Design, Synthesis, and In Vitro Anti-mycobacterial Activities of 1,2,3-Triazole-tetraethylene Glycol Tethered Isatin Dimers

Article abstract of DOI:10.1002/jhet.3349

We report herein the design, synthesis, and in vitro anti-mycobacterial activities of a series of 1,2,3-triazole-tetraethylene glycol tethered isatin dimers. Our results indicated that all the synthesized isatin dimers showed weak to moderate anti-mycobacterial activities against both Mycobacterium tuberculosis H37Rv and multidrug-resistant tuberculosis strains. Dimer 7g was found to be most active against the tested two strains with minimum inhibitory concentration of 128 and 64?μg/mL, which was eightfold more potent than INH (minimum inhibitory concentration: 512?μg/mL) against multidrug-resistant tuberculosis. Moreover, dimer 7g (CC₅₀: 62.5?μg/mL) also showed acceptable cytotoxicity against VERO cell line, could act as a lead for further investigation. The enriched structure–activity relationship may pave the way to find more effective anti-mycobacterial candidates.

Full text of DOI:10.1002/jhet.3349

Month 2018
Design, Synthesis, and In Vitro Anti-mycobacterial Activities of 1,2,3-
Triazole-tetraethylene Glycol Tethered Isatin Dimers
a
a
b
c
d
e
*
Shi-Jia Zhao, Zao-Sheng Lv, Jia-Lun Deng, Feng Gao, Guang-De Zhang, and Zhi Xu
aKey Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, Wuhan University of Science and
Technology, 430081, Hubei, People’s Republic of China
bHaiso Technology Co., Ltd., Wuhan 430074, People’s Republic of China
cDepartment of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing 210089,
People’s Republic of China
dSchool of Automobile and Traffic Engineering, Wuhan University of Science and Technology, Wuhan 430081,
People’s Republic of China
eIndustry Innovation & Research and Development Institute of Zhumadian, Huanghuai University, Zhumadian 463000,
People’s Republic of China
*E-mail: chemorgchem@126.com
Received June 22, 2018
DOI 10.1002/jhet.3349
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
We report herein the design, synthesis, and in vitro anti-mycobacterial activities of a series of 1,2,3-
triazole-tetraethylene glycol tethered isatin dimers. Our results indicated that all the synthesized isatin dimers
showed weak to moderate anti-mycobacterial activities against both Mycobacterium tuberculosis H37Rv and
multidrug-resistant tuberculosis strains. Dimer 7g was found to be most active against the tested two strains
with minimum inhibitory concentration of 128 and 64 μg/mL, which was eightfold more potent than INH
(minimum inhibitory concentration: 512 μg/mL) against multidrug-resistant tuberculosis. Moreover, dimer
7g (CC50: 62.5 μg/mL) also showed acceptable cytotoxicity against VERO cell line, could act as a lead
for further investigation. The enriched structure–activity relationship may pave the way to find more
effective anti-mycobacterial candidates.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
especially active against hard-to-treat TB such as drug-
resistant TB, multidrug-resistant TB (MDR-TB), and
extremely drug-resistant TB.
Isatin derivatives demonstrate diverse biological and
pharmacological properties such as anti-HIV [7,8],
anticancer [9], antimalarial [10], antibacterial [11], and anti-
TB activities [12–15] and occupy an important position in
medicinal chemistry. Recently, isatin dimers were found to
possess promising anti-TB potential and have been widely
studied [16–20]. The structure–activity relationship revealed
Mycobacterium tuberculosis (MTB), the main causative
agent of tuberculosis (TB), typically affects the lungs
(known as pulmonary TB) apart from other organs [1–3].
The first-line anti-TB agents, isoniazid (INH), rifampicin
(RIF), pyrazinamide (PZA), and ethambutol (EMB), are
the key weapons in the fight against TB, but the overuse
and misuse have triggered increased drug resistance [4–6].
