Design, Synthesis, and in vitro Anti-mycobacterial Activities of Propylene-tethered Heteronuclear Bis-isatin Derivatives

Article abstract of DOI:10.1002/jhet.3185

A series of novel propylene-tethered heteronuclear bis-isatin derivatives were designed, synthesized, and assessed for their in vitro and anti-mycobacterial activities. All hybrids exhibited considerable antibacterial and anti-mycobacterial activities against Mycobacterium tuberculosis H37Rv and multi-drug-resistant tuberculosis (MDR-TB) with minimum inhibitory concentration (MIC) ranging from 16 to 256?μg/mL. In particular, the heteronuclear bis-isatin 4i (MIC: 25 and 16?μg/mL) was most active against M.?tuberculosis H₃₇Rv and MDR-TB strains, which was fourfold and greater than eightfold more potent than the first-line anti-tubercular agents rifampicin (MIC: 64?μg/mL) and isoniazid (MIC: >128?μg/mL) against MDR-TB, could act as a lead for further optimization.

Full text of DOI:10.1002/jhet.3185

Month 2018 Design, Synthesis, and in vitro Anti-mycobacterial Activities of Propylene-
tethered Heteronuclear Bis-isatin Derivatives
b
b
b
Xue Hua,a
*
Guifu Zhang, Deqing Zhang, and Yequn Wu
aChemistry Teaching Group and Fundamental Medical Department, Shijiazhuang Medical College, Shijiazhuang, Hebei,
People’s Republic of China
bSchool of Nuclear Technology and Chemistry and Biology, Hubei University of Science and Technology, Xianning,
Hubei, People’s Republic of China
*
*E-mail: 517584801@qq.com
Received January 15, 2018
DOI 10.1002/jhet.3185
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel propylene-tethered heteronuclear bis-isatin derivatives were designed, synthesized, and
assessed for their in vitro and anti-mycobacterial activities. All hybrids exhibited considerable antibacterial
and anti-mycobacterial activities against Mycobacterium tuberculosis H37Rv and multi-drug-resistant
tuberculosis (MDR-TB) with minimum inhibitory concentration (MIC) ranging from 16 to 256 μg/mL. In
particular, the heteronuclear bis-isatin 4i (MIC: 25 and 16 μg/mL) was most active against M. tuberculosis
H37Rv and MDR-TB strains, which was fourfold and greater than eightfold more potent than the first-line
anti-tubercular agents rifampicin (MIC: 64 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR-TB,
could act as a lead for further optimization.
J. Heterocyclic Chem., 00, 00 (2018).
© 2018 Wiley Periodicals, Inc.

X. Hua, G. Zhang, D. Zhang, and Y. Wu
Vol 000
INTRODUCTION
As an ongoing research program and to continue our
effort to develop new anti-TB agents, a series of novel
propylene-tethered heteronuclear bis-isatin derivatives
were designed, synthesized, and screened for their
in vitro anti-mycobacterial activities. Our primary
objective was to optimize the potency of these
heteronuclear bis-isatin derivatives against MTB. A
preliminary structure–activity relationship (SAR) study is
also explored to facilitate the further development of bis-
isatin derivatives.
Tuberculosis (TB), which is the ninth leading cause
of death globally and the leading cause from a single
infectious agent, is caused predominately by
Mycobacterium tuberculosis (MTB) and generally
affects the lung [1–6]. According to the World Health
Organization estimation, around 10.4 million people fell
ill with TB in the year 2016, which led to 1.67 million
deaths [5]. Drug-resistant TB (DR-TB) such as multi-
DR TB (MDR-TB) is a continuing threat to human, and
there were 600,000 new cases with resistance to
rifampicin (RIF), of which 490,000 were MDR-TB [5].
Based on the previous facts, there is an urgent need to
develop new and more effective agents with great
potency against both drug-sensitive and drug-resistant
MTB organisms.
Isatin (1H-indole-2,3-dione, Fig. 1) derivatives exhibited
diverse biological properties such as antibacterial [7],
anticancer [8], antimalarial [9], and anti-TB activities
[10–15], and some isatin-based drugs such as sunitinib
and nintedanib have been approved for clinical use for the
treatment of various diseases [16]. The wide spectrum of
biological activities combined with the successful
application in clinical practice making isatin an important
prototype in drug development.
When compared with the corresponding monomeric
compounds, the dimeric compounds often displayed
some unique profiles such as enhanced biological
activities [17,18]. Our previous results demonstrated that
bis-isatin derivatives endowed with potential antibacterial
[19] and anti-TB activities [20], so bis-isatin dimers are
a reasonable choice to develop new anti-TB agents.
Currently, most of the studies focused on the
homonuclear bis-isatin derivatives, while heteronuclear
bis-isatin derivatives may have some unique properties
because they are bearing two different isatin moieties.
Thus, it is worth to investigate the biological activities
of heteronuclear bis-isatin derivatives.
RESULTS AND DISCUSSION
The desired bis-isatin derivatives 4a-j were obtained by
the synthetic route depicted in Scheme 1. Isatin was
alkylated with 1,3-dibromopropane with potassium
carbonate as base in DMF at room temperature to provide
the N-(2-bromopropyl) isatin 2 (yield: 63%) by literature
methods [21,22]. 5-Fluoroisatin was reacted with
methoxyamine or ethoxyamine hydrochloride in the
presence of potassium carbonate yielded 5-fluoro-
3-(methoxy/ethoxylimino) isatins 3a,b (yield: 78% and
69%) [23]. The intermediates 2 and 3a,b were utilized
for the synthesis of desired heteronuclear bis-isatin
derivatives 4a,b (yield: 74% and 58%) with potassium
carbonate as base [24]. Finally, condensations of targets
4a,b with hydroxylamine or methoxyamine or
ethoxyamine hydrochloride in the presence of sodium
bicarbonate provided targets 4c-j (23–79%) [25].
All heteronuclear bis-isatin derivatives 4a-j were
evaluated for their in vitro anti-mycobacterial activities
against MTB H37Rv and MDR-TB strains, and the
minimum inhibitory concentration (MIC) is obtained
from three independent experiments, defined as the
concentration of the compound required to give
complete inhibition of bacterial growth. The preliminary
results were listed in Table 1. The MDR-TB strain was
resistant to isoniazid, RIF and ethambutol.
The results showed that all propylene-tethered
heteronuclear bis-isatin derivatives 4a-j showed
considerable anti-mycobacterial activities against MTB
H37Rv and MDR-TB strains with MIC ranging from 50
to 256 μg/mL. The SAR revealed that bis-isatin
derivatives with mono-sunstituted group at C-3 position
of isatin motif were more active than the corresponding
bis-substituted analogs, and the relative contribution of
the substituents to the activity was as follows: O >
NNHCSNH2 > NOMe > NOEt > NOH. It is worth to
notice that the resistance index for the majority of bis-
isatin derivatives was around 1, suggesting they may be
bearing novel action mechanism.
Among the synthesized homonuclear and heteronuclear
bis-isatin derivatives, the heteronuclear bis-isatin 4a
Figure 1. Chemical structures of isatin and heteronuclear bis-isatin
derivatives. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Heteronuclear Bis-isatin Derivatives
Scheme 1. Synthesis of bis-isatin derivatives 4a-j.
enriched SAR paves the way for further development of
this kind of bis-isatin derivatives.
Table 1
Structures and anti-mycobacterial activities of hybrids 4a-j
EXPERIMENTAL SECTION
The general procedure for preparing targets 4a-j. The
mixture of isatin (10 mmol), 1,3-dibromopropane
(30 mmol), and potassium carbonate (50 mmol) in DMF
(100 mL) was stirred at room temperature for 3 days and
then filtered. The filtrate was concentrated under reduced
pressure to give crude product which was purified by
silica gel chromatography eluted with PE:EA = 2:1 to
give N-(2-bromopropyl) isatin 2 (yield: 63%) as a red solid.
5-Fluoroisatin (10 mmol) and potassium carbonate
(30 mmol) in a mixture of water (30 mL) and THF
(100 mL), methoxyamine or ethoxyamine hydrochloride
(12 mmol) were added. The mixture was stirred at 50°C
for 12 h. After cooling to room temperature, the mixture
was extracted with EA (100 mL × 2). The combined
organic layers were washed with H2O (100 mL × 2) and
brine (100 mL) in sequence and dried over Na2SO4.
After filtration, the filtrate was concentrated under
reduced pressure to give crude intermediates 3a,b, which
were used directly without further purification.
MIC (μg/mL)
MTB
MDR-
Compound
R1
R2
H37Rv
TB
4a
4b
4c
4d
4e
4f
4 g
4 h
4i
NOMe
NOEt
NOMe
NOMe
NOMe
O
O
NOMe
NOEt
NOH
50
64
64
100
100
200
200
100
100
100
200
100
128
128
256
128
128
256
256
64
NOMe NNHCSNH2
NOEt
NOEt
NOEt
NOEt
NOMe
NOEt
NOH
4j
NNHCSNH2
(MIC: 50 and 64 μg/mL) was most active against MTB
H37Rv and MDR-TB strains and has the potential for
further investigations.
The mixture of intermediates 2 (1.2 mmol), 3a,b
(1 mmol), and potassium carbonate (3 mmol) in DMF
(10 mL) was stirred at room temperature overnight.
TLC (PE:EA = 1:1) indicated the reaction completed.
After filtration, the filtrate was concentrated under
reduced pressure, and the residue was purified by silica
gel chromatography eluted with PE:EA = 2:1 to give
the desired heteronuclear bis-isatin derivatives 4a,b.
The mixture of 4a,b (1 mmol), sodium bicarbonate
(3 mmol), and hydroxylamine or methoxyamine or
CONCLUSIONS
In summary, a new class of novel propyl-tethered
heteronuclear bis-isatin derivatives was designed,
synthesized, and evaluated for their in vitro anti-
mycobacterial activities against MTB H37Rv and MDR-
TB in this paper. All bis-isatin derivatives exhibited
potential activities against the tested strains, and the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

X. Hua, G. Zhang, D. Zhang, and Y. Wu
Vol 000
ethoxyamine hydrochloride (1.2 mmol) in water (10 mL)
and THF (50 mL) was stirred at 50°C for 12 h. After
cooling to room temperature, the mixture was extracted
with EA (100 mL × 2). The combined organic layers
were washed with H2O (100 mL × 2) and brine
(100 mL) in sequence and dried over Na2SO4. After
filtration, the filtrate was concentrated under reduced
pressure to give a residue, which was purified by silica
gel chromatography eluted with PE:EA = 2:1 to give the
4.14, 4.22 (3H, s, NOMe), 7.12 (1H, t, Ar-H), 7.14–7.24
(2H, m, Ar-H), 7.35 (1H, td, Ar-H), 7.54 (1H, dd, Ar-H),
7.61–7.69 (2H, m, Ar-H), 13.28 (1H, s, NOH). ESI-MS
m/z: 397 [M + H]+. Elemental Anal. Calcd (%) for
C20H17FN4O4: C, 60.60; H, 4.32; N, 14.13; Found: C,
60.39; H, 4.15; N, 13.88.
2-(1-(3-(5-fluoro-3-(methoxyimino)-2-oxoindolin-1-yl)
propyl)-2-oxoindolin-3-ylidene)
(4f).
hydrazinecarbothioamide
Yellow solid, yield: 23%. Mp: 199–201°C. 1H
NMR (400 MHz, DMSO-d6) δ 1.91–1.99 (2H, m, -CH2-),
3.72–3.84 (4H, m, -CH2CH2-), 4.23 (3H, s, NOMe), 7.12
(1H, t, Ar-H), 7.19–7.24 (2H, m, Ar-H), 7.36 (1H, td, Ar-
H), 7.56 (1H, dd, Ar-H), 7.62 (1H, td, Ar-H), 7.68 (1H,
dd, Ar-H), 8.76, 9.10 (1H, s, NNHCSNH2), 12.20 (1H, s,
NNHCSNH2). ESI-MS m/z: 455 [M + H]+. Elemental
Anal. Calcd (%) for C21H19FN6O3S: C, 55.50; H, 4.21; N,
18.49; Found: C, 55.31; H, 4.07; N, 18.27.
3-(ethoxyimino)-5-fluoro-1-(3-(3-(methoxyimino)-2-
desired heteronuclear bis-isatin derivatives 4c-j.
1-1-(3-(5-Fluoro-3-(methoxyimino)-2-oxoindolin-1-yl)
propyl)indoline-2,3-dione (4a). Yellow solid, yield: 74%.
Mp: 181–183°C. 1H NMR (400 MHz, DMSO-d6) δ 1.91–
1.99 (2H, m, -CH2-), 3.74–3.83 (4H, m, -CH2CH2-), 4.15,
4.23 (3H, s, NOMe), 7.12 (1H, t, Ar-H), 7.18–7.24 (2H,
m, Ar-H), 7.35 (1H, td, Ar-H), 7.54 (1H, dd, Ar-H), 7.63
(1H, td, Ar-H), 7.67 (1H, dd, Ar-H). ESI-MS m/z: 382
[M + H]+. Elemental Anal. Calcd (%) for C20H16FN2O4:
C, 62.99; H, 4.23; N, 11.02; Found: C, 62.76; H, 4.07; N,
oxoindolin-1-yl)propyl)indolin-2-one (4g).
Yellow solid,
yield: 66%. Mp: 144–146°C. 1H NMR (400 MHz,
DMSO-d6) δ 1.34 (3H, t, NOCH2CH3), 1.92–1.99 (2H,
m, -CH2-), 3.74–3.83 (4H, m, -CH2CH2-), 4.21 (3H, s,
NOMe), 4.46 (2H, q, NOCH2CH3), 7.11 (1H, t, Ar-H),
7.18–7.23 (2H, m, Ar-H), 7.30–7.36 (2H, m, Ar-H), 7.52
(1H, dd, Ar-H), 7.62–7.66 (2H, m, Ar-H). ESI-MS m/z:
10.87.
1-(3-(3-(Ethoxyimino)-5-fluoro-2-oxoindolin-1-yl)propyl)
indoline-2,3-dione (4b).
Yellow solid, yield: 58%. Mp:
1
130–132°C. H NMR (400 MHz, DMSO-d6) δ 1.36 (3H,
t, NOCH2CH3), 1.92–1.99 (2H, m, -CH2-), 3.74–3.83
(4H, m, -CH2CH2-), 4.48 (2H, q, NOCH2CH3), 7.10 (1H,
t, Ar-H), 7.17–7.25 (2H, m, Ar-H), 7.29–7.37 (2H, m,
Ar-H), 7.52 (1H, dd, Ar-H), 7.61–7.67 (2H, m, Ar-H).
ESI-MS m/z: 396 [M + H]+. Elemental Anal. Calcd (%)
for C21H18FN3O4: C, 63.79; H, 4.59; N, 10.63; Found:
425 [M
+
H]+. Elemental Anal. Calcd (%) for
C22H21FN4O4: C, 62.26; H, 4.99; N, 13.20; Found: C,
62.13; H, 4.73; N, 13.04.
3-(ethoxyimino)-1-(3-(3-(ethoxyimino)-2-oxoindolin-1-yl)
propyl)-5-fluoroindolin-2-one (4h).
Yellow solid, yield:
C, 63.51; H, 4.38; N, 10.39.
1-5-Fluoro-3-(methoxyimino)-1-(3-(3-(methoxyimino)-2-
1
66%. Mp: 144–146°C. H NMR (400 MHz, DMSO-d6) δ
1.31–1.37 (6H, m, 2 × NOCH2CH3), 1.91–1.99 (2H, m, -
CH2-), 3.74–3.82 (4H, m, -CH2CH2-), 4.39–4.45 (4H, m,
2 × NOCH2CH3), 7.09 (1H, t, Ar-H), 7.20–7.25 (2H, m,
Ar-H), 7.29–7.34 (2H, m, Ar-H), 7.50 (1H, dd, Ar-H),
7.62–7.66 (2H, m, Ar-H). ESI-MS m/z: 439 [M + H]+.
oxoindolin-1-yl)propyl)indolin-2-one (4c).
Yellow solid,
yield: 79%. Mp: 152–153°C. 1H NMR (400 MHz,
DMSO-d6) δ 1.92–1.99 (2H, m, -CH2-), 3.74–3.82 (4H,
m, -CH2CH2-), 4.09, 4.17 (6H, s, 2 × NOMe), 7.11 (1H,
t, Ar-H), 7.18–7.23 (2H, m, Ar-H), 7.32 (1H, td, Ar-H),
7.53 (1H, dd, Ar-H), 7.62 (1H, td, Ar-H), 7.67 (1H, dd,
Ar-H). ESI-MS m/z: 411 [M + H]+. Elemental Anal.
Elemental Anal. Calcd (%) for C23H23FN4O4: C, 63.00;
H, 5.29; N, 12.78; Found: C, 62.82; H, 5.03; N, 12.54.
3-(ethoxyimino)-5-fluoro-1-(3-(3-(hydroxyimino)-2-
Calcd (%) for C21H19FN4O4: C, 61.46; H, 4.67; N,
13.65; Found: C, 61.19; H, 4.48; N, 13.52.
1-(3-(3-(Ethoxyimino)-2-oxoindolin-1-yl)propyl)-5-fluoro-3-
oxoindolin-1-yl)propyl)indolin-2-one (4i).
Yellow solid,
yield: 54%. Mp: 136–135°C. 1H NMR (400 MHz,
DMSO-d6) δ 1.35 (3H, t, NOCH2CH3), 1.91–1.99 (2H,
m, -CH2-), 3.74–3.82 (4H, m, -CH2CH2-), 4.42 (2H, t,
NOCH2CH3), 7.10 (1H, t, Ar-H), 7.23–7.26 (2H, m, Ar-
H), 7.29–7.35 (2H, m, Ar-H), 7.54 (1H, dd, Ar-H), 7.62–
7.68 (2H, m, Ar-H). ESI-MS m/z: 411 [M + H]+.
Elemental Anal. Calcd (%) for C21H19FN4O4: C, 61.46;
(methoxyimino)indolin-2-one (4d).
Yellow solid, yield:
1
47%. Mp: 125–127°C. H NMR (400 MHz, DMSO-d6) δ
1.36 (3H, t, NOCH2CH3), 1.91–1.96 (2H, m, -CH2-),
3.75–3.81 (4H, m, -CH2CH2-), 4.09, 4.22 (3H, s,
NOMe), 4.48 (2H, q, NOCH2CH3), 7.12 (1H, t, Ar-H),
7.17–7.23 (2H, m, Ar-H), 7.31 (1H, td, Ar-H), 7.53 (1H,
dd, Ar-H), 7.62 (1H, td, Ar-H), 7.68 (1H, dd, Ar-H). ESI-
MS m/z: 425 [M + H]+. Elemental Anal. Calcd (%) for
C22H21FN4O4: C, 62.26; H, 4.99; N, 13.20; Found: C,
H, 4.67; N, 13.65; Found: C, 61.28; H, 4.49; N, 13.46.
2-(1-(3-(3-(ethoxyimino)-5-fluoro-2-oxoindolin-1-yl)propyl)-
2-oxoindolin-3-ylidene) hydrazinecarbothioamide (4j).
Yellow solid, yield: 29%. Mp: 174–176°C. 1H NMR
(400 MHz, DMSO-d6) δ 1.91–1.99 (2H, m, -CH2-),
3.73–3.84 (4H, m, -CH2CH2-), 4.21 (3H, s, NOMe), 7.13
(1H, t, Ar-H), 7.18–7.23 (2H, m, Ar-H), 7.38 (1H, td, Ar-
H), 7.49 (1H, dd, Ar-H), 7.58 (1H, td, Ar-H), 7.64 (1H,
62.03; H, 4.76; N, 13.11.x
5-fluoro-1-(3-(3-(hydroxyimino)-2-oxoindolin-1-yl)propyl)-
3-(methoxyimino)indolin-2-one (4e).
61%. Mp: 196–198°C. H NMR (400 MHz, DMSO-d6) δ
1.91–1.99 (2H, m, -CH2-), 3.74–3.83 (4H, m, -CH2CH2-),
Yellow solid, yield:
1
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DOI 10.1002/jhet

Month 2018
Heteronuclear Bis-isatin Derivatives
[6] Xu, Z.; Gao, C.; Ren, Q. C.; Song, X. F.; Feng, L. S.; Lv, Z. S.
Eur J Med Chem 2017, 139, 429.
dd, Ar-H), 8.79, 9.12 (1H, s, NNHCSNH2), 12.18 (1H, s,
NNHCSNH2). ESI-MS m/z: 469 [M + H]+. Elemental
Anal. Calcd (%) for C22H21FN6O3S: C, 56.40; H, 4.52;
N, 17.94; Found: C, 56.13; H, 4.37; N, 17.69.
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Minimum inhibitory concentration determination. The
bis-isatin derivatives 4a-j along with the references RIF
and isoniazid were evaluated for their in vitro activities
against MTB H37Rv and MDR-TB via rapid direct
susceptibility test technique [11,12]. 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
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 re-
determined 7 days later. The MIC is defined as the
concentration of the compound required to give complete
inhibition of bacterial growth.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet