Bioorganic & Medicinal Chemistry Letters
Novel cycloalkylthiophene–imine derivatives bearing benzothiazole
scaffold: Synthesis, characterization and antiviral activity evaluation
Shaoyong Ke a, , , Yanhong Wei b, , Ziwen Yang a, Kaimei Wang a, Ying Liang a, Liqiao Shi a,
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a National Biopesticide Engineering Research Center, Hubei Academy of Agricultural Sciences, Wuhan 430064, People’s Republic of China
b College of Life Sciences, Wuhan University, Wuhan 430072, People’s Republic of 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 novel cycloalkylthiophene–imine derivatives containing benzothiazole unit were designed,
synthesized and evaluated for their anti-viral activities. The bio-evaluation results indicated that some
of the target compounds (such as 5g, 5i, 5u) exhibited good to moderate antiviral effect on CVB5,
ADV7 and EV71 viruses, however, these compounds did not have inhibition activity against H1N1 virus.
Especially, the compounds 4c and 4d also exhibited high antiviral activities, which provide a new and
efficient approach to evolve novel multi-functional antiviral agents by rational integration of active
pharmacophores.
Received 2 May 2013
Revised 23 June 2013
Accepted 15 July 2013
Available online xxxx
Keywords:
Cycloalkylthiophene–imine
Benzothiazole
Ó 2013 Elsevier Ltd. All rights reserved.
Synthesis
Antiviral activity
Benzothiazoles are an important class of heterocyclic scaffold
that consist of a five-membered 1,3-thiazole ring fused to a ben-
zene ring. Many compounds derived from this heterocycle exhibit
diverse pharmacological and synthetic interest due to their exten-
sive bioactivities, in particular, which also are extremely versatile
building blocks for the manufacture of various bioactive com-
pounds in medicinal and industrial fields.1–6 Notably, among all
these benzothiazole derivatives, 2-substituted benzothiazoles
(Fig. 1) are privileged heterocyclic systems because of their broad
applications range from medicinal agents, agrochemicals, materi-
als to chemsensors.7–18
On the other hand, cycloalkylthiophene units have also at-
tracted considerable attention for decades.19,20 Very recently,
many examples bearing this moiety have been reported to confirm
that the introduction of these pharmacophores can result in high
activity and broader activity spectra.21–25 Meanwhile, the flexible
properties and itself characteristics of imine (C@N) group make it
present important chemical and biological significance,26–28 and
which is always the focus field to researchers due to its lone elec-
tron pair and better coordination properties. Recently, the exten-
sive applications of imine compounds have also been
demonstrated,29–35 and many commercial medicines and agro-
chemicals all contain this unit, and so which has played signifi-
cantly important role in pharmaceutical industry.
Thus, based on the aforementioned statements, this work fo-
cused on the design, convenient synthesis, and antiviral evaluation
of novel series of cycloalkylthiophene–imine derivatives bearing
benzothiazole unit. We utilized cycloalkylthiophene scaffold as
key prototype structural unit and planed for the integration of ben-
zothiazole and imine pharmacophores to the core structure as
shown in Figure 2, and these novel three-block conjugations were
not yet reported in the literature, which might be developed as
lead compounds for novel antiviral agents.
The general procedures for the preparation of novel cycloalkyl-
thiophene–imine derivatives 5a–y are outlined in Scheme 1.
The key building blocks 2-(benzo[d]thiazol-2-yl)acetonitrile 1a,
b were constructed by cyclization reaction of 2-aminobenzenethiol
and malononitrile, which were conveniently transferred to the cor-
responding cycloalkylthiophene derivatives 4a–d via classical Ge-
wald three components reaction. The following condensation
reactions of intermediates 4a–d were treated with various alde-
hydes resulting in cycloalkylthiophene–imine derivatives 5a–y.
All target compounds gave satisfactory chemical analyses, and
the chemical structures of the synthesized compounds were sum-
marized in Table 1.
The in vitro cytotoxic effects of these cycloalkylthiophene–
imine derivatives 5a–y on RD (rhabdomyosarcoma), HepG2 (hepa-
tocellular liver carcinoma), Hela (cervical cancer), and MDCK (dog
kidney) cell lines were evaluated by the standard MTT (3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay.36
However, most of these compounds showed almost no toxic to
the tested cell lines, and the preliminary results were summarized
in the following Table 2.
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Corresponding authors. Tel.: +86 2759101956 (S.K.).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
Ke, Shaoyong
