12a as half white color solid,
212.6 mg with 35% yield. mp: 254–256 °C; 1H NMR
(300 MHz, DMSO-d6):δ 3.87 (s, 6H), 3.90 (s, 3H), 7.10 (d,
1H, J = 15.6 Hz), 7.18 (d, 2H, J = 8.5 Hz), 7.20 (t, 1H), 7.38
(s, 2H), 7.42 (t, 1H), 7.61 (t, 1H), 7.87–8.00 (m, 4H), 8.24
(s, 1H), 9.69 (d, 1H, J = 8.2 Hz); 13C NMR (75 MHz,
DMSO-d6):δ 57.4, 61.5, 104.7, 109.2, 115.6, 120.3, 122.4,
127.6, 127.9, 128.3, 129.7, 131.2, 131.6, 134.5, 135.6,
135.8, 139.6, 146.3, 149.6, 154.2, 159.7, 170.5; MS (ESI):
m/z 574 [M + H]+; Anal. Calcd for C34H27N3O4S: C, 71.19;
H, 4.74; N, 7.32. Found: C, 71.06; H, 4.63; N, 7.47.
(2E)-1-(4-Methoxyphenyl)-3-(4-(3-(4-(3,4,5-
trimethoxyphenyl)thiazol-2-yl)H-imidazo[1,2-a]
pyridin-2-yl)phenyl)prop-2-en-1-one (12d):
This compound 12d was prepared following the method
described for the preparation of the compound 12a,
employing 10(500 mg, 0.001 mmol) with 1-(4-methox-
yphenyl)ethanone(11d) (150 mg, 0.001 mmol) and crude
product was purified by column chromatography (ethyl
acetate/hexane: 8:2) to afford pure compound 12d as half
white color solid, 220.6 mg with 34% yield. mp:
260–262 °C,1H NMR (300 MHz, DMSO-d6):δ 3.87 (s, 6H),
3.90 (s, 3H), 3.93 (s, 3H), 6.88 (s, 1H), 7.08–7.13 (m, 3H),
7.18 (d, 2H, J = 8.5 Hz), 7.20 (t, 1H, c7), 7.38 (s, 2H), 7.43
(d, 2H, J = 8.7 Hz), 7.61 (t, 1H), 7.85–7.98 (m, 4H), 8.25
(s, 1H), 9.12 (d, 2H, J = 8.7 Hz), 9.69 (d, 1H, J = 8.2 Hz);
13C NMR (75 MHz, DMSO-d6):δ 56.5, 57.5, 61.6, 104.6,
109.5, 114.5, 115.7, 120.5, 122.4, 127.5, 127.8, 128.4,
128.7, 129.4, 131.5, 131.7, 134.6, 134.8, 135.7, 139.6,
145.4, 146.8, 149.4, 154.6, 159.7, 164.8, 171.7; MS (ESI):
m/z 604 [M + H]+; Anal. Calcd for C35H29N3O5S: C, 69.64;
H, 4.84; N, 6.96. Found: C, 69.81; H, 4.72; N, 7.12.
(2E)-1-(3,4,5-Trimethoxyphenyl)-3-(4-(3-(4-(3,4,5-
trimethoxyphenyl)thiazol-2-yl)H-imidazo[1,2-a]
pyridin-2-yl)phenyl)prop-2-en-1-one (12b)
This compound 12b was prepared following the method
described for the preparation of the compound 12a,
employing 10 (500 mg, 0.001 mmol) with 1-(3,4,5-tri-
methoxyphenyl)ethanone(11b) (210 mg, 0.001 mmol) and
crude product was purified by column chromatography
(ethyl acetate/hexane: 8:2) to afford pure compound 12b as
half white color solid, 233.4 mg with 33% yield. mp:
276–278 °C, 1H NMR (300 MHz, DMSO-d6):δ 3.79 (s,
6H), 3.87 (s, 6H), 3.90 (s, 3H), 3.94 (s, 3H), 7.09 (d, 1H, J
= 15.7 Hz), 7.17 (d, 2H, J = 8.3 Hz), 7.19 (t, 1H), 7.30 (s,
2H), 7.38 (s, 2H), 7.60 (t, 1H), 7.84–7.95 (m, 4H), 8.24 (s,
1H), 9.69 (d, 1H, J = 8.2 Hz); 13C NMR (75 MHz, DMSO-
d6):δ 57.4, 57.8, 61.5, 61.7, 104.5, 107.3, 109.3, 115.6,
120.4, 124.6, 127.5, 127.9, 128.3, 128.7, 131.4, 131.7,
134.6, 134.8, 135.7, 139.5, 140.6, 145.3, 145.9, 146.3,
149.6, 152.4, 154.3, 159.7, 171.3; MS (ESI): m/z 664 [M +
H]+; Anal. Calcd for C37H33N3O7S: C, 66.95; H, 5.01; N,
6.33. Found: C, 66.82; H, 4.88; N, 6.46.
(2E)-1-(4-Chlorophenyl)-3-(4-(3-(4-(3,4,5-
trimethoxyphenyl)thiazol-2-yl)H-imidazo[1,2-a]
pyridin-2-yl)phenyl)prop-2-en-1-one (12e)
This compound 12e was prepared following the method
described for the preparation of the compound 12a, employing
10 (500 mg, 0.001 mmol) with 1-(4-chlorophenyl)ethanone(11e)

Medicinal Chemistry Research
(0.13 ml, 0.001 mmol) and crude product was purified by col-
umn chromatography (ethyl acetate/hexane: 7:3) to afford pure
compound 12e as half white color solid, 342.7 mg with 53%
yield. mp: 287–289 °C,1H NMR (300 MHz, DMSO-d6):δ 3.87
(s, 6H), 3.90 (s, 3H), 7.12 (d, 1H, J = 15.8 Hz), 7.19 (d, 2H, J =
8.6 Hz), 7.21 (t, 1H), 7.38 (s, 2H), 7.51 (d, 2H, J = 8.8 Hz), 7.61
(t, 1H), 7.87-8.03 (m, 4H), 8.27 (s, 1H), 9.18 (d, 2H, J =
8.8 Hz), 9.69 (d, 1H, J = 8.2 Hz); 13C NMR (75 MHz, DMSO-
d6):δ 57.6, 61.7, 104.6, 109.7, 115.6, 120.4, 122.3, 127.6, 127.9,
128.4, 128.7, 130.4, 131.5, 131.8, 132.3, 134.6, 134.8, 135.7,
137.6, 139.5, 140.6, 145.7, 146.3, 149.7, 154.3, 159.6, 172.6;
MS (ESI): m/z 608 [M + H]+; Anal. Calcd for C34H26ClN3O4S:
C, 67.15; H, 4.31; N, 6.91. Found: C, 67.03; H, 4.44; N, 7.07.
8.2 Hz); 13C NMR (75 MHz, DMSO-d6):δ 57.6, 61.7,
104.5, 109.7, 115.6, 120.5, 122.7, 124.6, 127.5, 127.9,
128.5, 128.7, 131.6, 131.9, 132.4, 134.6, 134.7, 136.5,
139.6, 144.5, 145.5, 146.3, 149.6, 153.4, 154.7, 159.6,
171.7; MS (ESI): m/z 619 [M + H]+; Anal. Calcd for
C34H26N4O6S: C, 66.01; H, 4.24; N, 9.06. Found: C, 66.17;
H, 4.39; N, 9.22.
(2E)-3-(4-(3-(4-(3,4,5-Trimethoxyphenyl)thiazol-2-yl)
H-imidazo[1,2-a]pyridin-2-yl)phenyl)-1-(3,5-
dinitrophenyl)prop-2-en-1-one (12 h)
This compound 12h was prepared following the method
described for the preparation of the compound 12a,
employing 10 (500 mg, 0.001 mmol) with 1-(3,5-dini-
trophenyl)ethanone(11h) (210 mg, 0.001 mmol) and crude
product was purified by column chromatography (ethyl
acetate/hexane: 7:3) to afford pure compound 12h as half
white color solid, 410.3 mg with 58% yield. mp:
343–345 °C,1H NMR (300 MHz, DMSO-d6):δ 3.87 (s, 6H),
3.90 (s, 3H), 7.16 (d, 1H, J = 15.8 Hz), 7.19–7.28 (m, 3H),
7.38 (s, 2H), 7.62 (t, 1H), 7.88-7.97 (m, 4H), 8.27 (s, 1H),
9.44 (s, 2H), 9.69 (d, 1H, J = 8.2 Hz), 9.73 (s, 1H); 13C
NMR (75 MHz, DMSO-d6):δ 57.6, 61.7, 104.6, 109.8,
115.7, 120.5, 122.7, 125.6, 127.6, 127.9, 128.5, 128.7,
129.3, 131.6, 131.8, 134.6, 134.8, 136.8, 139.4, 145.6,
146.7, 149.6, 151.7, 154.8, 159.7, 171.8; MS (ESI): m/z 664
[M + H]+; Anal. Calcd for C34H25N5O8S: C, 61.53; H,
3.80; N, 10.55. Found: C, 61.39; H, 3.93; N, 10.72.
(2E)-1-(4-Bromophenyl)-3-(4-(3-(4-(3,4,5-
trimethoxyphenyl)thiazol-2-yl)H-imidazo[1,2-a]
pyridin-2-yl)phenyl)prop-2-en-1-one (12f)
This compound 12f was prepared following the method
described for the preparation of the compound 12a,
employing 10 (500 mg, 0.001 mmol) with 1-(4-bromophe-
nyl) ethanone (11f) (199 mg, 0.001 mmol) and crude pro-
duct was purified by column chromatography (ethyl acetate/
hexane: 7:3) to afford pure compound 12f as half white
color solid, 289.7 mg with 42% yield. mp: 293–295 °C,1H
NMR (300 MHz, DMSO-d6):δ 3.87 (s, 6H), 3.90 (s, 3H),
7.11 (d, 1H, J = 15.7 Hz), 7.18 (d, 2H, J = 8.6 Hz), 7.20 (t,
1H), 7.38 (s, 2H), 7.56 (d, 2H, J = 8.7 Hz), 7.61 (t, 1H),
7.86-7.94 (m, 4H), 8.26 (s, 1H), 9.10 (d, 2H, J = 8.7 Hz),
9.69 (d, 1H, J = 8.2 Hz);13C NMR (75 MHz, DMSO-d6):δ
57.5, 61.6, 104.6, 109.7, 115.6, 120.5, 122.4, 127.5, 127.9,
128.5, 128.7, 129.3, 131.5, 131.7, 132.5, 132.7, 134.5,
134.8, 136.5, 137.2, 139.5, 145.3, 146.5, 149.7, 154.4,
159.7, 171.7; MS (ESI): m/z 654 [M + H]+; Anal. Calcd for
C34H26BrN3O4S: C, 62.58; H, 4.02; N, 6.44. Found: C,
62.41; H, 4.16; N, 6.59.
4-((2E)-3-(4-(3-(4-(3,4,5-Trimethoxyphenyl)thiazol-2-
yl)H-imidazo[1,2-a]pyridin-2-yl)phenyl)acryloyl)
benzonitrile (12i):
This compound 12i was prepared following the method
described for the preparation of the compound 12a,
employing 10 (500 mg, 0.001 mmol) with 4-
acetylbenzonitrile (11i) (145 mg, 0.001 mmol) and crude
product was purified by column chromatography (ethyl
acetate/hexane: 7:3) to afford pure compound 12i as half
white color solid, 106.8 mg with 17% yield. mp:
295–297 °C,1H NMR (300 MHz, DMSO-d6):δ 3.87 (s, 6H),
3.90 (s, 3H), 7.14 (d, 1H, J = 15.6 Hz), 7.17–7.26 (m, 3H),
7.38 (s, 2H), 7.62 (t, 1H), 7.87–7.96 (m, 4H), 8.13 (d, 2H,
J = 8.8 Hz), 8.27 (s, 1H), 9.51 (d, 2H, J = 8.8 Hz), 9.69 (d,
1H, J = 8.2 Hz); 13C NMR (75 MHz, DMSO-d6):δ 57.6,
16.7, 104.6, 109.8, 115.6, 116.4, 118.7, 120.5, 122.7,
127.6, 127.9, 128.5, 128.8, 131.5, 131.7, 132.4, 133.7,
134.7, 134.9, 136.5, 139.6, 142.5, 145.7, 146.4, 149.7,
154.6, 159.7, 171.8; MS (ESI): m/z 599[M + H]+; Anal.
Calcd for C35H26N4O4S: C, 70.22; H, 4.38; N, 9.36. Found:
C, 70.09; H, 5.00; N, 9.51.
(2E)-3-(4-(3-(4-(3,4,5-Trimethoxyphenyl)thiazol-2-yl)
H-imidazo[1,2-a]pyridin-2-yl)phenyl)-1-(4-
nitrophenyl)prop-2-en-1-one (12 g):
This compound 12g was prepared following the method
described for the preparation of the compound 12a,
employing 10 (500 mg, 0.001 mmol) with 1-(4-nitrophenyl)
ethanone (11g) (165 mg, 0.001 mmol) and crude product
was purified by column chromatography (ethyl acetate/
hexane: 7:3) to afford pure compound 10 g as half white
color solid, 365.4 mg with 56% yield. mp: 300–302 °C,1H
NMR (300 MHz, DMSO-d6):δ 3.87 (s, 6H), 3.90 (s, 3H),
7.15 (d, 1H, J = 15.7 Hz), 7.17-7.25 (m, 3H), 7.38 (s, 2H),
7.62 (t, 1H), 7.86-7.94 (m, 4H), 8.15 (d, 2H, J = 8.9 Hz),
8.27 (s, 1H), 9.32 (d, 2H, J = 8.9 Hz), 9.69 (d, 1H, J =

Medicinal Chemistry Research
(2E)-3-(4-(3-(4-(3,4,5-Trimethoxyphenyl)thiazol-2-yl)
H-imidazo[1,2-a]pyridin-2-yl)phenyl)-1-p-tolylprop-
2-en-1-one (12j)
their anticancer effects on four human cancer cell lines
including MCF-7 (breast carcinoma), A549 (lung carci-
noma), DU-145 (prostate carcinoma), and MDA MB-231
(breast carcinoma) by employing MTT method and etopo-
side used as positive control. Among them, compound 12b
exhibited potent anticancer activities against four cancer cell
lines than positive control. This compound may act as drug
lead one in cancer chemotherapy.
This compound 12j was prepared following the method
described for the preparation of the compound 12a,
employing 10 (500 mg, 0.001 mmol) with 1-p-tolylethanone
(11j) (0.13 ml, 0.001 mmol) and crude product was purified
by column chromatography (ethyl acetate/hexane: 7:3) to
afford pure compound 12j as half white color solid,
241.7 mg with 39% yield. mp: 270–272 °C, 1H NMR
(300 MHz, DMSO-d6):δ 2.48 (s, 3H), 3.87 (s, 6H), 3.90 (s,
3H), 7.12 (d, 1H, J = 15.5 Hz), 7.18 (d, 2H, J = 8.6 Hz),
7.21 (t, 1H), 7.32-7.41 (m, 4H), 7.62 (t, 1H), 7.85-7.94 (m,
4H), 8.26 (s, 1H), 9.69 (d, 1H, J = 8.2 Hz); 13C NMR
(75 MHz, DMSO-d6):δ 24.8, 57.6, 61.7, 104.7, 109.7,
115.6, 120.7, 122.6, 127.5, 127.8, 128.5, 128.9, 129.5,
130.2, 131.6, 131.7, 1134.6, 134.8, 136.5, 136.8, 139.6,
144.5, 145.9, 146.4, 149.7, 154.6, 159.7, 170.6; MS (ESI):
m/z 588 [M + H]+; Anal. Calcd for C35H29N3O4S: C, 71.53;
H, 4.97; N, 7.15. Found: C, 71.66; H, 4.85; N, 7.03.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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