Synthesis and antiproliferative evaluation of 13-aryl-13H-benzo[g] benzothiazolo [2,3-b]quinazoline-5,14-diones

Article abstract of DOI:10.1016/j.bmcl.2014.02.018

A simple synthesis of novel 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-dione derivatives was accomplished in excellent yields via the reaction of 2-aminobenzothiazole, aromatic aldehydes and 2-hydroxy-1,4-naphthoquinone in the presence of amberlyst-15. The antiproliferative activities of all the synthesized compounds were assessed on two different human cancer cell lines (HepG2 and Hela), and the results showed that most of the new compounds showed good to potent cytotoxic activities.

Full text of DOI:10.1016/j.bmcl.2014.02.018

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1462–1465
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiproliferative evaluation of 13-aryl-13H-benzo[g]-
benzothiazolo [2,3-b]quinazoline-5,14-diones
⇑
Liqiang Wu , Chong Zhang, Weilin Li
School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple synthesis of novel 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-dione deriva-
tives was accomplished in excellent yields via the reaction of 2-aminobenzothiazole, aromatic aldehydes
and 2-hydroxy-1,4-naphthoquinone in the presence of amberlyst-15. The antiproliferative activities of all
the synthesized compounds were assessed on two different human cancer cell lines (HepG2 and Hela),
and the results showed that most of the new compounds showed good to potent cytotoxic activities.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 14 November 2013
Revised 24 January 2014
Accepted 6 February 2014
Available online 15 February 2014
Keywords:
Amberlyst-15
2-Hydroxy-1,4-naphthoquinone
Aldehydes
1,4-Naphthoquinones
Antiproliferative
Solvent-free
The 1,4-naphthoquinone ring is a key structural unit for numer-
ous natural products,1 synthetic pharmaceuticals.2 Structures
embedded with 1,4-naphthoquinone units display potential
medicinal properties such as anticancer,3 antifungal,4 antibacte-
rial,5 antiviral,6 anti-inflammatory,7 antimalaria,8 antiplatelet,9
antithrombotic,10 antiallergic,11 apoptotic12 and lipoxygenase
inhibiting13 activities. Furthermore, 1,4-naphthoquinones have
also been shown to inhibit human DNA topoisomerase.14 A number
of 1,4-naphthoquinone derivatives having nitrogen atom present
in them received a great deal of attention for their anticancer activ-
ity.3e,5c,15 Therefore, the development of facile approaches to access
these novel targets with structural diversity is highly desirable and
valuable for medicinal chemistry and drug discovery.
selective products while retaining majority of the atoms of the
starting material. MCRs have received considerable attention be-
cause of its wide range of applications in pharmaceutical chemistry
for the creation of structural diversity and combinatorial libraries
for drug discovery.16
In recent years, the use of solid acidic catalysts has offered
important advantages in organic synthesis, for example, opera-
tional simplicity, environmental compatibility, nontoxic, reusabil-
ity, low cost and ease of isolation. A tremendous upsurge of
interest in various chemical transformations processes by catalysts
under heterogeneous conditions has occurred. One of those heter-
ogeneous catalysts is amberlyst-15. It makes reaction processes
convenient, more economic and environmentally benign. Owing
to the numerous advantages associated with this cheap and non-
hazardous catalyst, amberlyst-15 has been explored as a powerful
Multicomponent reactions (MCRs) typically involve more than
two reactants to combine in a sequential manner giving highly
O
O
Ar
N
N
Amberlyst-15
neat, 100 oC
+
+
ArCHO
NH2
S
S
OH
N
O
O
1
2
3
4
Scheme 1. Synthesis of 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-diones using amberlyst-15 as a catalyst.
⇑
Corresponding author. Tel./fax: +86 371 3029879.
E-mail address: wliq1974@163.com (L. Wu).
http://dx.doi.org/10.1016/j.bmcl.2014.02.018
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

L. Wu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1462–1465
1463
Table 1
catalyst for various organic transformations under mild
conditions.17
Optimization of the reaction conditions for three-component synthesis of 13-phenyl-
13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-dionea
As a consequence of our continued interest in the synthesis of
novel heterocycles employing domino protocols,18 herein we
report for the first time a facile synthesis of a library of novel
13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-diones
via the one-pot three-component domino reactions of 2-amino-
benzothiazole, aromatic aldehydes and 2-hydroxy-1,4-naphtho-
quinone in the presence of amberlyst-15 (Scheme 1). Most
importantly, these previously unreported novel series of 1,4-naph-
thoquinone derivatives having azacyclo exhibited different range
Entry
Catalyst (mol %)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Amberlyst-15 (10)
InCl3 (10)
ZrOCl4 (10)
ZnCl2 (10)
TFA (10)
p-TsOH (10)
Sulfamic acid (10)
Silica sulfuric acid (10)
10
2
2
5
2
2
2
2
87
51
63
39
67
78
74
69
a
of significant cytotoxic activities varying from 1.66 to 189.59 lM
Reaction conditions: 2-aminobenzothiazole (1 mmol), benzaldehyde (1 mmol),
due to structural differences. It was worthwhile to note that all
these compounds had lesser cytotoxicity on non-cancerous HEK
293 cells.
2-hydroxy-1,4-naphthoquinone (1 mmol); 100 °C; neat.
b
Isolated yield.
At the outset, the reaction of 2-aminobenzothiazole (1 mmol),
benzaldehyde (1 mmol) and 2-hydroxy-1,4-naphthoquinone (1 mmol)
was selected as a template reaction to investigate the catalyst effect
at 100 °C under solvent-free conditions (Table 1, entries 1–8). A
comparison of catalytic activity between Brønsted and Lewis acids
showed highest catalytic activity of amberlyst-15 under solvent-free
conditions at 100 °C (Table 1, entry 1).
Based on the optimized reaction conditions, a series of 13-aryl-
13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-diones were
synthesized. The results, summarized in Table 2, showed that the
three-component reaction in the presence of amberlyst-15 gave
the corresponding products in moderate to good yields. This meth-
odology can be applied to aromatic aldehydes either with electron-
withdrawing groups (such as, nitro, halogen) or electron-donating
groups (such as, methoxy, methyl) with excellent yields under the
same conditions. Therefore, we conclude that the electronic nature
of substituents of the aromatic aldehyde had no significant effect
on the reaction. Even the heterocyclic aldehyde could be used in
Table 2
Preparation of 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-5,14-dionesa
Entry
Ar
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
C6H5
4-F–C6H4
2
2
1.5
3
3
1.5
3
2
3
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
87
85
93
85
90
89
79
88
82
84
4-Me–C6H4
2,5-(MeO)2–C6H3
3,4,5-(MeO)3–C6H2
4-NO2–C6H4
2,4-Cl2–C6H3
4-Cl–C6H4
2-Furanyl
2-Thiophenyl
4j
a
Reaction conditions: 2-aminobenzothiazole (1 mmol), aldehyde (1 mmol), 2-
hydroxy-1,4-naphthoquinone (1 mmol), amberlyst-15 (0.1 mmol); 100 °C; neat.
b
Isolated yield.
O
O
O
OH
Ar
OH
OH
-H2O, H+
O
OH
H+
3
O
Ar
H
Ar
H
5
2
Ar
O
O
N
S
O
N
H2N
Ar
S
1
OH
H2N
H+
O
O
6
O
O
Ar
O
O
Ar
N
N
-H2O
air-oxidation
S
S
N
N
H
4
Scheme 2. A plausible mechanistic pathway to explain the amberlyst-15 catalyzed formation of compounds 4.

1464
L. Wu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1462–1465
Table 3
all these compounds have lesser cytotoxicity on non-cancerous
HEK 293 cells.
Antiproliferative activities of 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]quinazoline-
5,14-diones
In summary, we have developed an efficient and simple proce-
dure to generate 13-aryl-13H-benzo[g]benzothiazolo [2,3-b]qui-
nazoline-5,14-dione derivatives via the amberlyst-15 catalyed
three-component condensation of 2-aminobenzothiazole, aromatic
aldehydes and 2-hydroxy-1,4-naphthoquinone. Moreover, the
cytotoxic activities of these compounds were evaluated in vitro
on two different cancer cell lines, and the results show that some
compounds exhibited good antiproliferative activities against
HepG2 and Hela.
a
Compd
IC50
(
lM)
HepG2
1.66 0.92
Hela
HEK293
4a
4b
4c
4d
4e
4f
4g
4h
2.99 0.39
3.96 0.16
3.81 0.08
124.61 2.31
9.32 0.38
29.04 1.08
2.68 0.21
15.57 0.43
6.62 0.28
4.23 0.39
1.31 0.04
4.16 0.17
15.08 0.67
5.18 0.13
>200
11.04 0.46
50.34 2.88
4.90 1.06
25.92 2.89
10.14 0.87
5.90 0.54
1.06 0.05
9.4 0.45
1.70 0.11
189.59 13.52
5.03 0.21
14.33 0.60
3.56 0.96
23.42 3.12
9.07 0.76
5.76 0.43
1.15 0.03
4i
4j
Acknowledgments
Adriamycin
We are pleased to acknowledge the financial support from
Scientific Research Fund of Xinxiang Medical University (No.
2013QN130).
a
The means of triplicates SD.
this reaction (Table 2, entries 9 and 10). However, when the ali-
phatic aldehyde was applied to this reaction, no expected product
was obtained. The structures of the isolated products 4 were de-
duced on the basis of IR, 1H NMR, 13C NMR, mass spectrometry
and elemental analysis.19 The IR spectrum of 4a showed absorp-
tions at 1688 and 1622 cmꢀ1 indicating the presence of C@O and
C@N-bonds, respectively. The mass spectrum of 4a displayed the
molecular ion [M+H]+ peak at m/z = 395, which was consistent
with the 1:1:1 adduct of 2-aminobenzothiazole, benzaldehyde
and 2-hydroxy-1,4-naphthoquinone with the loss of two equiva-
lent water molecule. The 1H NMR spectrum of 4a showed two
doublet of doublets (d = 8.42 and 8.09 ppm, J = 1.2, 8.0 Hz) arising
from the protons peri to the quinone C@O. A singlet was observed
(d = 6.77 ppm) for the CH group of C-13 position. The 13C NMR
spectrum of 4a showed characteristic signals at d = 56.2 ppm
(due to the Ph–CH group), 179.8 and175.9 ppm (arising from the
two nonequivalent carbonyl groups).
A proposed mechanism for the reaction is outlined in Scheme 2.
It is highly probable that amberlyst-15 catalyzes the formation of a
carbocation in a reversible reaction with the aromatic aldehyde.
The higher reactivity of the carbocation compared with the car-
bonyl species is utilized to facilitate Knoevenagel condensation be-
tween arylaldehyde 2 and 2-hydroxy-1,4-naphthoquinone 3 via
intermediate 5, and after dehydration olefin 6 is produced. Subse-
quent Michael-type addition of 2-aminobenzothiazole 1 to the ole-
fin followed by intramolecular nucleophilic cyclization,
dehydration, and aromatization by air-oxidation affords the corre-
sponding products 4.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
02.018.
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