Therefore, it is imperative to develop new anti-TB drugs
© 2018 Wiley Periodicals, Inc.

S.-J. Zhao, Z.-S. Lv, J.-L. Deng, F. Gao, G.-D. Zhang, and Z. Xu
Vol 000
that the linker between the two isatin motifs has great
influence on the anti-TB activity [18–20]. The previous
research indicated that the noncovalent interactions such as
hydrogen bonds play a pivotal role for compounds in exert
the anti-TB efficacy [18]. 1,2,3-Triazole and tetraethylene
glycol fragments have the potential to exert several
noncovalent
interactions,
and
1,2,3-triazole
and
tetraethylene glycol are eminent linkers [1,18]. Thus, the
isatin dimers tethered through 1,2,3-triazole-tetraethylene
glycol may have potential anti-TB activity.
Based on the aforementioned facts and as a continuous
research program, a new class of isatin dimers tethered
via 1,2,3-triazole-tetraethylene glycol was designed,
synthesized, and evaluated for their in vitro anti-TB
activity against MTB H37Rv and MDR-TB strains in this
study. Our primary objective was to identify optimized
linker between the two istain moieties and facilitate the
further development of these dimers. The illustration of
the design strategy is depicted in Figure 1.
Figure 1. Design strategy of 1,2,3-triazole-tetraethylene glycol tethered
isatin dimers. TB, tuberculosis. [Color figure can be viewed at
wileyonlinelibrary.com]
Scheme 1. Synthesis of 1,2,3-triazole-tetraethylene glycol tethered isatin dimers 7a–j. TEA, triethylamine.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and In Vitro Anti-mycobacterial Activities of 1,2,3-Triazole-
tetraethylene Glycol Tethered Isatin Dimers
RESULTS AND DISCUSSION
As presented in Table 1, all 1,2,3-triazole-tetraethylene
glycol tethered isatin dimers 7a–j showed weak to
moderate in vitro anti-mycobacterial activities against
MTB H37Rv and MDR-TB strains with MIC in a range
of from 64 to >512 μg/mL and were far less active than
the first-line anti-TB agents RIF (MIC: 0.39 μg/mL) and
INH (MIC: 0.05 μg/mL) against drug-sensitive MTB
H37Rv strain. The structure–activity relationship revealed
that introduction of electron-withdrawing ─F at C-5
position of isatin moiety could boost up the activity,
while electron-donating ─Me was detrimental to the
activity; for C-3 position, the relative contribution order
1,2,3-Triazole-tetraethylene glycol tethered isatin dimers
7a–j were synthesized according to the route described in
Scheme 1. Tetraethylene glycol 1 reacted with tosyl
chloride in presence of triethylamine provided
intermediate 2, which was then alkylated with C-5
substituted isatins 3 with potassium carbonate (K2CO3) as
base yielded the intermediate 4. Introduction of azido by
treatment of intermediate 4 with sodium azide gave the
precursor 5. Alkylation of C-5 substituted isatins 3 with
propargyl bromide in presence of K2CO3 yielded
intermediate 6, which was consequently used for the
synthesis of the desired 1,2,3-triazole-tetraethylene glycol
tethered isatin dimers 7a–c via click chemistry with
copper acetate (Cu(OAc)2) as catalyst. Finally,
condensations of targets 7a–c with the requested amine
hydrochlorides in the presence of sodium bicarbonate
provided targets 7d–j [13].
All 1,2,3-triazole-tetraethylene glycol tethered isatin
dimers 7a–j were evaluated for their in vitro anti-
mycobacterial activities against MTB H37Rv and MDR-TB
strains as well as cytotoxicity in VERO cell line, and the
results were presented in Table 1. The MDR-TB strain was
resistant to both INH and RIF. The minimum inhibitory
concentration (MIC) is defined as the lowest concentration
that inhibits the visible bacterial growth.
of
the
substituents
to
the
activity
was
─NOMe > ─NOEt > ─NNHCONH2 > ─O > ─NOH.
In particular, dimer 7g was found to be the most active
against the two tested strains with MIC of 128 and
64 μg/mL, which was eightfold more potent than INH
(MIC: 512 μg/mL) against MDR-TB.
The 1,2,3-triazole-tetraethylene glycol tethered isatin
dimers 7a–j were subsequently examined for toxicity in a
mammalian VERO cell line [13], and the results were
reported in Table 1. As shown in Table 1, all 1,2,3-
triazole-tetraethylene glycol tethered isatin dimers showed
acceptable cytotoxicity against VERO cell line with CC50
ranging from 62.5 to 500 μg/mL. The structure–
cytotoxicity relationship revealed that introduction of
electron-withdrawing ─F at C-5 position of isatin moiety
Table 1
Structures and anti-mycobacterial activities of isatin dimers 7a–j.
MIC (μg/mL)
Compound
R1
R2
MTB H37Rv
MDR-TB
CC50 (μg/mL)
7a
7b
7c
7d
7e
H
Me
F
H
F
H
F
H
F
O
O
O
NOH
NOH
512
512
256
>512
512
128
128
256
128
256
0.05
0.39
256
512
256
>512
>512
256
64
256
128
512
512
32
250
500
62.5
500
125
125
62.5
125
125
62.5
125
500
7f
NOMe
NOMe
NOEt
NOEt
NNHCONH2
7g
7h
7i
7j
INH
RIF
H
MDR-TB, multidrug-resistant tuberculosis; MIC, minimum inhibitory concentration; MTB, Mycobacterium tuberculosis.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S.-J. Zhao, Z.-S. Lv, J.-L. Deng, F. Gao, G.-D. Zhang, and Z. Xu
Vol 000
increased the cytotoxicity, while electron-donating ─Me
decreased the cytotoxicity; in general, introduction of
─NOMe, ─NOEt, and ─NOH seems to have no
significant influence on the cytotoxicity when compared
with the ketone isatin dimers, but installation of
─NNHCONH2 increased the cytotoxicity. The most
active isatin dimer 7g (CC50: 62.5 μg/mL) displayed
acceptable cytotoxicity, warrant further investigation.
C27H27N5O7: C, 60.78; H, 5.10; N, 13.13; found: C,
60.49; H, 5.01; N, 12.89.
5-Methyl-1-((1-(2-(2-(2-(2-(5-methyl-2,3-dioxoindolin-1-yl)
ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)
indoline-2,3-dione (7b).
Yellow solid, yield: 51%. 1H
NMR (400 MHz, DMSO-d6) 2.28, 2.29 (6H, s, 2 × Me),
3.41–3.49 (8H, m, 4 × ─CH2─), 3.65 (2H, t, ─CH2─),
3.73 (2H, t, ─CH2─), 3.83 (2H, t, ─CH2─), 4.44 (2H, t,
─CH2─), 4.98 (2H, s, ─CH2─), 7.12 (2H, d, Ar─H),
7.38 (2H, s, Ar─H), 7.51 (2H, d, Ar─H), 8.06 (1H, s,
triazole─H). ESI-MS m/z: 584 [M + Na]+. Elemental
Anal. Calcd (%) for C29H31N5O7: C, 62.02; H, 5.56; N,
CONCLUSIONS
12.47; found: C, 61.77; H, 5.47; N, 12.29.
In conclusion, a new set of 1,2,3-triazole-tetraethylene
glycol tethered isatin dimers was synthesized and
evaluated for their in vitro anti-mycobacterial activities
against MTB H37Rv and MDR-TB in this paper. All the
synthesized dimers displayed weak to moderate activities
against the tested two strains. The most active isatin
dimer 7g displayed considerable activity against
MDR-TB and acceptable cytotoxicity, warrant further
optimization.
5-Fluoro-1-((1-(2-(2-(2-(2-(5-fluoro-2,3-dioxoindolin-1-yl)
ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)
indoline-2,3-dione (7c).
Yellow solid, yield: 68%. 1H
NMR (400 MHz, DMSO-d6) 3.41–3.52 (8H, m,
4 × ─CH2─), 3.64 (2H, t, ─CH2─), 3.75 (2H, t,
─CH2─), 3.85 (2H, t, ─CH2─), 4.46 (2H, t, ─CH2─),
4.98 (2H, s, ─CH2─), 7.29 (2H, dd, Ar─H), 7.51 (2H,
dd, Ar─H), 7.56 (2H, td, Ar─H), 8.11 (1H, s,
triazole─H). ESI-MS m/z: 592 [M + Na]+. Elemental
Anal. Calcd (%) for C27H25F2N5O7: C, 56.94; H, 4.42;
N, 12.30; found: C, 56.71; H, 4.19; N, 12.12.
3-(Hydroxyimino)-1-((1-(2-(2-(2-(2-(3-(hydroxyimino)-2-
oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-
yl)methyl)indolin-2-one (7d). Yellow solid, yield: 77%. 1H
EXPERIMENTAL SECTION
The general procedure for preparing targets 7a–j. The
intermediates 5 and 6 were synthesized by the literature
reported procedures [15,18]. The mixture of intermediates
5 (10 mmol), 6 (10 mmol), and Cu(OAc)2 (0.5 mmol) in
DMF (10 mL) was stirred at room temperature for 12 h.
The mixture was concentrated under reduced pressure,
and the residue was purified by silica gel chromatography
eluted with PE:EA = 1:1 to give the desired isatin dimers
7a–c. To a mixture of isatin dimers 7a–c (1 mmol) and
NaHCO3 (6 mmol) in water (10 mL) and MeOH
(50 mL), the requested amine hydrochloride (3 mmol)
was added. The mixture was stirred at 50°C for 12 h.
After cooling to room temperature, the mixture was
extracted with EA (20 mL × 2). The combined organic
layers were washed with H2O (50 mL × 2) and brine
(50 mL) in sequence and dried over anhydrous Na2SO4.
After filtration, the filtrate was concentrated under
reduced pressure to give a residue that was purified by
silica gel chromatography eluted with PE:EA = 1:1 to
give the desired satin dimers 7d–j.
NMR (400 MHz, DMSO-d6) 3.38–3.48 (8H, m,
4 × ─CH2─), 3.63 (2H, t, ─CH2─), 3.73 (2H, t,
─CH2─), 3.83 (2H, t, ─CH2─), 4.45 (2H, t, ─CH2─),
4.96 (2H, s, ─CH2─), 7.05 (2H, d, Ar─H), 7.14 (2H, d,
Ar─H), 7.40 (2H, d, Ar─H), 8.02 (2H, t, Ar─H), 8.10
(1H, s, triazole─H), 13.44 (2H, s, 2 × NOH). ESI-MS m/
z: 586 [M + Na]+. Elemental Anal. Calcd (%) for
C27H29N7O7: C, 57.54; H, 5.19; N, 17.40; found: C,
57.37; H, 4.95; N, 17.21.
5-Fluoro-1-((1-(2-(2-(2-(2-(5-fluoro-3-(hydroxyimino)-2-
oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-
yl)methyl)-3-(hydroxyimino)indolin-2-one (7e).
Yellow
solid, yield: 71%. 1H NMR (400 MHz, DMSO-d6)
3.39–3.50 (8H, m, 4 × ─CH2─), 3.64 (2H, t, ─CH2─),
3.73 (2H, t, ─CH2─), 3.84 (2H, t, ─CH2─), 4.45 (2H, t,
─CH2─), 4.98 (2H, s, ─CH2─), 7.15 (2H, dd, Ar─H),
7.25 (2H, dd, Ar─H), 7.78 (2H, t, Ar─H), 8.11 (1H, s,
triazole─H), 13.85 (2H, s, 2 × NOH). ESI-MS m/z: 622
[M
+
Na]+. Elemental Anal. Calcd (%) for
C27H27F2N7O7: C, 54.09; H, 4.54; N, 16.35; found: C,
53.88; H, 4.29; N, 16.11.
1-((1-(2-(2-(2-(2-(2,3-Dioxoindolin-1-yl)ethoxy)ethoxy)
ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)indoline-2,3-dione
3-(Methoxyimino)-1-((1-(2-(2-(2-(2-(3-(methoxyimino)-2-
oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-
yl)methyl)indolin-2-one (7f). Yellow solid, yield: 53%. 1H
NMR (400 MHz, DMSO-d6) 3.37–3.48 (8H, m,
4 × ─CH2─), 3.64 (2H, t, ─CH2─), 3.74 (2H, t,
─CH2─), 3.83 (2H, t, ─CH2─), 4.24, 4.26 (6H, s,
2 × NOMe), 4.45 (2H, t, ─CH2─), 4.97 (2H, s,
─CH2─), 7.03 (2H, d, Ar─H), 7.12 (2H, d, Ar─H), 7.41
1
(7a).
Yellow solid, yield: 57%. H NMR (400 MHz,
DMSO-d6) 3.39–3.51 (8H, m, 4 × ─CH2─), 3.63 (2H, t,
─CH2─), 3.74 (2H, t, ─CH2─), 3.84 (2H, t, ─CH2─),
4.45 (2H, t, ─CH2─), 4.96 (2H, s, ─CH2─), 7.11 (2H, t,
Ar─H), 7.26 (2H, d, Ar─H), 7.54 (2H, d, Ar─H), 7.68
(2H, t, Ar─H), 8.10 (1H, s, triazole─H). ESI-MS m/z:
556 [M + Na]+. Elemental Anal. Calcd (%) for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and In Vitro Anti-mycobacterial Activities of 1,2,3-Triazole-
tetraethylene Glycol Tethered Isatin Dimers
(2H, d, Ar─H), 7.59–7.63 (2H, m, Ar─H), 8.06 (1H, s,
triazole─H). ESI-MS m/z: 614 [M + Na]+. Elemental
Anal. Calcd (%) for C29H33N7O7: C, 58.87; H, 5.62; N,
16.57; found: C, 58.65; H, 5.51; N, 16.43.
5-Fluoro-1-((1-(2-(2-(2-(2-(5-fluoro-3-(methoxyimino)-2-
oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-
agents RIF and INH were evaluated for their in vitro
activities against MTB H37Rv and MDR-TB by rapid
direct susceptibility test technique [13]. The wells of a
sterile 48-well plate were filled with 100-mL twofold
diluted tested compounds and 100-mL MTB H37Rv or
MDR-TB suspension containing 4 × 10À3 mg cells. Pure
medium replaced the diluted compounds in two wells as
the positive control of growth and deionized water
instead of the culture in other two wells as the negative
control of growth in the plates. The plates were covered
and sealed and then incubated at 37°C in a wet box. The
positive and negative control wells should show obvious
difference after 3 days. The MIC was determined by
observing the quantity and state of the cells in each test
well by a continuous visual high magnification system
and redetermined 7 days later. The MIC is defined as the
concentration of the compound required to give complete
inhibition of bacterial growth.
yl)methyl)-3-(methoxyimino)indolin-2-one (7g).
Yellow
solid, yield: 68%. 1H NMR (400 MHz, DMSO-d6)
3.41–3.51 (8H, m, 4 × ─CH2─), 3.64 (2H, t, ─CH2─),
3.74 (2H, t, ─CH2─), 3.85 (2H, t, ─CH2─), 4.46 (2H, t,
─CH2─), 4.98 (2H, s, ─CH2─), 7.14 (2H, dd, Ar─H),
7.21 (2H, dd, Ar─H), 7.67 (2H, t, Ar─H), 8.11 (1H, s,
triazole─H). ESI-MS m/z: 650 [M + Na]+. Elemental
Anal. Calcd (%) for C29H31F2N7O7: C, 55.50; H, 4.98;
N, 15.62; found: C, 55.26; H, 4.77; N, 15.39.
3-(Ethoxyimino)-1-((1-(2-(2-(2-(2-(3-(ethoxyimino)-2-
oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-
yl)methyl)indolin-2-one (7h). Yellow solid, yield: 51%. 1H
NMR (400 MHz, DMSO-d6) 1.32–1.41 (6H, m,
2 × NOCH2CH3), 3.39–3.49 (8H, m, 4 × ─CH2─), 3.63
(2H, t, ─CH2─), 3.74 (2H, t, ─CH2─), 3.84 (2H, t,
REFERENCES AND NOTES
─CH2─),
4.42–4.54
(6H,
m,
─CH2─
and
2 × NOCH2CH3), 4.96 (2H, s, ─CH2─), 7.05 (2H, t,
Ar─H), 7.15 (2H, d, Ar─H), 7.42 (2H, t, Ar─H), 7.84
(2H, d, Ar─H), 8.06 (1H, s, triazole─H). ESI-MS m/z:
642 [M + Na]+. Elemental Anal. Calcd (%) for
C31H37N7O7: C, 60.09; H, 6.02; N, 15.82; found: C,
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59.83; H, 5.91; N, 15.67.
3-(Ethoxyimino)-1-((1-(2-(2-(2-(2-(3-(ethoxyimino)-5-fluoro-
2-oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-
4-yl)methyl)-5-fluoroindolin-2-one (7i). Yellow solid, yield:
1
46%. H NMR (400 MHz, DMSO-d6) 1.34–1.42 (6H, m,
2 × NOCH2CH3), 3.40–3.51 (8H, m, 4 × ─CH2─), 3.64
(2H, t, ─CH2─), 3.75 (2H, t, ─CH2─), 3.84 (2H, t,
─CH2─),
4.43–4.52
(6H,
m,
─CH2─
and
2 × NOCH2CH3), 4.98 (2H, s, ─CH2─), 7.12–7.16 (2H,
m, Ar─H), 7.28 (2H, td, Ar─H), 7.62–7.65 (2H, m,
Ar─H), 8.11 (1H, s, triazole─H). ESI-MS m/z: 678
[M
+
Na]+. Elemental Anal. Calcd (%) for
C31H35F2N7O7: C, 56.79; H, 5.38; N, 14.95; found: C,
56.54; H, 5.12; N, 14.79.
2-(1-((1-(2-(2-(2-(2-(3-(2-Carbamoylhydrazono)-2-
oxoindolin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-
yl)methyl)-2-oxoindolin-3-ylidene)hydrazinecarboxamide
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(7j).
Yellow solid, yield: 39%. 1H NMR (400 MHz,
DMSO-d6) 3.39–3.48 (8H, m, 4 × ─CH2─), 3.64 (2H, t,
─CH2─), 3.73 (2H, t, ─CH2─), 3.84 (2H, t, ─CH2─),
4.46 (2H, t, ─CH2─), 4.96 (2H, s, ─CH2─), 7.11–7.20
(8H, m, 2 × NNHCONH2 and Ar─H), 7.35 (2H, t, Ar─H),
7.61 (2H, d, Ar─H), 8.06 (1H, s, triazole─H), 11.68 (2H,
s, 2 × NNHCONH2). ESI-MS m/z: 670 [M + Na]+.
Elemental Anal. Calcd (%) for C29H33N11O7: C, 53.78; H,
5.14; N, 23.79; found: C, 53.55; H, 4.93; N, 23.57.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet