Design, Synthesis, and Biological Evaluation of 2-(4-Aminophenyl)benzothiazole Analogues as Antiproliferative Agents

Article abstract of DOI:10.1002/jhet.3427

A series of 28 novel 2-(4-aminophenyl)benzothiazole analogues have been synthesized and characterized using various analytical techniques like ¹H NMR, ¹³C NMR, electrospray ionization mass spectrometry, and IR and bioevaluated for their antiproliferative activity over a group of three human cancer cell lines, namely, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MDA-MB-231), using sulforhodamine B assay method. Few synthesized molecules (5a, 5c, 5d, 5f, 7b, and 7j) displayed effective growth inhibition (GI₅₀) activity against the tested human cancer cell lines at lower micromolar concentration (GI₅₀) values in the range 0.2–1.7?μM. Noticeably, compound 7b exhibited reasonable activity in all three cancer cell lines in the GI₅₀ range 0.55–1.2?μM. Further, when 7b was screened for tubulin polymerization inhibition, it exhibited more than 55% inhibition at concentration of 5.0?μM. The molecular docking simulations supported the molecular interactions of the derivatives with the targeted receptor. These derivatives may serve as lead structures for development of potential anticancer drug candidates, and 7b might act as a potential microtubule polymerization inhibitor.

Full text of DOI:10.1002/jhet.3427

Month 2018
Suresh Narva,a
Design, Synthesis, and Biological Evaluation of 2-(4-Aminophenyl)
benzothiazole Analogues as Antiproliferative Agents
Surendar Chitti,a Suresh Amaroju,a Sridhar Goud,b Mallika Alvala,b Debanjan Bhattacharjee,c
c
a
*
Nishant Jain, and Chandra Sekhar Kondapalli Venkata Gowri
aDepartment of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500078, Telangana, India
bNational Institute of Pharmaceutical Education and Research-Hyderabad, Hyderabad 500037, Telangana, India
cCentre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, Telangana,
India
*E-mail: kvgc@hyderabad.bits-pilani.ac.in; kvgcs.bits@gmail.com
Received August 10, 2018
DOI 10.1002/jhet.3427
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of 28 novel 2-(4-aminophenyl)benzothiazole analogues have been synthesized and characterized
using various analytical techniques like 1H NMR, 13C NMR, electrospray ionization mass spectrometry, and
IR and bioevaluated for their antiproliferative activity over a group of three human cancer cell lines, namely,
lung cancer (A549), cervical cancer (HeLa), and breast cancer (MDA-MB-231), using sulforhodamine B as-
say method. Few synthesized molecules (5a, 5c, 5d, 5f, 7b, and 7j) displayed effective growth inhibition
(GI50) activity against the tested human cancer cell lines at lower micromolar concentration (GI50) values
in the range 0.2–1.7 μM. Noticeably, compound 7b exhibited reasonable activity in all three cancer cell lines
in the GI50 range 0.55–1.2 μM. Further, when 7b was screened for tubulin polymerization inhibition, it ex-
hibited more than 55% inhibition at concentration of 5.0 μM. The molecular docking simulations supported
the molecular interactions of the derivatives with the targeted receptor. These derivatives may serve as lead
structures for development of potential anticancer drug candidates, and 7b might act as a potential microtu-
bule polymerization inhibitor.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
Among all the benzothiazole derivatives, N-[4-(1,3-
benzothiazol-2-yl)phenyl] acetamides are potent and active
in certain human breast cancer cell lines [8]. Among the
benzothiazole derivatives, structurally related benzothiazole
such as 2-(4-amino-3-methylphenyl) benzothiazole
Benzothiazole is a fused bicyclic system and is a well-
known nucleus in anticancer research. Many modifications
happened on benzothiazole moiety, and several research
groups evaluated them for various biological activities.
Benzothiazole exhibits interesting pharmacological
activities such as anti-inflammatory [1], antimicrobial [2],
antitumor [3], and anticonvulsant [4]. Subbarao et al.
reported that triazole/tetrazole mimics of combretastatin-
A4 (CA-4) and benzothiazole hybrids (A) as potent
tubulin polymerization inhibitors [5]. In their subsequent
work, they synthesized the 2-arylamino benzothiazole-
arylpropenone motifs (B, D) and evaluated for microtubule
inhibition [6]. Kamal et al. illustrated that 3-substituted
2-phenyl imidazo[2,1-b]benzothiazole analogues (C) inhibit
the polymerization of tubulin [7]. Figure 1 depicts the
benzothiazole-based tubulin polymerization inhibitors.
(DF203,
5-fluorobenzothiazole
NSC674495),
2-(4-amino-3-methylphenyl)-
(5F203, NSC703786),
2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX610,
formerly GW610, NSC721648), and Phase I clinical trial
moiety Phortress (NSC 710305) exhibited notable in vitro
antitumor activity against malignant cell lines [9,10].
Benzothiazole-basedanticanceragentsareshowninFigure2.
Piperazine is a prominent six-membered nitrogen
containing heterocycle of noteworthy significance in
pharmaceutical chemistry [11]. The existence of this
piperazine heterocycle can be witnessed in several
identified drugs, belonging to different pharmacological
classes [12]. Several researchers have developed
© 2018 Wiley Periodicals, Inc.

S. Narva, S. Chitti, S. Amaroju, S. Goud, M. Alvala,
Vol 000
D. Bhattacharjee, N. Jain, and C. S. Kondapalli Venkata Gowri
Figure 1. Benzothiazole containing tubulin polymerization inhibitors.
Figure 2. Benzothiazole-based anticancer agents.
piperazine-based anticancer agents [13–16]. Piperazine
containing few anticancer analogues (E, F, G, and H) are
depicted in Figure 3.
From the past decades, 1,2,3-triazole derivatives have
significant position in medicinal chemistry due to their
easy synthesis by click chemistry [17] and attractive
biological activities, such as antibiotic, antifungal,
antehelmintic [18–21], and anticancer activity in different
human cancer cell lines [22–25].
Taxane-site, vinca, and colchicine domain are the three
main well-known microtubule binding sites. Herein, we
designed and synthesized a series of novel benzothiazole
derivatives, which were structurally similar to familiar
tubulin inhibitor nocodazole. Bioisosteric replacement of
five-membered imidazole ring of nocodazole with
thiazole leads to our proposed derivatives, as outlined in
Figure 4.
Molecular hybridization is the comprehensible approach
to design new drug-like candidates by the combination of
two or more active derivatives or pharmacophoric entities
identified and derived from known bioactive drug
molecules [26,27]. In pursuance of our continuing efforts
on the design of unique anticancer agents and realizing the
significance of these heterocycles and their derivatives in
chemotherapy, we designed and synthesized novel 2-(4-
Figure 3. Piperazine bearing microtubule inhibitors (E, F) and anticancer
agents (G, H). [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of 2-(4-Aminophenyl)
benzothiazole Analogues as Antiproliferative Agents
Figure 4. Design strategy and scaffold structure of new tubulin inhibitors. [Color figure can be viewed at wileyonlinelibrary.com]
aminophenyl)benzothiazole derivatives and performed
antiproliferative evaluation on A549 (lung cancer), HeLa
(cervical cancer), and MDA-MB-231 (breast cancer) cancer
cell lines. The emerged active compounds were subjected
to cytotoxicity studies against HEK293 (human embryonic
kidney) cell line at 50 μM.
compound 4 showed absorption band at 1650 cmÀ1 due
to carbonyl group of carboxamide, and mass spectrum
revealed (m + 1) peak at m/z 303.11. N-(4-(Benzo[d]
thiazol-2-yl)phenyl)-2-chloroacetamide (4) on treatment
with different substituted piperazines in N,N-
dimethylmethanamide at 100°C for 2 h yielded the
products 5a–q (Scheme 1).
2-(4-Aminophenyl)benzothiazole (3) on treatment with
propargyl bromide yielded 4-(benzo[d]thiazol-2-yl)-N-
(prop-2-ynyl) aniline (6) in 80% yield after purification.
The IR spectrum of 6 showed absorption bands at 2132
and 3325 cmÀ1 due to C≡C and ≡C─H stretching
frequency, respectively, and mass spectrum revealed
(M + 1) peak at m/z 265.15. 4-(Benzo[d]thiazol-2-yl)-N-
(prop-2-ynyl) aniline (6) on treatment with various
aromatic azides in the presence of CuSO4.5H2O, sodium
ascorbate in t-BuOH:H2O (1:1) gave the final products
RESULTS AND DISCUSSION
Chemistry. The synthetic strategies for the synthesis of
the intermediates and title compounds are depicted in
Schemes 1 and 2. We synthesized 2-(4-aminophenyl)
benzothiazole (3) by the reaction of 2-aminothiophenol
(1) with p-amino benzoic acid (2) in polyphosphoric acid
at 220°C as per reported procedure [28]. The IR spectrum
of compound 3 showed absorption bands at 3290 and
3385 cmÀ1 due to symmetric and asymmetric stretching
of NH2 and 1670 cmÀ1peak due to C═N stretching
vibrations, and mass spectrum revealed (m + 1) peak at
m/z 227.09. 2-(4-Aminophenyl)benzothiazole (3) was
treated with chloroacetyl chloride in the presence of
triethylamine at 0°C to yield N-(4-(benzo[d]thiazol-2-yl)
phenyl)-2-chloroacetamide (4). The IR spectrum of
1
7a–k (Scheme 2) in 55–90% yields. In general, H NMR
spectra of all the title compounds displayed two
multiplets of piperazine protons in the range 2.5–
3.7 ppm. Two sharp doublets resonated in the range
7.50–7.90 ppm due to C-5 and C-6 protons of the
benzothiazole moiety. Two sharp doublets resonated in
the range 8.10–8.20 ppm due to C-4 and C-7 protons of
Scheme 1. Reagents and conditions: (a) polyphosphoric acid, 220°C, 30 min; (b) chloroacetyl chloride, Et3N, CH2Cl2, 0°C to room temperature, 30 min;
(c) substituted piperazines, dimethylformamide, 100°C, 2 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Narva, S. Chitti, S. Amaroju, S. Goud, M. Alvala,
Vol 000
D. Bhattacharjee, N. Jain, and C. S. Kondapalli Venkata Gowri
Scheme 2. Reagents and conditions: (d) propargyl bromide, K2CO3, dimethylformamide, 70°C, 1 h; (e) various aromatic azides, CuSO4.5H2O, sodium
ascorbate, t-BuOH: H2O (1:1), 2 h.
the benzothiazole moiety. Two sharp doublets resonated in
the range 7.81–7.97 ppm due to phenyl protons. The acetyl
methylene protons showed singlet in the range 3.29–3.39,
and further, the structure of the title compounds were
substantiated from 13C NMR and electrospray ionization
mass spectrometry. All the compounds were evaluated
for their antiproliferative activity, and the results are
summarized in Tables 1 and 2.
reproducibility [31,32]. The growth inhibition results
(expressed as GI50) of synthesized compounds 5a–q and
7a–k are shown in Tables 1 and 2.
From the antiproliferative activity results, all the
synthesized analogues showed growth inhibition (GI50)
values ranging from 0.18 to 14.3 μM. The structure
activity relationship of 2-(4-aminophenyl)benzothiazole
derivatives reveals that compounds with electron
donating groups at para position like methyl (5f) and
hydroxy (5g) exhibited good activity than compounds
having electron withdrawing groups like nitro (5h) and
chloro (5c) against A549 cell line. Pyridine containing
derivative (5e) exhibited better activity than phenyl (5a),
benzyl (5n), and pyrimidine (5o) derivatives against
A549 cell line. The fluoro substitution (5d) at ortho
position replaced with chloro (5i) enhanced the
Antiproliferative activity.
In vitro antiproliferative
activity of the synthesized compounds 5a–q and 7a–k
was carried out against A549 (lung cancer), HeLa
(cervical cancer), and MDA-MB-231 (breast cancer)
human cancer cell lines, employing sulforhodamine B
assay method [29,30]. The sulforhodamine B assay
emerged to be more approachable than MTT assay, with
enhanced linearity with cell number and advanced
Table 1
a
Antiproliferative activity (GI50 in μM) of compounds (5a–q).
Entry
R
A549
HeLa
MDA-MB-231
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
C6H5
(C6H5)2CH2
4-ClC6H4
2-FC6H4À
2-Pyridyl
4-MeC6H4
4-OHC6H4
4-NO2C6H4
2-ClC6H4
3-OHC6H4
(4-FC6H4)2CH2
3-OCH3C6H4
C6H5-CH-CH3
C6H5CH2
2-Pyrimidyl
Boc
0.89 0.03
2.07 0.09
1.02 0.09
0.96 0.02
0.52 0.01
0.25 0.02
0.18 0.03
1.36 0.07
0.78 0.03
0.14 0.02
4.58 0.23
0.52 0.01
0.82 0.01
12.3 0.45
6.54 0.6
6.75 0.09
6.28 0.1
<0.01
0.56 0.02
0.92 0.01
0.98 0.04
1.0 0.09
0.84 0.02
1.65 0.07
1.0 0.01
0.45 0.02
1.69 0.08
0.95 0.02
6.9 0.24
1.38 0.04
1.23 0.02
8.3 0.16
6.73 0.20
14.1 0.7
1.4 0.17
4.9 0.02
4.1 0.08
14.3 1.9
1.23 0.17
<0.01
1.0 0.08
0.81 0.01
0.86 0.02
1.03 0.07
0.84 0.02
0.83 0.01
0.8 0.01
1.07 0.8
0.95 0.03
0.41 0.01
0.94 0.02
0.81 0.01
0.86 0.04
0.09 0.001
0.023 0.002
5q
Boc
–
–
Doxorubicin
Paclitaxel
<0.01
<0.01
All experiments were independently performed thrice.
Most active compounds are highlighted in bold.
aGI50, 50% growth inhibition.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of 2-(4-Aminophenyl)
benzothiazole Analogues as Antiproliferative Agents
Table 2
a
Antiproliferative activity (GI50 in μM) of compounds (7a–k).
Entry
R
A549
HeLa
MDA-MB-231
7a
7b
7c
7d
7e
7f
7g
7h
3-CF3
3-OCH3
2-Br
4-Cl
4-CH2CH3
2-I
4-NO2
2,4-diCl
3-Cl,4-F
3-Cl
4-F
–
0.49 0.02
0.55 0.02
0.81 0.01
0.71 0.01
0.83 0.02
0.49 0.04
1.24 0.08
2.53 0.09
2.42 0.12
0.45 0.03
4.2 0.15
<0.01
0.96 0.02
0.98 0.05
1.03 0.08
1.09 0.06
1.4 0.12
7.2 0.06
1.7 0.06
4.6 0.23
10.4 0.87
1.4 0.07
2.8 0.2
5.6 0.32
3.5 0.16
2.8 0.18
0.56 0.03
0.14 0.02
<0.01
1.8 0.04
0.99 0.05
0.91 0.01
0.8 0.03
1.0 0.09
1.2 0.05
7i
7j
7k
Doxorubicin
Paclitaxel
0.09 0.001
0.023 0.002
–
<0.01
<0.01
All experiments were independently performed thrice.
Most active compounds are highlighted in bold.
aGI50, 50% Growth inhibition.
antiproliferative activity. The hydroxy group at third
position (5j) or fourth position (5g) on phenyl ring has no
impact on the activity against A549 cell line.
Replacement of methoxy group with hydroxy group at
meta position enhanced the activity in A549 cell line.
The chloro substitution at meta position on phenyl of
triazole derivative (7j) showed better activity (0.45 μM)
than other chloro derivatives like p-chloro (7d), 3-chloro-
4-fluoro (7i), and 2,4-dichloro (7h) derivatives against
A549 (lung cancer) cell line.
the possibility of its cytotoxicity response similar to
tubulin inhibitor CA-4. A hallmark of tubulin inhibitors
is stalling of cell cycle in G2/M phase 1. Thus, we
treated HeLa cells with 7b or CA-4 for a duration of
24 h. Flow cytometry analysis showed that 55% of HeLa
cells accumulated in G2/M phase in 7b treated cells; in
comparison, CA-4 showed 77% HeLa cells. Dimethyl
sulfoxide-treated cells exhibited a normal cell cycle
distribution. Overall, these results support the suggestion
that 7b arrests cells in G2/M similar to CA-4 (A). Since
CA-4 is a potent tubulin polymerization inhibitor, we
elucidated the effect of 7b and CA-4 in perturbing in vivo
tubulin polymerization.Hence, HeLa cells were treated
with 7b and CA-4 for 24 h; subsequently, cells were
permeabilized with triton-x-100; soluble and insoluble
fractions were collected. Immunoblot analysis for tubulin
revealed a drastic shift in tubulin to soluble fraction in
CA-4 and 7b-treated cells, whereas dimethyl sulfoxide-
treated cells showed an equal distribution of tubulin
protein in both the fractions (B). To further confirm our
flow cytometry and tubulin polymerization results, we
performed immunoblot for G2/M marker, Cyclin B1. 7b
robustly induced Cyclin B1 protein in HeLa cells similar
to CA-4 (C) (Fig. 5). Taken together, 7b behaves similar
to CA-4 in its mode of action. 7b-treated cells undergo
G2/M arrest corroborated by flow cytometry analysis and
Cyclin B1 protein levels and exert its cytotoxic activity
through inhibition of tubulin polymerization.
2-(4-Aminophenyl)benzothiazole analogues exhibited
moderate activity against HeLa cancer cell line. 2-(4-
Aminophenyl)benzothiazole piperazine analogues (5a–q)
exhibited better activity than 2-(4-aminophenyl)
benzothiazole triazole derivatives (7a–k) against HeLa
cancer cell line. Among all the piperazine derivative, 5n
was observed to possess strongest antitumor activity
againstHeLacelllinewiththeGI50 of0.41μM, respectively.
2-(4-Aminophenyl)benzothiazole triazole derivatives
(7a–k) exhibited better activity than 2-(4-aminophenyl)
benzothiazole piperazine analogues (5a–q) against MDA-
MB-231 cancer cell line. Among all the derivatives,
p-fluoro phenyl containing triazole derivative (7k)
exhibited better activity (0.14 μM). p-Fluoro containing
triazole derivative (7k) showed better growth inhibition
than compounds with electron withdrawing groups like p-
nitro (7g), p-chloro (7d), and electron donating groups
like p-ethyl (7e) against MDA-MB-231 cancer cell line.
Compared with 2,4-dichloro analogue (7h) and 3-chloro-
4-fluoro analogue (7i), 4-fluoro analogue (7k) exhibited
better activity against breast cancer (MDA-MB-231)
cancer cell line. m-chloro (7j) analogue had better activity
than m-trifluoro methyl (7a) and m-methoxy (7b)
analogues against breast cancer (MDA-MB-231) cell line.
Tubulin polymerization. Among the congeners, 7b with
3-methoxy substitution similar to CA-4 was explored for
Cytotoxicity studies. Most active compounds 5a, 5c,
5d, 5f, 7b, and 7j were subjected to cytotoxicity studies
against HEK293 cell line. Cytotoxicity assay of 5a, 5c,
5d, 5f, 7b, and 7j was determined. Cell viability was
measured by in vitro MTT assay. Cells were exposed to
compounds for 24 h at 50-μM concentration, and data
clearly indicate that the active compounds were not toxic
at even 50 μM.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Narva, S. Chitti, S. Amaroju, S. Goud, M. Alvala,
Vol 000
D. Bhattacharjee, N. Jain, and C. S. Kondapalli Venkata Gowri
Figure 5. 7b induces G2/M phase arrest and regulates the G2/M related protein in HeLa cells. (a) Cells treated with 5-μM compound 7b for 24 h were
collected and processed for analysis. (b) Immunoblot analysis. (c) Western blot analysis.
Molecular modelling studies. Molecular docking studies
revealed that compound 7b bind to the colchicine binding site
of the tubulin with a binding affinity of À7.137 compared to
colchicine (À5.76) and doxorubicin (À4.074). The ─NH
group of the 7b showed a hydrogen bond interaction with
Asn:A:101 at distance of 2.06 Å and strong hydrophobic
interactions with Tyr 224, Ala 317, Ile 378, Leu 255, Leu
248, Val318, and Ala 316 (Fig. 6 and Table 3).
Single crystal X-ray crystallographic structure of
compound 5g.
Single crystal X-ray of compound 5g
Figure 6. Molecular docking of 7b to colchicine binding site of tubulin. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of 2-(4-Aminophenyl)
benzothiazole Analogues as Antiproliferative Agents
Table 3
Amino acid interaction pattern of 7b, colchicine, and doxorubicin.
Entry
Ligand interaction
Docking score
7b
À7.137
Colchicine
À5.76
Doxorubicin
À4.074
Most active compounds are highlighted in bold.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Narva, S. Chitti, S. Amaroju, S. Goud, M. Alvala,
Vol 000
D. Bhattacharjee, N. Jain, and C. S. Kondapalli Venkata Gowri
Figure 7. ORTEP diagram showing the X-ray crystal structure of compound 5g. (N1 is highly disordered). [Color figure can be viewed at
wileyonlinelibrary.com]
(Fig. 7) is recorded and crystallographic data deposited to
the Cambridge Crystallographic Data Center, and
corresponding deposition number is 1575678. (Complete
details are available in the Supporting Information.).
by distillation prior to use. Solvents for chromatography
(pet ether and ethyl acetate) were distilled prior to use.
Evaporations were carried out under reduced pressure on
Heidolf rotary evaporator. Melting points were obtained
1
using Stuart SMP30 system and are uncorrected. H and
13C NMR spectra were recorded on Avance-III 400 MHz
(400 MHz for 1H, 100 MHz for 13C), in CDCl3 or
DMSO-d6. Chemical shifts have been expressed in parts
per million (δ) relative to tetramethylsilane (δ = 0.0) as
an internal standard and coupling constants (J) in hertz.
Low-resolution mass spectra liquid chromatography–
mass spectrometry were recorded on LC/MS-2020
Shimadzu (Shimadzu Corp., Kyoto, Japan). IR spectra
were recorded with an FTIR spectrophotometer (Jasco
FTIR-4200, Tokyo, Japan).
CONCLUSION
In summary, various 2-(4-aminophenyl)benzothiazole
analogues have been designed and efficaciously
synthesized. The structures of all the target compounds
were elucidated using various spectroscopic techniques.
Single crystal developed for 5g proved the authenticity of
the final compounds. Further, these conjugates were
evaluated for their growth inhibitory activity against
A549, HeLa, and MDA-MB-231 human cancer cell lines.
Most of the tested 2-(4-aminophenyl)benzothiazole
analogues demonstrated appealing growth inhibitory
activity against tested cancer cell lines. Among all the
derivatives, 5a, 5c, 5d, 5f, 7b, and 7j displayed maximum
growth inhibitory activity at lower concentrations. Our
conclusion from this work with synthesis, antiproliferative
activity, and molecular modelling experiments revealed
that these 2-(4-aminophenyl)benzothiazole motifs could
be prospective candidates for further development of
novel anticancer agents.
Synthesis of 2-(4-aminophenyl)benzothiazole (3).
2-(4-Aminophenyl)benzothiazole (3) was synthesized by
an already reported procedure. 4-Aminobenzoic acid (1 g,
0.0072 mol) (2) was dissolved in polyphosphoric acid at
220°C. 2-Aminothiophenol (0.9 g, 0.0072 mol) was
added, and the resulting solution stirred at 220°C for
30 min. After cooling, the reaction mixture was poured
into aqueous ammonia (10 mL). The precipitate was
collected and washed with water (50 mL). The product
was purified by column chromatography (pet ether/ethyl
acetate 30%) to give 2-(4-aminophenyl)benzothiazole (3)
1
as a white solid. H NMR (400 MHz, DMSO-d6) δ 8.04
(d, J = 7.25 Hz, 1H), 7.93 (d, J = 7.25 Hz, 1H), 7.70 (dd,
J = 11.0, 2.0 Hz, 1H), 7.68 (dd, J = 10.9, 2.1 Hz, 1H),
7.63 (dd, J = 8.25, 2 Hz, 1H), 7.48 (t, J = 7.25 Hz, 1H),
7.46 (t, J = 7.25 Hz, 1H), 6.87 (t, J = 8.75 Hz, 1H), 5.98
(s, 2H). 13C NMR (100.61 MHz, DMSO-d6) 167.21,
154.65, 149.34, 135.56, 133.02, 127.54, 125.65, 123.23,
122.65, 120.85, 118.35. LCMS (m/z): Calcd. for
C13H10N2S 226.06. Found 227.12 [M + H]+, TLC Rf = 0.2.
EXPERIMENTAL
Chemistry. General.
All reagents were purchased
from commercial sources and used with further
purification wherever necessary. All reactions were
monitored by analytical thin-layer chromatography (TLC)
performed on E-Merck 0.25 mm pre-coated silica gel
aluminum plates (60 F254) using a mixture of pet ether
and ethyl acetate. Visualization of the spots on TLC
plates was achieved by exposure to ultraviolet light.
Column chromatography was performed using silica gel
(Acme, 100-200mesh). Solvents were dried and purified
Synthesis
of
N-(4-(benzo[d]thiazol-2-yl)phenyl)-2-
chloroacetamide (4).
2-(4-Aminophenyl)benzothiazole
(3) (0.5 g, 0.0022 mmol) and triethylamine (0.31 mL,
0.0022 mmol) were stirred in 5 mL of dry dichloromethane
(CH2Cl2) at 0°C for 15 min under nitrogen atmosphere.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of 2-(4-Aminophenyl)
benzothiazole Analogues as Antiproliferative Agents
Chloroacetyl chloride (0.17 mL, 0.0022 mmol) was added
dropwise slowly through a syringe. After stirring at 0°C for
15 min, resultant mixture was warmed to room temperature
(RT) and stirred for additional 1 h. After the reaction was
complete, as indicated by TLC (pet ether/ethylacetate
30%), 50 ml of water was added, and the compound was
extracted from aqueous layer with 3 × 10 mL of CH2Cl2.
The organic layers were collected, dried over anhydrous
MgSO4, and concentrated under reduced pressure to yield
the desired product as a pale green solid. 1H NMR
(400 MHz, CDCl3) δ 8.14 (d, J = 7.25 Hz, 1H), 7.99 (d,
J = 7.25 Hz, 1H), 7.70 (dd, J = 11.0, 2.0 Hz, 2H), 7.68 (dd,
J = 10.9, 2.1 Hz, 2H), 7.63 (dd, J = 8.25, 2.0 Hz, 1H), 7.48
(t, J = 7.25 Hz, 1H), 7.34 (s, 1H), 4.23 (s, 2H). 13C NMR
(100.61 MHz, CDCl3) δ 167.87, 154.12, 149.34, 135.21,
133.01, 127.32, 125.81,124.11, 123.51, 122.02, 120.21,
118.32, 83.87. LCMS (m/z): Calcd. for C15H11ClN2OS
302.02. Found 303.01 [M + H]+, TLC Rf = 0.8.
2H), 7.75 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 2H),
7.55–7.47 (m, 2H), 7.43–7.37 (m, 2H), 7.23–7.28 (m,
2H), 7.15–7.14 (m, 1H), 7.12 (d, J = 0.8 Hz, 1H), 6.91
(d, J = 2.1 Hz, 2H), 5.01 (s, 1H), 3.27 (d, J = 2.9 Hz,
4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H). 13C NMR
(100.61 MHz, CDCl3) δ 169.80, 168.26, 154.83, 142.73,
138.52, 133.81, 129.31, 129.01, 128.21, 126.22, 125.21,
124.80, 121.81, 121.64, 121.01, 119.86, 83.87, 61.65,
53.34, 49.68. LCMS (m/z): Calcd. for C32H30N4OS
518.22. Found 519.23 [M + H]+, TLC Rf = 0.4.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(4-chlorophenyl)
piperazin-1-yl) acetamide (5c).
Brown solid; yield 92%,
0.42 g, mp 203–204°C; IR (KBr, cmÀ1) 3465, 3046,
1
1645, 1292, 1135, 755. H NMR (400 MHz, CDCl3) δ
9.36 (s, 1H), 8.09 (d, J = 1.8 Hz, 1H), 8.12–8.06 (m, 2H),
7.75 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.54–
7.48 (m, 2H), 7.43–7.37 (m, 1H), 7.15–7.14 (m, 1H),
7.14 (d, J = 0.8 Hz, 1H), 6.73 (d, J = 2.3 Hz, 2H), 3.27
(d, J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H). 13C
NMR (100.61 MHz, CDCl3) δ 169.85, 168.36, 154.95,
149.21, 138.22, 134.42, 129.60, 120.99, 126.37, 125.17,
124.90, 121.88, 121.44, 121.11, 119.77, 114.46, 61.16,
51.37, 49.56. LCMS (m/z): Calcd. for C25H23ClN4OS
462.13. Found 463.14 [M + H]+, TLC Rf = 0.45.
General procedure for synthesis of N-(4-(benzo[d]thiazol-2-
yl)phenyl)-2-(2,4-substituted
piperazin-1-yl)
acetamide
(5a–q). a solution of substituted piperazines
To
(0.9933 mmol) in dry dimethylformamide (3 mL) was
added triethylamine (0.13 mL, 1.9866 mmol) and
potassium iodide (16.48 mg, 0.0993 mmol) at RT under
N2 atmosphere. Then, compound 4 (0.3 g, 0.9933 mmol)
was added to the above solution, and resultant mixture
was heated for 3 h at 125°C. After the reaction was
complete, as indicated by TLC, dimethylformamide was
evaporated under reduced pressure. The obtained residue
was diluted with 30 mL of water. The compound was
extracted from aqueous layer with 3 × 5 mL of CH2Cl2.
The organic layers were collected, dried over anhydrous
MgSO4, and evaporated. The resultant residue was
purified by column chromatography (pet ether/ethyl
acetate 50%) to yield compounds 5a–q.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(2-fluorophenyl)
piperazin-1-yl) acetamide (5d). Brown solid; yield 87%,
0.38 g, mp 203–204°C; IR (KBr, cmÀ1) 3470, 3045,
1
1640, 1290, 1135, 1065. H NMR (400 MHz, CDCl3) δ
9.45 (s, 1H), 8.13 (d, J = 1.9 Hz, 1H), 8.12–8.07 (m,
2H), 7.91–7.88 (m, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.75
(d, J = 2.0 Hz, 1H), 7.54–7.48 (m, 1H), 7.43–7.37 (m,
1H), 7.15–7.13 (m, 1H), 6.91–7.06 (m, 3H), 3.27 (d,
J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H). 13C
NMR (100.61 MHz, CDCl3) δ 169.65, 168.46, 155.75,
154.67, 138.51, 137.22, 133.82, 129.09, 126.54, 125.57,
125.27, 124.48, 122.87, 121.88, 121.64, 119.81, 116.46,
115.56, 63.16, 54.37, 51.56. LCMS (m/z): Calcd. for
C25H23FN4OS 446.15. Found 447.14 [M + H]+, TLC
Rf = 0.5.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-phenylpiperazin-1-
yl) acetamide (5a). Brown solid; yield 95%, 0.4 g, mp
195–197°C; IR (KBr, cmÀ1) 3465, 3046, 1645, 1292,
1
1135. H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.09
(d, J = 1.8 Hz, 1H), 8.12–8.07 (m, 2H), 7.95–7.91 (m,
1H), 7.75 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 2H),
7.54–7.48 (m, 1H), 7.43–7.37 (m, 1H), 7.15–7.14 (m,
1H), 7.12 (d, J = 0.8 Hz, 1H), 6.91 (d, J = 2.1 Hz, 2H),
3.27 (d, J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H).
13C NMR (100.61 MHz, CDCl3) δ 169.83, 168.26,
154.93, 149.25, 138.12, 133.62, 129.61, 129.01, 126.32,
125.11, 124.82, 121.98, 121.34, 121.01, 119.86, 114.42,
61.15, 51.34, 49.58, LCMS (m/z): Calcd. for C25H24N4OS
428.17. Found 429.19 [M + H]+, TLC Rf = 0.6.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(pyridin-2-yl)
piperazin-1-yl) acetamide (5e).
Brown solid; yield 82%,
0.34 g, mp 208–209°C; IR (KBr, cmÀ1) 3435, 3043,
1
1660, 1290, 1130. H NMR (400 MHz, CDCl3) δ 9.35
(s, 1H), 8.11 (d, J = 1.9 Hz, 1H), 8.10–8.06 (m, 2H),
8.04 (d, J = 2.0 Hz, 1H), 7.94–7.90 (m, 1H), 7.77 (d,
J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.55–7.48 (m,
1H), 7.43–7.37 (m, 1H), 7.15–7.13 (m, 1H), 6.70 (d,
J = 2.1 Hz, 1H), 6.62–629 (m, 1H), 3.27 (d, J = 2.9 Hz,
4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H). 13C NMR
(100.61 MHz, CDCl3) δ 169.85, 168.56, 158.21, 154.93,
148.25, 138.49, 138.32, 133.83, 129.01, 126.65, 125.52,
124.82, 121.98, 121.64, 119.89, 118.12, 106.67, 63.65,
51.34, 47.58. LCMS (m/z): Calcd. for C24H23N5OS
429.16. Found 430.17 [M + H]+, TLC Rf = 0.3.
2-(4-Benzhydrylpiperazin-1-yl)-N-(4-(benzo[d]thiazol-2-yl)
phenyl) acetamide (5b). White solid; yield 78%, 0.4 g, mp
202–204°C; IR (KBr, cmÀ1) 3443, 3035, 1655, 1295,
1
1130. H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.08
(d, J = 1.8 Hz, 1H), 8.13–8.06 (m, 2H), 7.95–7.90 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Narva, S. Chitti, S. Amaroju, S. Goud, M. Alvala,
Vol 000
D. Bhattacharjee, N. Jain, and C. S. Kondapalli Venkata Gowri
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(p-tolyl)piperazin-1-
yl) acetamide (5f). Brown solid; yield 65%, 0.28 g, mp
CDCl3) δ 169.55, 168.56, 154.67, 150.10, 138.50,
133.80, 130.09, 129.09, 129.01, 127.74, 126.66, 125.37,
124.98, 124.58, 123.77, 121.88, 121.64, 119.81, 63.26,
54.37, 51.46. LCMS (m/z): Calcd. for C25H23ClN4OS
210–211°C; IR (KBr, cmÀ1) 3465, 3050, 1665, 1290,
1
1130. H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 8.11
462.12. Found 463.13 [M + H]+, TLC Rf = 0.45.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(3-hydroxyphenyl)
(d, J = 1.9 Hz, 1H), 8.10–8.06 (m, 2H), 7.94–7.90 (m,
1H), 7.77 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H),
7.54–7.48 (m, 1H), 7.43–7.37 (m, 1H), 7.15–7.13 (m,
1H), 7.12 (d, J = 0.8 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H),
6.89 (d, J = 2.1 Hz, 1H), 3.27 (d, J = 2.9 Hz, 4H), 3.25
(s, 2H), 2.86–2.82 (m, 4H), 2.32 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 168.42, 167.46, 154.15, 148.80,
140.01, 134.94, 129.84, 129.76, 129.44, 128.51, 126.36,
125.10, 123.02, 121.61, 119.45, 116.62, 62.02, 53.60,
50.04, 20.49. LCMS (m/z): Calcd. for C26H26N4OS
piperazin-1-yl) acetamide (5j).
Brown solid; yield 81%,
0.35 g, mp 228–229°C; IR (KBr, cmÀ1) 3568, 3438, 3013,
1645, 1292, 1135. 1H NMR (400 MHz, CDCl3) δ 9.33 (s,
1H), 8.14 (d, J = 1.7 Hz, 1H), 8.09–8.04 (m, 2H), 7.97–
7.90 (m, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.72 (d, J = 2.1 Hz,
1H), 7.54–7.48 (m, 1H), 7.43–7.37 (m, 1H), 7.15–7.13
(m, 1H), 6.59 (d, J = 2.2 Hz, 1H), 6.33 (d, J = 2.2 Hz,
1H), 6.21 (s, 1H), 5.95 (s, 1H) 3.27 (d, J = 2.9 Hz, 4H),
3.25 (s, 2H), 2.86–2.82 (m, 4H). 13C NMR (100.61 MHz,
CDCl3) δ 169.65, 168.66, 159.47, 154.50, 151.32, 138.50,
133.81, 131.23, 129.02, 126.76, 125.36, 124.68, 121.80,
121.66 119.88, 108.55, 107.01, 100.10, 63.26, 54.37,
51.46. LCMS (m/z): Calcd. for C25H24N4O2S 444.16.
442.18. Found 443.19 [M + H]+, TLC Rf = 0.5.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(4-hydroxyphenyl)
piperazin-1-yl) acetamide (5g).
Brown solid; yield 94%,
0.41 g, mp 232–234°C; IR (KBr, cmÀ1) 3575, 3430,
1
3040, 1640, 1290, 1135. H NMR (400 MHz, CDCl3) δ
Found 445.17 [M + H]+, TLC Rf = 0.35.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(bis(4-fluorophenyl)
9.33 (s, 1H), 8.14 (d, J = 1.7 Hz, 1H), 8.09–8.04 (m,
2H), 7.97–7.90 (m, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.72
(d, J = 2.1 Hz, 1H), 7.54–7.48 (m, 1H), 7.43–7.37 (m,
1H), 7.15–7.13 (m, 1H), 7.12 (d, J = 0.8 Hz, 1H), 6.79
(d, J = 2.2 Hz, 1H), 6.59 (d, J = 2.2 Hz, 1H), 5.95 (s,
1H) 3.27 (d, J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m,
4H). 13C NMR (100.61 MHz, CDCl3) δ 169.78, 168.46,
154.49, 148.21, 148.03, 138.52, 133.82, 129.02, 126.59,
125.30, 124.51, 121.88, 121.65, 119.87, 116.96, 115.78,
61.16, 51.37, 48.46. LCMS (m/z): Calcd. for
C25H24N4O2S 444.16. Found 445.18 [M + H]+, TLC
methyl)piperazin-1-yl) acetamide (5k).
Pale green solid;
yield 91%, 0.5 g, mp 199–200°C; IR (KBr, cmÀ1) 3438,
3064, 1655, 1288, 1135, 1085. 1H NMR (400 MHz,
CDCl3) δ 9.37 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H), 8.13–
8.06 (m, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.77 (d,
J = 2.4 Hz, 1H), 7.55–7.47 (m, 1H), 7.23–7.28 (m, 2H),
7.15–7.14 (m, 4H), 7.12–7.09 (m, 4H), 5.01 (s, 1H), 3.27
(d, J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H). 13C
NMR (100.61 MHz, CDCl3) δ 169.81, 168.36, 160.19,
154.43, 138.52, 138.31, 129.81, 129.01, 126.60, 126.22,
125.31, 124.50, 121.81, 121.64, 119.89, 116.09, 84.87,
62.65, 53.34, 49.68. LCMS (m/z): Calcd. for chemical
formula: C32H28F2N4OS 554.19. Found 555.20
Rf = 0.35.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(4-nitrophenyl)
piperazin-1-yl) acetamide (5h). Yellow solid; yield 94%,
0.44 g, mp 246–247°C; IR (KBr, cmÀ1) 3435, 3030, 1650,
1
[M + H]+, TLC Rf = 0.55.
1530, 1320,1295, 1130. H NMR (400 MHz, CDCl3) δ
9.36 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.1 Hz,
2H), 8.12–8.06 (m, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.79 (d,
J = 2.0 Hz, 1H), 7.54–7.48 (m, 1H), 7.43–7.37 (m, 1H),
7.15–7.14 (m, 1H), 7.04 (d, J = 0.8 Hz, 2H), 3.27 (d,
J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H). 13C
NMR (100.61 MHz, CDCl3) δ 169.86, 168.36, 155.87,
154.55, 138.52, 137.49, 134.42, 129.09, 126.37, 125.17,
124.80, 124.67, 121.88, 121.64, 119.77, 112.46, 61.16,
51.37, 49.36. LCMS (m/z): Calcd. for C25H23N5O3S
473.15. Found 474.15 [M + H]+, TLC Rf = 0.45.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(3-methoxyphenyl)
piperazin-1-yl) acetamide (5l). Pale green solid; yield 69%,
0.31 g, mp 195–196°C; IR (KBr, cmÀ1) 3467, 3065, 1665,
1285, 1210, 1130. 1H NMR (400 MHz, CDCl3) δ 9.41 (s,
1H), 8.13 (d, J = 1.9 Hz, 1H), 8.10–8.06 (m, 2H), 7.94–
7.90 (m, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.75 (d,
J = 2.0 Hz, 1H), 7.54–7.48 (m, 1H), 7.43–7.37 (m, 1H),
7.15–7.13 (m, 1H), 6.53 (d, J = 2.1 Hz, 1H), 6.39 (d,
J = 2.1 Hz, 1H), 6.34 (s, 1H), 3.69 (s, 3H), 3.27 (d,
J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H). 13C
NMR (100.61 MHz, CDCl3) δ 169.65, 168.65, 161.48,
154.50, 150.32, 138.51, 133.80, 130.61, 129.02, 126.76,
125.36, 124.68, 121.80, 121.65 119.88, 110.55, 106.61,
98.10, 63.26, 55.01, 54.37, 49.86. LCMS (m/z): Calcd.
for C26H26N4O2S 458.18. Found 459.19 [M + H]+, TLC
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(2-chlorophenyl)
piperazin-1-yl) acetamide (5i).
Green solid; yield 63%,
0.28 g, mp 199–200°C;IR (KBr, cmÀ1) 3465, 3040,
1
1640, 1287, 1146, 745. H NMR (400 MHz, CDCl3) δ
9.37 (s, 1H), 8.06 (d, J = 1.8 Hz, 1H), 8.10–8.04 (m,
2H), 7.88 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 2H),
7.54–7.48 (m, 1H), 7.43–7.37 (m, 1H), 7.15–7.14 (m,
1H), 7.14 (d, J = 0.8 Hz, 1H), 6.70–6.73 (m, 1H), 6.71
(d, J = 2.1 Hz, 1H), 3.27 (d, J = 2.9 Hz, 4H), 3.25 (s,
2H), 2.86–2.82 (m, 4H). 13C NMR (100.61 MHz,
Rf = 0.4.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(1-phenylethyl)
piperazin-1-yl) acetamide (5m).
Pale green solid; yield
79%, 0.35 g, mp 127–127°C; IR (KBr, cmÀ1) 3460,
1
3045, 1645, 1292, 1135. H NMR (400 MHz, CDCl3) δ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of 2-(4-Aminophenyl)
benzothiazole Analogues as Antiproliferative Agents
9.44 (s, 1H), 8.10 (d, J = 1.9 Hz, 1H), 8.12–8.08 (m, 2H),
7.95–7.91 (m, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.71 (d,
J = 2.0 Hz, 1H), 7.54–7.48 (m, 1H), 7.43–7.37 (m, 1H),
7.40–7.32 (m, 1H), 7.25–7.29 (m, 2H), 7.26 (d,
J = 1.2 Hz, 2H), 4.19–4.15 (m, 1H), 3.27 (d, J = 2.9 Hz,
4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H), 1.12 (d,
J = 2.3 Hz, 3H). 13C NMR (100.61 MHz, CDCl3) δ
169.81, 168.36, 154.43, 145.67, 138.52, 138.31, 129.81,
129.01, 128.82, 128.54, 127.32, 126.61, 125.31, 124.51,
121.81, 121.64, 73.17, 62.65, 53.34, 49.68, 20.02. LCMS
(m/z): Calcd. for chemical formula: C27H28N4OS 456.19.
Found 457.21 [M + H]+, TLC Rf = 0.5.
Tert-butyl4-(2-((4-(benzo[d]thiazol-2-yl)phenyl)amino)-2-
oxoethyl)piperazine-1-carboxylate (5q).
Pale green solid;
yield 78%, 0.35 g, mp 226–227°C; IR (KBr, cmÀ1) 3465,
3046, 1740, 1645, 1292, 1215, 1135. 1H NMR
(400 MHz, CDCl3) δ 9.37 (s, 1H), 8.09 (d, J = 1.8 Hz,
1H), 8.12–8.07 (m, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.71
(d, J = 2.0 Hz, 1H), 3.27 (d, J = 2.9 Hz, 4H), 3.25 (s,
2H), 2.86–2.82 (m, 4H), 1.28 (s, 9H). 13C NMR
(100.61 MHz, CDCl3) δ 169.83, 168.26, 154.93, 154.17,
138.12, 133.62, 129.61, 129.01, 126.32, 124.82, 121.98,
79.18, 61.15, 53.81, 51.34, 49.58, 45.32, 28.12. LCMS
(m/z): Calcd. for C24H28N4O3S 452.19. Found 453.20
[M + H]+, TLC Rf = 0.5.
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-benzylpiperazin-1-
yl) acetamide (5n). Pale green solid; yield 85%, 0.37 g, mp
General procedure for the synthesis of 4-(benzo[d]thiazol-
180–182°C; IR (KBr, cmÀ1) 3454, 3056, 1650, 1290, 1137.
1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.10 (d,
J = 1.9 Hz, 1H), 8.12–8.06 (m, 2H), 7.95–7.90 (m, 1H),
7.76 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.54–
7.48 (m, 1H), 7.43–7.37 (m, 1H), 7.36–7.32 (m, 2H),
7.26–7.29 (m, 1H), 7.24 (d, J = 1.3 Hz, 2H), 3.79 (s, 2H),
3.27 (d, J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m, 4H).
13C NMR (100.61 MHz, CDCl3) δ 169.83, 168.26,
154.53, 138.71, 138.52, 133.82, 129.01, 128.87, 128.45,
127.32, 126.32, 125.31, 124.52, 121.98, 121.64, 119.86,
65.54, 61.15, 51.34, 49.58. LCMS (m/z): Calcd. for
C26H26N4OS 442.18. Found 443.20 [M + H]+, TLC Rf = 0.5.
2-yl)-N-((substituted
aniline (7a–k).
phenyl-1H-1,2,3-triazol-4-yl)methyl)
Alkylation of 2-(4-aminophenyl)
benzothiazole (3) with propargyl bromide in N,N-
dimethylformamide yielded compound 6 in 80% after
column purification with pet ether and ethyl acetate
(20%). To a stirred solution of compound 6 (0.3 g,
1.1363 mmol) and substituted azide (1.25 mmol) in tert-
butanol and water (1:1) (3 mL), CuSO4.5H2O (56.74 mg,
0.2272 mmol) and sodium ascorbate (45.01 mg,
0.2272 mmol) were added, and the reaction mixture was
stirred at RT for 2 h. After completion of the reaction, as
indicated by TLC ((pet ether/ethyl acetate 50%)), tert-
butanol was removed under reduced pressure. The
residue was extracted with ethyl acetate (3 × 10 mL), and
combined organic layers were collected and washed with
saturated brine solution, dried over anhydrous MgSO4,
and concentrated in vacuo to get the crude product. The
product was further purified by column chromatography
using 50–80% ethyl acetate in pet ether to afford the title
N-(4-(Benzo[d]thiazol-2-yl)phenyl)-2-(4-(pyrimidin-2-yl)
piperazin-1-yl) acetamide (5o).
Brown solid; yield 76%,
0.32 g, mp 167–168°C; IR (KBr, cmÀ1) 3460, 3045,
1
1640, 1290, 1130. H NMR (400 MHz, CDCl3) δ 9.36
(s, 1H), 8.47 (d, J = 2.0 Hz, 2H), 8.11 (d, J = 1.9 Hz,
1H), 8.10–8.06 (m, 2H), 8.04 (d, J = 2.0 Hz, 1H), 7.94–
7.90 (m, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.75 (d,
J = 2.0 Hz, 1H), 7.43–7.37 (m, 1H), 6.90–6.93 (m, 1H),
3.27 (d, J = 2.9 Hz, 4H), 3.25 (s, 2H), 2.86–2.82 (m,
4H). 13C NMR (100.61 MHz, CDCl3) δ 169.85, 168.56,
158.21, 154.93, 148.25, 138.49, 138.32, 133.83, 129.01,
126.65, 124.82, 121.98, 121.64, 119.89, 118.12, 106.67,
63.65, 51.34, 47.58. LCMS (m/z): Calcd. for
C23H22N6OS 430.16. Found 431.17 [M + H]+, TLC
Rf = 0.35.
compounds.
4-(Benzo[d]thiazol-2-yl)-N-((1-(3-(trifluoromethyl)phenyl)-
1H-1,2,3-triazol-4-yl)methyl) aniline (7a).
Brown solid;
yield 91%, 0.46 g, mp 213–214°C; IR (KBr, cmÀ1) 3465,
1
3046, 1292, 1035. H NMR (400 MHz, CDCl3) δ 8.02
(dd, J = 8.1, 1.2 Hz, 1H), 7.98–7.91 (m, 2H), 7.91 (d,
J = 0.8 Hz, 1H), 7.85 (dd, J = 8.0, 1.3 Hz, 1H), 7.51 (d,
J = 1.9 Hz, 2H), 7.39–7.36 (m, 2H), 7.23 (dd, J = 8.0,
2.1 Hz, 1H), 6.97 (dd, J = 8.3, 2.5 Hz, 1H), 6.88–6.85
(m, 2H), 4.62 (s, 2H). 13C NMR (101 MHz, CDCl3) δ
168.49, 160.59, 154.29, 149.80, 146.14, 137.23, 134.48,
131.21, 130.55, 129.67, 126.08, 124.43, 121.64, 120.12,
119.92, 114.68, 112.87, 112.38, 106.36, 55.66, 39.47.
LCMS (m/z): Calcd. for C23H16F3N5S 451.11. Found
Tert-butyl4-(2-((4-(benzo[d]thiazol-2-yl)phenyl)amino)-2-
oxoethyl)-3-oxopiperazine-1-carboxylate (5p). Brown solid;
yield 87%, 0.4 g, mp 150–151°C; IR (KBr, cmÀ1) 3468,
3042, 1735, 1643, 1293, 1220, 1132. 1H NMR (400 MHz,
CDCl3) δ 9.31 (s, 1H), 8.10 (d, J = 1.9 Hz, 1H), 8.12–8.06
(m, 2H), 7.76 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 2.0 Hz,
2H), 7.54–7.48 (m, 1H), 7.43–7.37 (m, 1H), 3.89 (s, 2H),
3.27 (d, J = 2.9 Hz, 4H), 3.25 (s, 2H), 1.28 (s, 9H). 13C
NMR (100.61 MHz, CDCl3) δ 169.83, 168.26, 163.21,
154.53, 138.71, 138.52, 133.82, 129.01, 128.87, 128.45,
124.52, 79.08, 65.54, 61.15, 53.21, 51.34, 50.12, 49.48,
32.58, 28.12. LCMS (m/z): Calcd. for C24H26N4O4S
466.17. Found 467.18 [M + H]+, TLC Rf = 0.5.
452.19 [M + H]+, TLC Rf = 0.6.
4-(Benzo[d]thiazol-2-yl)-N-((1-(3-methoxyphenyl)-1H-1,2,3-
triazol-4-yl)methyl) aniline (7b). Brown solid; yield 67%,
0.31 g, mp 152–154°C; IR (KBr, cmÀ1) 3465, 3046,
1292, 1210. 1H NMR (400 MHz, CDCl3) δ 8.00 (dd,
J = 8.1, 1.2 Hz, 1H), 7.97–7.93 (m, 2H), 7.90 (d,
J = 0.8 Hz, 1H), 7.86 (dd, J = 8.0, 1.3 Hz, 1H), 7.49–
7.38 (m, 2H), 7.36–7.30 (m, 2H), 7.22 (dd, J = 8.0,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Narva, S. Chitti, S. Amaroju, S. Goud, M. Alvala,
Vol 000
D. Bhattacharjee, N. Jain, and C. S. Kondapalli Venkata Gowri
2.1 Hz, 1H), 6.97 (dd, J = 8.3, 2.5 Hz, 1H), 6.78–6.75 (m,
2H), 4.62 (s, 2H), 3.88 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.49, 160.59, 154.29, 149.80, 146.14,
137.93, 134.58, 130.55, 129.17, 126.08, 124.43, 123.45,
121.44, 119.92, 114.68, 112.87, 112.38, 106.36, 55.66,
39.47, 29.73. LCMS (m/z): Calcd. for C23H19N5OS
7.3 Hz, 1H), 7.27–7.20 (m, 1H), 6.79 (d, J = 2.0 Hz, 1H),
6.77 (d, J = 2.0 Hz, 1H), 4.67 (s, 2H). 13C NMR
(101 MHz, CDCl3) δ 168.51, 154.28, 149.83, 145.29,
140.24, 139.91, 134.57, 131.59, 129.28, 129.14, 127.84,
126.09, 124.43, 123.75, 123.43, 122.43, 121.44, 119.14
114.01, 39.50. LCMS (m/z): Calcd. for C22H16IN5S
413.13. Found 414.15 [M + H]+, TLC Rf = 0.5.
509.07. Found 510.09 [M + H]+, TLC Rf = 0.55.
4-(Benzo[d]thiazol-2-yl)-N-((1-(4-nitrophenyl)-1H-1,2,3-
triazol-4-yl)methyl) aniline (7g). Brown solid; yield 75%,
4-(Benzo[d]thiazol-2-yl)-N-((1-(2-bromophenyl)-1H-1,2,3-
triazol-4-yl)methyl) aniline (7c). Brown solid; yield 87%,
0.45 g, mp 161–162°C; IR (KBr, cmÀ1) 3460, 3040,
1290, 575. 1H NMR (400 MHz, CDCl3) δ 8.01 (dd,
J = 8.1, 1.2 Hz, 1H), 7.96–7.94 (m, 2H), 7.90 (d,
J = 0.8 Hz, 1H), 7.86 (dd, J = 8.0, 1.3 Hz, 1H), 7.49–
7.38 (m, 2H), 7.36–7.30 (m, 2H), 7.22 (dd, J = 8.0,
2.1 Hz, 1H), 6.97 (dd, J = 8.3, 2.5 Hz, 1H), 6.78–6.75
(m, 2H), 4.62 (s, 2H). 13C NMR (100.61 MHz, CDCl3) δ
168.53, 154.29, 149.82, 145.14, 136.44, 134.58, 133.94,
131.30, 129.15, 128.55, 126.10, 124.44, 123.87, 123.46,
122.45, 121.44, 118.61, 112.97, 114.12, 39.48. LCMS
(m/z): Calcd. for C22H16BrN5S 461.03. Found 462.11
0.36 g, mp 193–194°C; IR (KBr, cmÀ1) 3439, 3065,
1
1545, 1336, 1292. H NMR (400 MHz, CDCl3) δ 8.44
(d, J = 2.1 Hz, 2H), 8.05–7.99 (m, 3H), 7.94 (d,
J = 2.1 Hz, 2H), 7.93 (d, J = 2.0 Hz, 1H), 7.86 (dd,
J = 8.0, 1.2 Hz, 1H), 7.81 (s, 1H), 7.53–7.47 (m, 1H),
6.79 (d, J = 2.0 Hz, 2H), 4.67 (s, 2H). 13C NMR
(101 MHz, CDCl3) δ 168.52, 154.26, 149.73,147.90,
142.24, 139.91, 134.37, 129.28, 129.14, 128.84, 125.12,
124.43, 123.95, 122.04, 120.14, and 119.14 114.01,
39.47. LCMS (m/z): Calcd. for C22H16N6O2S 428.11.
Found 429.18 [M + H]+, TLC Rf = 0.55.
4-(Benzo[d]thiazol-2-yl)-N-((1-(2,4-dichlorophenyl)-1H-
[M + H]+, TLC Rf = 0.55.
1,2,3-triazol-4-yl)methyl) aniline (7h). Brown solid; yield
4-(Benzo[d]thiazol-2-yl)-N-((1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methyl) aniline (7d). Brown solid; yield 81%,
87%, 0.44 g, mp 203–204°C; IR (KBr, cmÀ1) 3460,
0.38 g, mp 223–225°C; IR (KBr, cmÀ1) 3455, 3068,
1
3040, 1290, 785. H NMR (400 MHz, CDCl3) δ 8.01–
1
1285, 755. H NMR (400 MHz, CDCl3) δ 8.01–7.97 (m,
7.97 (m, 2H), 7.95 (d, J = 2.0 Hz, 2H), 7.93 (d,
J = 2.0 Hz, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.81 (s,
1H),7.69 (s, 1H), 7.53–7.47 (m, 1H), 7.51 (d, J = 1.9 Hz,
1H), 7.38 (d, J = 1.9 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H),
4.70 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 168.52,
154.26, 149.73, 144.64, 139.91, 135.57, 132.78, 132.59,
130.12, 130.04, 129.67, 129.28, 129.14, 128.84, 126.69,
125.32, 124.53, 119.14, 114.01, 39.51. LCMS (m/z):
Calcd. for C22H15Cl2N5S 451.04. Found 452.09
2H), 7.95 (d, J = 2.0 Hz, 2H), 7.93 (d, J = 2.0 Hz, 1H),
7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.81 (s, 1H), 7.53–7.47
(m, 1H), 7.49 (d, J = 1.9 Hz, 2H), 6.79 (d, J = 2.0 Hz,
2H), 6.77 (d, J = 2.0 Hz, 1H), 4.67 (s, 2H). 13C NMR
(101 MHz, CDCl3) δ 168.52, 154.26, 149.73, 140.24,
139.91, 134.37, 131.59, 129.28, 129.14, 128.84, 126.09,
125.12, 124.43, 123.75, 122.04, 119.14 114.01, 39.51.
LCMS (m/z): Calcd. for C22H16ClN5S 417.09. Found
418.10 [M + H]+, TLC Rf = 0.5.
[M + H]+, TLC Rf = 0.6.
4-(Benzo[d]thiazol-2-yl)-N-((1-(3-chloro-4-fluorophenyl)-
4-(Benzo[d]thiazol-2-yl)-N-((1-(4-ethylphenyl)-1H-1,2,3-
triazol-4-yl)methyl) aniline (7e). Brown solid; yield 72%,
1H-1,2,3-triazol-4-yl)methyl) aniline (7i).
Brown solid;
0.33 g, mp 208–209°C; IR (KBr, cmÀ1) 3472, 3058,
yield 73%, 0.36 g, mp 212–214°C;IR (KBr, cmÀ1) 3460,
1
1
1298. H NMR (400 MHz, CDCl3) δ 8.02–7.99 (m, 2H),
3040, 1290, 1075, 755. H NMR (400 MHz, CDCl3) δ
7.95 (d, J = 2.0 Hz, 2H), 7.93 (d, J = 2.0 Hz, 1H), 7.86
(dd, J = 8.0, 1.2 Hz, 1H), 7.89 (s, 1H), 7.53–7.47 (m,
1H), 7.39 (d, J = 1.9 Hz, 2H), 6.81 (d, J = 2.1 Hz, 2H),
6.78 (d, J = 2.1 Hz, 1H), 4.66 (s, 2H), 2.05 (m, 2H), 1.32
(t, J = 5.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
168.52, 154.26, 149.73, 144.56, 140.24, 139.91, 134.87,
134.37, 131.59, 129.28, 129.14, 128.84, 125.12, 124.43,
123.75, 119.14, 114.01, 39.51, 29.05, 14.29. LCMS (m/
z): Calcd. for C24H21N5S 411.15. Found 412.16
8.02–7.96 (m, 2H), 7.95 (d, J = 2.0 Hz, 2H), 7.93 (d,
J = 2.0 Hz, 1H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.81 (s,
1H), 7.79 (d, J = 2.0 Hz, 1H), 7.49–7.47 (m, 1H), 7.19–
7.15 (m, 1H), 6.89 (d, J = 2.0 Hz, 2H), 4.67 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 168.52, 158.67, 154.26,
149.73, 139.91, 133.78, 132.89, 130.12, 129.67, 129.28,
129.14, 128.84, 127.21, 125.32, 124.53, 120.08, 119.14,
116.34, 114.01, 39.50. LCMS (m/z): Calcd. for
C22H15ClFN5S 435.07. Found 436.11 [M + H]+, TLC
[M + H]+, TLC Rf = 0.55.
Rf = 0.6.
4-(Benzo[d]thiazol-2-yl)-N-((1-(2-iodophenyl)-1H-1,2,3-
triazol-4-yl)methyl) aniline (7f). Brown solid; yield 86%,
4-(Benzo[d]thiazol-2-yl)-N-((1-(3-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methyl) aniline (7j). Brown solid; yield 78%,
0.49 g, mp 155–157°C; IR (KBr, cmÀ1) 3469, 3043,1298,
0.36 g, mp 208–210°C; IR (KBr, cmÀ1) 3460, 3049,
1298, 756. 1H NMR (400 MHz, CDCl3) δ 8.02 (dd,
J = 8.1, 1.2 Hz, 1H), 7.98–7.91 (m, 2H), 7.90 (d,
J = 0.8 Hz, 1H), 7.86 (dd, J = 8.0, 1.3 Hz, 1H), 7.51 (d,
J = 1.9 Hz, 2H), 7.39–7.36 (m, 2H), 7.22 (dd, J = 8.0,
1
525. H NMR (400 MHz, CDCl3) δ 8.01–7.97 (m, 2H),
7.95 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.86
(dd, J = 8.0, 1.2 Hz, 1H), 7.79 (s, 1H), 7.53–7.47 (m,
1H), 7.44 (dd, J = 7.9, 5.1 Hz, 2H), 7.33 (dd, J = 8.2,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Biological Evaluation of 2-(4-Aminophenyl)
benzothiazole Analogues as Antiproliferative Agents
[10] Ravindra, M. K.; Tulshiram, L. D.; Ramaiah, M. J.; Kishore,
K. S. V.; Pushpa Valli, S. N. C. V. L.; Sudheer, K. T.; Appalanaidu, K.;
Rao, Y. K.; Bhadra, M. P. Bioorg Med ChemLett 2015, 25, 654.
[11] Jida, M.; Soueidan, M.; Willand, N.; Niedercorn, F. A.;
Pelinski, L.; Laconde, G.; Poulain, D.; Deprez, B. Tetrahedron Lett
2011, 52, 1705.
[12] Cho, S. D.; Song, S. Y.; Kim, K. H.; Zhao, B. X.; Ahn, C.; Joo,
W. H.; Yoon, Y. J.; Falck, J. R.; Shin, D. S. Bull Korean Chem Soc 2004,
25, 415.
[13] Wu, Y.; Feng, D.; Gao, M.; Wang, Z.; Yan, P.; Gu, Z.; Guan,
Q.; Zuo, D.; Bao, K.; Sun, J.; Wu, Y.; Zhang, W. Sci Rep 2017, 7,
17120.
[14] Chopra, A.; Anderson, A.; Giardina, C. J Biol Chem 2014,
289, 2978.
2.1 Hz, 1H), 6.97 (dd, J = 8.3, 2.5, Hz, 1H), 6.88–6.85 (m,
2H), 4.62 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 168.49,
160.59, 154.29, 149.80, 146.14, 137.23, 134.48, 131.21,
130.55, 129.67, 126.08, 124.43, 121.64, 119.92, 114.68,
112.87, 112.38, 106.36, 55.66, 39.47. LCMS (m/z):
Calcd. for C22H16ClN5S 417.08. Found 418.09 [M + H]+,
TLC Rf = 0.5.
4-(Benzo[d]thiazol-2-yl)-N-((1-(4-fluorophenyl)-1H-1,2,3-
triazol-4-yl)methyl) aniline (7k). Brown solid; yield 83%,
0.37 g, mp 213–214°C; IR (KBr, cmÀ1) 3460, 3075,
1
1287, 1065. H NMR (400 MHz, CDCl3) δ 8.04–7.99
[15] Lin, H. H.; Wu, W. Y.; Cao, S. L.; Liao, J.; Ma, L.; Gao, M.;
Li, Z. F.; Xu, X. Bioorg Med Chem Lett 2013, 23, 3304.
[16] Fytas, C.; Zoidis, G.; Tsotinis, A.; Fytas, G.; Khan, M. A.;
Akhtar, S.; Rahman, K. M.; Thurston, D. E. Eur J Med Chem 2015,
93, 281.
[17] Maracic, S.; Kraljevic, T. G.; Paljetak, H. C.; Peric, M.;
Matijasic, M.; Verbanac, D.; Cetina, M.; Malic, S. R. Bioorg Med Chem
2015, 23, 7448.
[18] Holla, B. S.; Mahalinga, M.; Karthikeyan, M. S.; Poojary, B.;
Akberali, P. M.; Kumari, N. S. Eur J Med Chem 2005, 40, 1773.
[19] Wang, X. L.; Wan, K.; Zhou, C. H. Eur J Med Chem 2010,
45, 4631.
(m, 2H), 7.96 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.0 Hz,
1H), 7.85 (dd, J = 8.0, 1.2 Hz, 1H), 7.81 (s, 1H), 7.60–
7.57 (m, 1H), 7.49 (d, J = 2.0 Hz, 2H), 7.29–7.25 (m,
2H), 6.79 (d, J = 2.0 Hz, 2H), 4.60 (s, 2H). 13C NMR
(101 MHz, CDCl3) δ 168.52,162.96, 154.26, 149.73,
140.24, 139.91, 134.37, 132.49, 129.68, 126.09, 125.12,
124.43, 123.75, 122.54, 119.14, 115.23, 114.01, 39.59.
LCMS (m/z): Calcd. for C22H16FN5S 401.11. Found
402.17 [M + H]+, TLC Rf = 0.5.
[20] Odlo, K.; Hentzen, J.; Chabert, J. F. D.; Ducki, S.; Gani, O. A.
S. M.; Sylte, I.; Skrede, M.; Florenes, V. A.; Hansen, T. V. Bioorg Med
Chem 2008, 16, 4829.
[21] Li, W. T.; Wu, W. H.; Tang, C. H.; Tai, R.; Chen, S. T. Comb
Sci 2011, 13, 72.
[22] Kamal, A.; Shankaraiah, N.; Devaiah, V.; Laxma Reddy, K.;
Juvekar, A.; Sen, S.; Kurianb, N.; Zingdeb, S. Bioorg Med Chem Lett
2008, 18, 1468.
[23] Wang, M.; Xia, Y.; Fan, Y.; Rocchi, P.; Qu, F.; Iovanna, J. L.;
Peng, L. Bioorg Med Chem Lett 2010, 20, 5979.
Acknowledgments. We acknowledge the financial support from
the Department of Science and Technology (DST) (DST/SB/S1/
OC-60/2013) and DST FIST grant (SR/FST/CSI-240/2012)
Government of India, New Delhi. Central analytical lab facilities
of BITS Pilani Hyderabad Campus are greatfully acknowledged.
N. S. thanks UGC, New Delhi, for the award of senior research
fellowship.
[24] He, R.; Chen, Y.; Ougolkov, A. V.; Zhang, J. S.; Savoy, D. N.;
Billadeau, D. D.; Kozikowski, A. P. J Med Chem 2010, 53, 1347.
[25] Aufort, M.; Herscovici, J.; Bouhours, P.; Moreau, N.; Girard,
C. Bioorg Med Chem Lett 2008, 18, 1195.
CONFLICT OF INTEREST
[26] Viegas, J. C.; Danuello, A.; Bolzani, V. S.; Barreiro, E. J.;
Fraga, C. A. M. Curr Med Chem 2007, 14, 1829.
Authors declare no conflict of interest.
[27] Walsh, J. J.; Bell, A. Curr Pharm Des 2009, 15, 2970.
[28] Chua, M. S.; Shi, D. F.; Wrigley, S.; Tracey, D. B.; Hutchin-
son, I.; Shaw, P. N.; Barrett, D. A.; Stanley, L. A.; Malcolm, F.; Stevens,
G. J Med Chem 1999, 42, 381.
REFERENCES AND NOTES
[29] Antonsson, B. Mol Cell Biochem 2004, 256, 141.
[30] Taguchi, T.; Kato, Y.; Baba, Y.; Nishimura, G.; Tanigaki,
Y.; Horiuchi, C.; Mochmatsu, I.; Tsukuda, M. Oncol Rep 2004,
11, 421.
[1] Ban, M.; Taguchi, H.; Katsushima, T.; Takahashi, M.; Shinoda,
K.; Watanabe, A.; Tominaga, T. Bioorg Med Chem 1998, 6, 1069.
[2] Bondock, S. S.; Fadaly, W.; Metwally, M. A. Eur J Med Chem
2010, 45, 3692.
[31] Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon,
J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J Natl
Cancer Inst 1990, 82, 1107.
[32] Rubinstein, L. V.; Shoemaker, R. H.; Paull, K. D.; Simon, R.
M.; Tosini, S.; Skehan, P.; Scudiero, D. A.; Monks, A.; Boyd, M. R. J
Natl Cancer Inst 1990, 82, 1113.
[3] Chung, Y.; Shin, Y. K.; Zhan, C. G.; Lee, S.; Cho, H. Arch
Pharm Res 2004, 27, 893.
[4] Siddiqui, N.; Pandeya, S. N.; Khan, S. A.; Stables, J.; Rana, A.;
Alam, M.; Arshad, M. F.; Bhatt, M. A. Bioorg Med Chem Lett 2007, 17, 255.
[5] Subbarao, A. V.; Swapna, K.; Shaik, S. P.; Nayak, V. L.;
Reddy, T. S.; Sunkari, S.; Shaik, T. B.; Bagul, C.; Kamal, A. Bioorg
Med Chem 2017, 13, 977.
[6] Subbarao, A. V.; Rao, B. B.; Sunkari, S.; Shaik, S. P.; Shaik,
B.; Kamal, A. Med Chem Commun 2017, 8, 924.
[7] Kamal, A.; Sultana, F.; Ramaiah, M. J.; Srikanth, Y. V. V.;
Viswanath, A.; Kishor, C.; Sharma, P.; Pushpavalli, S. N. C. V. L.;
Addlagatta, A.; Bhadra, M. P. Chem Med Chem 2012, 7, 292.
[8] Afzal, O.; Akhtar, M. S.; Kumar, S.; Ali, M. R.; Jaggi, M.;
Bawa, S. Eur J Med Chem 2016, 121, 318.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[9] Bradshaw, T. D.; Westwell, A. D. Curr Med Chem 2004, 11,
1241.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet