Moxifloxacin/Gatifloxacin-1,2,3-triazole-isatin Hybrids with Hydrogen-Bond Donor and Their In Vitro Anticancer Activity

Article abstract of DOI:10.1002/jhet.3670

A series of novel moxifloxacin/gatifloxacin-1,2,3-triazole-isatin hybrids (8a–i) were designed, synthesized, and screened for their in vitro anticancer activity in this paper. All of the synthesized hybrids were active against A549 and HepG2 cancer cell lines, whereas the parent drugs moxifloxacin and gatifloxacin were devoid of activity. Among them, hybrid 8i (IC₅₀: 41.1–98.3 μM) showed considerable activity against A549, HepG2, and MCF-7 cancer cell lines, and it was no inferior to Vorinostat (IC₅₀: 64.32 to >100 μM) against the three cancer cell lines. Thus, this kind of hybrids has potentiality for discovery of new anticancer candidates for clinical deployment in the control and eradication of cancers.

Full text of DOI:10.1002/jhet.3670

Month 2019
Moxifloxacin/Gatifloxacin-1,2,3-triazole-isatin Hybrids with Hydrogen-
Bond Donor and Their In Vitro Anticancer Activity
Rongxing Chen,a† Hao Zhang,b† Tianwei Ma, Huarui Xue, Zhong Miao, Liyan Chen, and Xiangkui Shi
a
a
a
a
a
*
aXuzhou Women & Children’s Healthcare Hospital, Xuzhou, Jiangsu 221009, People’s Republic of China
bDepartment of Neurosurgery, Xuzhou Central Hospital, Second Division, Xuzhou, Jiangsu 221009, People’s Republic of
China
*E-mail: ysk83907278@163.com
†These authors contributed equally.
Received July 15, 2019
DOI 10.1002/jhet.3670
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel moxifloxacin/gatifloxacin-1,2,3-triazole-isatin hybrids (8a–i) were designed, synthe-
sized, and screened for their in vitro anticancer activity in this paper. All of the synthesized hybrids were ac-
tive against A549 and HepG2 cancer cell lines, whereas the parent drugs moxifloxacin and gatifloxacin were
devoid of activity. Among them, hybrid 8i (IC50: 41.1–98.3 μM) showed considerable activity against A549,
HepG2, and MCF-7 cancer cell lines, and it was no inferior to Vorinostat (IC50: 64.32 to >100 μM) against
the three cancer cell lines. Thus, this kind of hybrids has potentiality for discovery of new anticancer candi-
dates for clinical deployment in the control and eradication of cancers.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
hybridization of the pharmacophore moiety of quinolone
with isatin opens a door for the opportunities on the
development of novel anticancer agents.
Cancer, which can invade or spread almost any part of
the body, is the second leading cause of death globally
and is estimated to be responsible for 9.6 million deaths
in 2018 [1,2]. Lung, prostate, colorectal, stomach, liver,
and breast cancers, the most common causes of cancer
death, account for half of the cancer mortality burden
globally [3]. The anticancer agents are essential for the
treatment of cancers, and over 100 drugs have been
approved for this purpose [4]. However, the emergence
of drug-resistant especially multidrug-resistant cancers
along with side effects and low specificity of cancer
agents, creating an urgent need to develop novel
anticancer drugs [5,6].
Many fluoroquinolone-isatin hybrids such as
moxifloxacin-isatin and gatifloxacin-isatin hybrids possess
a variety of biological activity, and the structure–activity
relationship (SAR) revealed that the linker between
fluoroquinolone and isatin moieties was closely related
with the activity [13–15]. The recent research results
demonstrated that 1,2,3-triazole as the linker between
fluoroquinolone and isatin motifs could improve the
biological activity [16–20], whereas N-acylated fluoroqui-
nolone derivatives showed enhanced activity and reduced
cytotoxicity when compared with the parent drugs,
implying acetyl might also be an excellent linker [21,22].
Quinolone,
which
possesses
a
variety
of
Based on the aforementioned considerations,
a
pharmacological properties, is a privileged structural
moiety in various drugs including anticancer agents
Voreloxin and Quarfloxin [7–9]. Isatin is an excellent
reservoir of bioactive substances, and its derivatives
possess a variety of biological properties especially
anticancer activity that is related to their ability to induce
cell death for many cancer cell lines [10–12]. Thus,
series of novel moxifloxacin/gatifloxacin-1,2,3-triazole-
isatin hybrids tethered via acetyl between moxifloxacin/
gatifloxacin and 1,2,3-triazole moieties were designed,
synthesized, and evaluated for their in vitro anticancer
activity against a panel of cancer cell lines in this paper.
The illustration of the design strategy is depicted in
Figure 1.
© 2019 Wiley Periodicals, Inc.

R. Chen, H. Zhang, T. Ma, H. Xue, Z. Miao, L. Chen, and X. Shi
Vol 000
using potassium carbonate (K2CO3) as base generated N-
propargyl isatin intermediates 2a–d [23]. 2-Azidoacetic
acid 4 that was obtained by the treatment of 2-
bromoacetic acid 3 with sodium azide in H2O reacted
with dicyclohexylcarbodiimide and N-hydroxysucci-
nimide to generate succinimidyl ester 5. Condensation of
moxifloxacin/gatifloxacin with succinimidyl ester 5 in
presence of N,N-diisopropylethylamine as base provided
the key intermediates 2-azidoacetyl moxifloxacin/
gatifloxacin 6a,b. Cyclization of N-propargyl isatin
intermediates 2a–d with 2-azidoacetyl moxifloxacin/
gatifloxacin 6a,b with copper acetate (Cu (OAc)2) as
catalyst gave the moxifloxacin/gatifloxacin-1,2,3-triazole-
isatin hybrids 7a–f. Finally, condensation of moxiflo-
xacin/gatifloxacin-1,2,3-triazole-isatin hybrids 7a–f with
the requested amine hydrochlorides in presence of
NaHCO3 in a mixture of tetrahydrofuran and H2O
yielded oxime/thiocarbamide-containing moxifloxacin/
gatifloxacin-1,2,3-triazole-isatin hybrids 8a–i.
Figure 1. The design strategy of moxifloxacin/gatifloxacin-1,2,3-triazole-
isatin hybrids. [Color figure can be viewed at wileyonlinelibrary.com]
RESULTS AND DISCUSSION
The synthetic routes for moxifloxacin-1,2,3-triazole-
isatin hybrids 8a–f and gatifloxacin-1,2,3-triazole-isatin
hybrids 8g–i were depicted in Schemes 1 and 2,
respectively. Alkylation of isatin/5-fluoroisatin/7-
fluoroisatin/5-methylisatin 1a–d with propargyl bromide
Scheme 1. Synthesis route of moxifloxacin-1,2,3-triazole-isatin hybrids 8a–f.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Moxifloxacin/Gatifloxacin-1,2,3-triazole-isatin Hybrids with Hydrogen-Bond
Donor and Their In Vitro Anticancer Activity
Scheme 2. Synthesis route of gatifloxacin-1,2,3-triazole-isatin hybrids 8g–i.
The hybrids moxifloxacin/gatifloxacin-1,2,3-triazole-
isatin hybrids 8a–i were evaluated for their in vitro
anticancer activities against six human cancer cell lines
A549 (lung carcinoma), HepG2 (liver cancer), MCF-7
(breast cancer), PC-3 (prostate), SW620 (metastatic
colorectal adenocarcinoma), and MGC-803 (gastric) by
CCK-8 Assay Kit [24], and the IC50 values were
presented in Table 1.
As can be seen from Table 1, none of the synthesized
moxifloxacin/gatifloxacin-1,2,3-triazole-isatin hybrids 8a–
i were active against PC-3, SW620, and MGC-803 cancer
cell lines. However, all of them were active against A549
Table 1
Anticancer activities of moxifloxacin/gatifloxacin-1,2,3-triazole-isatin hybrids 8a–i.
IC50 (μM)
Compd.
A549
86.2
HepG2
MCF-7
PC-3
SW620
MGC-803
8a
8b
8c
8d
8e
8f
8g
8h
81.5
63.1
60.6
93.2
97.9
89.7
68.8
62.5
41.1
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
98.3
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
—
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
—
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
—
79.4
67.7
99.4
98.3
91.6
75.0
75.9
44.2
>100
>100
76.3
8i
Moxifloxacin
Gatifloxacin
Vorinostat [24]
>100
>100
64.2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Chen, H. Zhang, T. Ma, H. Xue, Z. Miao, L. Chen, and X. Shi
Vol 000
[2] Cancer control: knowledge into action. World Health Organi-
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and HepG2 cells, and compound 8i was also active against
MCF-7, whereas the parent drugs moxifloxacin and
gatifloxacin were devoid of activity against all tested
cancer cells. The SAR indicated that the fluoroquinolone
moiety was closely related with the activity, and
gatifloxacin hybrids were more potent than the
corresponding moxifloxacin analogues; substituents at C-
3 position of isatin moiety also affected the activity
remarkably, and oxime > thiocarbamide; introduction of
either electron-withdrawing fluoro or electron-donating
methyl at C-5 or C-7 position of isatin could enhance the
activity, and methyl at C-5 position was better than
fluoro; the position of fluoro also has great influence on
the activity, and fluoro at C-7 position was more
favorable than C-5 position. Among them, hybrid 8i
(IC50: 41.1–98.3 μM) showed considerable activity
against A549, HepG2, and MCF-7 cancer cell lines, and
it was no inferior to Vorinostat (IC50: 64.32 to >100 μM)
against the three cancer cell lines. Thus, this hybrid can
potentially serve as a lead for the development of novel
anticancer chemotherapeutic agents.
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In conclusion,
a series of novel moxifloxacin/
gatifloxacin-1,2,3-triazole-isatin hybrids 8a–i were
designed, synthesized, and screened for their in vitro
anticancer activity in this paper. Some of the synthesized
hybrids were active against A549, HepG2, and MCF-7
cancer cell lines, whereas the parents moxifloxacin and
gatifloxacin were inactive. Among them, the most active
hybrid 8i was no inferior to Vorinostat against A549,
HepG2, and MCF-7, demonstrating the potential of
fluoroquinolone-1,2,3-triazole-isatin hybrids as novel
anticancer prototypes. The SAR was also discussed, and
the enriched SAR pointed out the direction for further
rationale design and modification of these hybrids.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
For the analytical data, please see Data S1.
REFERENCES AND NOTES
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new cases and 9.6 million cancer deaths in 2018. World Health Organiza-
tion, 2018.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet