Design and efficient synthesis of A-278637 derivatives as potential potassium channel opener

Article abstract of DOI:10.1016/j.bmcl.2010.10.127

A series of thieno[3,2-b]quinoline derivatives designed based on A-278637 scaffold, were synthesized efficiently via one-pot three-component reaction under solvent-free and catalyst-free conditions. This work provides a new compound library with potential

Full text of DOI:10.1016/j.bmcl.2010.10.127

Bioorganic & Medicinal Chemistry Letters 21 (2011) 453–455
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and efficient synthesis of A-278637 derivatives as potential
potassium channel opener
⇑
Tuanjie Li, Xiaodong Feng, Changsheng Yao , Chenxia Yu, Bei Jiang, Shujiang Tu
School of Chemistry and Chemical Engineering, Key Laboratory of Biotechnology for Medicinal Plant, Xuzhou Normal University, Xuzhou, Jiangsu 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of thieno[3,2-b]quinoline derivatives designed based on A-278637 scaffold, were synthesized
efficiently via one-pot three-component reaction under solvent-free and catalyst-free conditions. This
work provides a new compound library with potential biological activity for biomedical screening.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 September 2010
Revised 21 October 2010
Accepted 23 October 2010
Available online 29 October 2010
Keywords:
Thieno[3,2-b]quinoline
Multicomponent reaction
Biomedical screening
Solvent-free synthesis
Thiophene derivatives are interesting because of their
antifungal,1 antibacterial,2 anti-acetylcholinesterase,3 analgesic,
antipyretic and antiinflammatory activities.4 Recently, these com-
pounds have also been reported as Cdc7 kinase inhibitors,5 NMDA
receptor antagonists,6 and so on. In addition, some synthesized com-
pounds with thienopyridine core unit exhibit antimalarial,7 and
antimicrobial8 activities. A-278637 (I), a preclinical potassium chan-
nel opener developed by Abbott, was reported to selectively inhibit
spontaneous bladder contractions.9–14 So the research of its deriva-
tives is of great significance. However, only a few studies on the
synthesis and bioactivity of thienoquinoline analogs based on thie-
nopyridine core have been documented in the literature.8,14 In view
of the important biological properties of the thienoquinoline deriv-
atives, it is worthy of modifying this significant scaffold further.
Besides, an N-alkylated dihydropyridine derivative, AC394 (II), can
potentiate the antitumor effect of adriamycin and show antimeta-
static activity.15 So the aryl group was removed and hydrocarbyl
substituents were introduced at positions 4, 6 and 9 of A-278637
(I), thus the ultimate structure (III) was obtained. These modifica-
tions may contribute to the bioactivity differences and provide a
new compound library with potential biological activity for biomed-
ical screening.
OMe
N
O
F
OMe
Br
O
O
O
S
O
O
O
O
S
O
MeO
N
N
N
H
(CH2)3Ph
III
AC394(II)
A-278637(I)
The known synthesis methods of thienoquinoline derivatives
had many drawbacks, including multistage procedures, drastic
reaction conditions, long reaction time, low yields and the use of
catalyst and organic solvents. Recently, the progress in the field
of solvent-free reactions is gaining much attention because of their
high efficiency and selectivity, easy separation and purification,
mild reaction conditions, and eco-friendliness.16 Many organic
reactions and complex transformations have been reported to pro-
ceed under solvent-free conditions.17,18 In addition, by virtue of the
convergence of productivity, facile execution, and generally high
yield of products, one-pot multicomponent reactions (MCRs) have
attracted considerable attention from the point of view of ideal
synthesis.19 Therefore, if a one-pot MCR could be carried out under
solvent-free conditions, it may be most efficient and eco-friendly.
In continuing our work on the design and efficient synthesis of po-
tential biologically active heterocyclic compounds,20 herein we
⇑
Corresponding author. Tel: +86 (516) 83500365; fax: +86 (516) 83403165.
E-mail address: csyao@xznu.edu.cn (C. Yao).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.127

454
T. Li et al. / Bioorg. Med. Chem. Lett. 21 (2011) 453–455
shall report a simple work-up, three-component and catalyst-free
synthesis of a range of new thienoquinoline derivatives, which
may prove to be of biological interest (Scheme 1).
also to heterocyclic and aliphatic aldehydes (entry 17 and 18). Par-
ticularly noteworthy was the fact that hydrogen atom at position 4
can be substituted with phenyl bearing either electron-donating
group (such as a methyl, entry 13–18) or electron-withdrawing
group (such as halide groups, entry 19 and 20), or even with alkyl
group (such as benzyl, entry 21 and 22), which highlighted the
wide scope of this three-component condensation. Therefore, we
concluded that the nature of the substituents of the aldehydes
and enaminones had no obvious effect on this reaction.
The effect of solvent on the reaction was initially examined by
reacting 3-fluorophenyl aldehyde (1 mmol) and dihydrothiophen-
3(2H)-one-1,1-dioxide (1 mmol) with 3-phenylamino-5,5-dimeth-
ylcyclohex-2-enone (1 mmol) without catalyst. When the reaction
was performed below 50 °C, only trace amount of expected prod-
uct was obtained in the presence/absence of solvents, as indicated
by TLC. So the model reaction was carried out using AcOH, CHCl3,
EtOH, DMF and water as solvents at 60 °C to investigate the solvent
effect. As can be seen in Table 1, the reaction under solvent-free
condition provided the best yield in the shortest reaction time
(Table 1, entry 6). So we carried out the solventless reaction to syn-
thesize the desired products.
To optimize the temperature for the synthesis, the previous
three reagents were reacted under solvent-free condition at tem-
peratures ranging from 60 to 120 °C (Table 2). We found that the
yield of 4a was improved and the reaction time was shortened as
the temperature was increased from 60 to 90 °C (Table 2, entries
1–4). The yield plateaued when the temperature was further in-
creased from 100 to 110 °C (Table 2, entries 5–6). Therefore, a reac-
tion temperature of 90 °C was considered to be most suitable.
Based on the optimized reaction conditions (solvent-free,
catalyst-free, 90 °C), a series of N-substituted thieno[3,2-b]quino-
line derivatives were synthesized. The results are summarized in
Table 3.
All the products were characterized by IR, 1H NMR and HRMS
data.21 The structure of 4j was also established by X-ray crystallo-
graphic analysis (Fig. 1).22
Although the detailed mechanism of the above reaction remains
to be fully clarified, the formation of N-substituted thieno[3,2-b]
quinoline derivatives could be explained by a possible reaction se-
quence similar to the previous reports, which is presented in Scheme
2.23 The product 4 may be synthesized via sequential condensation,
addition and cyclization. The condensation between aldehyde 1 and
Table 3
Synthesis of product 4 under solvent-free condition at 90 °Ca
Entry
Product
R1
R2
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4a
4b
4c
4d
4e
4f
4g
4h
4i
3-FC6H4
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
8
9
9
9
8
8
10
9
85
80
78
80
83
77
81
84
83
78
75
72
86
80
81
76
68
59
63
65
46
52
3,4-Cl2C6H3
3-NO2C6H4
4-NO2C6H4
3-ClC6H4
3-BrC6H4
4-ClC6H4
4-BrC6H4
3-CH3OC6H4
2-FC6H4
3,4-(OCH2O)C6H3
3-FC6H4
To examine the efficiency and the applicability of this three-
component reaction, a series of aldehydes and enaminones were
submitted to the optimized reaction conditions. As shown in Table
3, this protocol could be applied not only to aromatic aldehydes
with either electron-withdrawing groups (such as nitro or halide
groups) or electron-donating groups (such as alkoxyl groups), but
9
4j
4k
4l
10
12
12
9
9
9
4m
4n
4o
4p
4q
4r
4s
4t
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-ClC6H4
C6H5CH2
C6H5CH2
4-FC6H4
4-BrC6H4
4-CH3OC6H4
n-C3H7
Thiophene-2-yl
3-FC6H5
3-FC6H4
4-ClC6H4
4-BrC6H4
R1
O
O
O
S
9
O
S
O
O
10
10
12
12
15
14
solvent-free
R1CHO
NHR2
N
O
R2
4u
4v
1
2
3
4
a
General procedure: 1 mmol
1 and 1 mmol 2 were triturated together for
Scheme 1. Synthesis of A-278637 derivatives.
30 min. Then 1 mmol 3 was added and mixed thoroughly. The mixture was kept at
90 °C until completion (monitored by TLC).
b
Isolated yield.
Table 1
Solvent effect on the synthesis of 4a
Entry
Solvent
T (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
AcOH
CHCl3
EtOH
DMF
H2O
60
60
60
60
60
60
20
18
18
16
20
15
32
28
22
25
36
52
Solvent-free
Table 2
Temperature optimization for the synthesis of 4a
Entry
T (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
60
70
80
15
12
10
8
7
6
52
63
78
85
80
80
68
90
100
110
120
6
Figure 1. Crystal structure of 4j.

T. Li et al. / Bioorg. Med. Chem. Lett. 21 (2011) 453–455
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S
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S
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NHR2
CHR1
R1CHO
3
O
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1
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R1
O
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O
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R1
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S
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S
O
O
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S
N
N
NHR2
HO
R2
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4
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7
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In summary, we have provided an efficient three-component
route using readily available starting materials for the synthesis
of a series of thieno[3,2-b]quinoline derivatives under solvent-free
and catalyst-free conditions. The experimental simplicity, higher
yields, short reaction time, eco-friendly and the simple workup
procedure, makes the procedure attractive to modify the scaffold
of A-278637. The new series of thieno[3,2-b]quinoline derivatives
may prove to be of biological interest and provide new classes of
compounds with potential biological activity for biomedical
screening.
Acknowledgments
20. (a) Tu, S. J.; Miao, C. M.; Fang, F.; Feng, Y. J.; Li, T. J.; Zhuang, Q. Y.; Zhang, X. J.;
Zhu, S. L.; Shi, D. Q. Bioorg. Med. Chem. Lett. 2004, 14, 1533; (b) Tu, S. J.; Zhu, X.
T.; Zhang, J. P.; Xu, J. N.; Zhang, Y.; Wang, Q.; Jia, R. H.; Jiang, B.; Zhang, J. Y.; Yao,
C. S. Bioorg. Med. Chem. Lett. 2006, 16, 2925; (c) Tu, S. J.; Zhang, J. P.; Zhu, X. T.;
Xu, J. N.; Zhang, Y.; Wang, Q.; Jia, R. H.; Jiang, B.; Zhang, J. Y. Bioorg. Med. Chem.
Lett. 2006, 16, 3578; (d) Yao, C. S.; Lei, S.; Wang, C. H.; Yu, C. X.; Shao, Q. Q.; Tu,
S. J. Chin. J. Chem. 2008, 26, 2107; (e) Yao, C. S.; Lei, S.; Wang, C. H.; Yu, C. X.; Tu,
S. J. J. Heterocycl. Chem. 2008, 45, 1609; (f) Wei, P.; Zhang, X. H.; Tu, S. J.; Yan, S.;
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21. The experimental procedures of synthesis and the spectroscopic data of the
synthesized compounds are available in Supplementary data.
We are grateful for financial support by Natural Science
Foundation of China (Nos. 20672090 and 200810102050), the
Major Basic Research Project of the Natural Science Foundation
of the Jiangsu Higher Education Institutions (09KJA430003),
Natural Science Foundation of Xuzhou City (XM09B016), Graduate
Foundation of Xuzhou Normal University (2010YLB029) and Qing
Lan Project (08QLT001).
Supplementary data
22. The single-crystal growth was carried out in ethanol at room temperature. X-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.10.127.
ray crystallographic analysis was performed using
a Rigaku Saturn
diffractometer. Crystal data for 4j: C26H27NO4S, colorless, crystal dimension
0.20 Â 0.14 Â 0.12 mm, Monoclinic, space group P121/n1, a = 11.2488(14),
b = 14.8013(18),
c = 13.3866(16) Å,
b = 92.747(7)°,
V = 2226.3(5) Å3,
References and notes
Mr = 449.55, Z = 4, Dc = 1.341 g/cm3, k = 0.71070 Å,
l(Mo Ka ,
) = 0.179 mmÀ1
F(0 0 0) = 952, S = 1.041, R1 = 0.0489, wR2 = 0.1250. CCDC 790992 contains the
supplementary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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