Design, Synthesis, and In Vitro Anti-mycobacterial Activities of Propylene Tethered Benzofuran–Isatin Hybrids

Article abstract of DOI:10.1002/jhet.3387

A series of novel propylene tethered benzofuran–isatin hybrids 5a–j were designed, synthesized, and assessed for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug-resistant (MDR)-MTB strains

Full text of DOI:10.1002/jhet.3387

Month 2018 Design, Synthesis, and In Vitro Anti-mycobacterial Activities of Propylene
Tethered Benzofuran–Isatin Hybrids
*
Hua Guo
School of Chemistry and Life Science, Anshan Normal University, Anshan 114007, People’s Republic of China
*E-mail: m13704127672@163.com
Received June 3, 2018
DOI 10.1002/jhet.3387
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel propylene tethered benzofuran–isatin hybrids 5a–j were designed, synthesized, and
assessed for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv
and multidrug-resistant (MDR)-MTB strains. All hybrids exhibited promising anti-mycobacterial activities
against the tested two pathogens with minimum inhibitory concentration (MIC) ranging from 2 to
32 μg/mL, and the resistance index for a significant part of the hybrids was ≤1, indicating their potential
for the treatment of drug-resistant tuberculosis. Hybrid 5g (MIC: 2 and 4 μg/mL) was found to be the most
active against MTB H37Rv and MDR-MTB, which was eightfold and >32-fold more active than the first-
line anti-tuberculosis drugs rifampicin (MIC: 32 μg/mL) and isoniazid (MIC: >128 μg/mL) against
MDR-MTB, and it could act as a starting point for further optimization.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
Benzofuran and isatin derivatives occupy an important
position in medicinal chemistry, which is attributed to
their fascinating array of pharmacological properties [7–9].
Some benzofuran and isatin derivatives exhibited
excellent anti-TB activity [10–12], and the most
representative example is TAM16 (Fig. 1). TAM16 is an
inhibitor of polyketide synthase 13 with highly in vivo
anti-TB efficacy, which was comparable with the first-line
TB agent INH, both as a monotherapy and in combination
with RIF, and the frequency of resistance for TAM16 was
around 100-fold lower than INH [13]. Thus, hybridization
of the benzofuran and isatin pharmacophores into one
single molecule may provide more effective candidates.
Our previous research results demonstrated that the
linker between the two pharmacophores has significant
influence on the anti-TB activity [14–19], and some
hybrids tethered by propylene exhibited excellent
Tuberculosis (TB), which is an infectious disease
usually caused by Mycobacterium tuberculosis (MTB),
generally affects the lungs but can also affect other parts
of the body [1,2]. TB is one of the most deadly
infectious diseases, and 10.4 million people fell ill in
2016, resulted in 1.67 million deaths [3]. The drug-
susceptible TB can be cured by the first-line anti-TB
agents such as isoniazid (INH), rifampicin (RIF),
pyrazinamide, streptomycin, and ethambutol, but the
emergency and widely spread of drug-resistant TB,
multidrug-resistant TB (MDR-TB), and extremely drug-
resistant TB create an urgent need to develop novel, fast-
acting, and high-effective anti-TB drugs against both
drug-susceptible and drug-resistant strains of MTB to
prevent the spread of TB [4–6].
© 2018 Wiley Periodicals, Inc.

H. Guo
Vol 000
potency. Based on the aforementioned results and as a part
of an ongoing program to optimize benzofuran–isatin
hybrids as anti-TB agents, a series of propylene tethered
benzofuran–isatin hybrids were designed, synthesized,
and evaluated for their in vitro anti-TB activity against
MTB H37Rv and MDR-MTB in this study. Illustration of
the design strategy is depicted in Figure 2.
Figure 1. Chemical structure of TAM16.
RESULTS AND DISCUSSION
The benzofuran–isatin hybrids 5a–j were achieved by the
synthetic route depicted in Scheme 1. C-5 substituted isatins
were alkylated with 1,3-dibromopropane in presence
of potassium carbonate in DMF at room temperature
to provide the intermediates N-(2-bromopropyl)isatins
2a–c. Cyclization of ethyl 3-(4-methoxyphenyl)-3-
oxopropanoate
3 and benzoquinone catalysized by
copper(II) triflate afforded the benzofuran intermediate 4
[13]. Phenolic hydroxyl of benzofuran 4 was alkylated
with intermediates 2a–c with potassium carbonate as
base to give benzofuran–isatin hybrids 5a–c. Finally,
Figure 2. Illustration of the design strategy for propylene tethered
benzofuran–isatin hybrids. TB, tuberculosis. [Color figure can be
viewed at wileyonlinelibrary.com]
Scheme 1. Synthesis of propylene tethered benzofuran–isatin hybrids 5a–j.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Design, Synthesis, and In Vitro Anti-mycobacterial Activities of Propylene
Tethered Benzofuran–Isatin Hybrids
condensations of targets 5a–c with the requested amine
hydrochlorides yielded targets 5d–j.
their action mechanism may differ with the first-line anti-
TB agents.
The synthesized hybrids were screened for their
in vitro anti-mycobacterial activities against MTB
H37Rv and MDR-MTB strains. The minimum inhibitory
concentration (MIC) is defined as the lowest
concentration that inhibits the visible bacterial growth.
The MIC values of the compounds along with TAM16,
INH, and RIF for comparison were presented in
μg/mL in Table 1.
Among the synthesized benzofuran–isatin hybrids, the
hybrid 5g (MIC: 2 and 4 μg/mL) was found to be the
most active against MTB H37Rv and MDR-MTB strains,
which was eightfold and >32-fold more potent than the
first-line anti-TB agents RIF (MIC: 32 μg/mL) and INH
(MIC: >128 μg/mL) against MDR-MTB, warranting
further investigation.
The data revealed that all hybrids exhibited promising
activity with MIC in a range of 2 to 32 μg/mL against
MTB H37Rv and MDR-MTB but were far less potent
than TAM16 (MIC: <0.06 μg/mL). The structure–
activity relationship indicated that substituents on C-3
and C-5 positions of isatin motif have great influence
on the anti-mycobacterial activity, which was in
accordance with previous studies [14–17]: incorporation
of alkyloxyamines on C-3 position could enhance the
activity, while hydroxyimino was detrimental to the
activity, which may be attributed to hydroxyimino that
decreased the lipophilicity; introduction of halogen atoms
─Cl and ─Br was favorable to the activity, but electron-
donating ─Me disfavored the activity.
CONCLUSIONS
A new class of propylene tethered benzofuran–isatin
hybrids 5a–j was designed, synthesized, and evaluated
for their in vitro anti-mycobacterial activity in this paper.
All hybrids showed considerable activity, and some of
them were more potent than the first-line anti-TB agents
against MDR-MTB. The structure–activity relationship
was enriched, which may pave the way for further
optimization.
EXPERIMENTAL SECTION
Notably, the resistance index for a great part of
benzofuran–isatin hybrids was around 1, suggesting that
General procedure for the preparation of 5a–j.
The
mixture of C-5 substituted isatins (10 mmol), 1,3-
dibromopropane (20 mmol), and potassium carbonate
(40 mmol) in DMF (50 mL) was stirred at room
temperature overnight. After filtration, the filtrate was
concentrated under reduced pressure. The reside was
purified by silica gel chromatography eluted with
petroleum ether:EtOAc = 3:1 to give N-(3-bromopropyl)
isatin derivatives 2a–c as red solids.
Table 1
Structures and anti-mycobacterial activity of propylene tethered
benzofuran–isatin hybrids 5a–j.
To a mixture of 3-(4-methoxyphenyl)-3-oxopropanoate
3 (10 mmol) and Cu (OTf)2 (5 mol%, 0.11 g) in
anhydrous toluene (35 mL) was added dropwise a
solution of benzoquinone (7 mmol) dissolved in toluene
(5 mL) under N2 atmosphere. After addition, the mixture
was stirred at 110°C overnight. After cooling to room
temperature, the mixture was quenched with sat. NH4Cl
(20 mL) and then extracted with EtOAc (30 mL × 3).
The combined organic layers were washed with brine
(50 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by
silica gel chromatography eluted with petroleum ether:
EtOAc = 10:1 to give benzofuran 4 as a brown solid.
The mixture of compounds 2a–c (5 mmol), 4 (4 mmol),
and potassium carbonate (12 mmol) in DMF (50 mL) was
stirred at room temperature overnight. After filtration, the
filtrate was concentrated under reduced pressure. The
residue was purified by silica gel chromatography eluted
with petroleum ether:EtOAc to give benzofuran–isatin
hybrids 5a–c.
MIC (μg/mL)
Compd.
R1
Cl
Me
Br
Cl
Me
Br
Cl
Me
Br
H
R2
MTB H37Rv
MDR-MTBa
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
TAM16
INH
RIF
O
O
O
8
16
8
16
32
16
2
4
4
8
8
16
16
8
32
32
4
8
4
NOH
NOH
NOH
NOMe
NOMe
NOMe
NOEt
—
8
—
—
—
<0.06
0.12
0.5
<0.06
>128
32
—
—
INH, isoniazid; MDR-MTB, multidrug-resistant Mycobacterium tuber-
culosis; MIC, minimum inhibitory concentration; RIF, rifampicin.
aResistant to ethambutol, INH, and RIF.
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H. Guo
Vol 000
The mixture of 5a–c (1 mmol), sodium bicarbonate
(2 mmol), and hydroxylamine or methoxyamine or
ethoxyamine hydrochloride (1.2 mmol) in a mixture of
water (10 mL) and THF (30 mL) was stirred at 50°C for
3 h. After cooling to room temperature, the mixture was
extracted with EtOAc (20 mL × 3). The combined
organic layers were washed with brine (50 mL) and then
concentrated under reduced pressure. The residue was
purified by silica gel chromatography eluted with
petroleum ether:EtOAc = 3:1 to give the rest benzofuran–
isatin hybrids 5d–j.
for C29H25ClN2O7: C, 63.45; H, 4.59; N, 5.10; found: C,
63.33; H, 4.38; N, 4.96.
Ethyl
5-(3-(3-(hydroxyimino)-5-methyl-2-oxoindolin-1-yl)
propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
(5e). Yield: 64%. 1H NMR (400 MHz, DMSO-d6) δ 1.37
(3H, t, CO2CH2CH3), 2.12 (2H, t, ─CH2─), 3.89 (3H, s,
OCH3), 3.96 (2H, t, ─CH2─), 4.08 (2H, t, ─CH2─),
4.35 (2H, q, CO2CH2CH3), 6.94 (1H, d, Ar–H), 7.04–
7.18 (4H, m, Ar–H), 7.26 (1H, d, Ar–H), 7.58 (1H, d,
Ar–H), 7.68 (1H, d, Ar–H), 8.04 (2H, d, Ar–H), 13.45
(1H, brs, NOH). ESI-MS m/z: 529 [M + H]+. Elemental
Anal. Calcd (%) for C30H28N2O7: C, 68.17; H, 5.34; N,
Ethyl
5-(3-(5-chloro-2,3-dioxoindolin-1-yl)propoxy)-2-(4-
5.30; found: C, 67.97; H, 5.15; N, 5.03.
methoxyphenyl)benzofuran-3-carboxylate
(5a).
Yield:
Ethyl (Z)-5-(3-(5-bromo-3-(hydroxyimino)-2-oxoindolin-1-
yl)propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
(5f). Yield: 63%. 1H NMR (400 MHz, DMSO-d6) δ 1.37
47%. 1H NMR (400 MHz, DMSO-d6) δ 1.37 (3H, t,
CO2CH2CH3), 2.11 (2H, t, ─CH2─), 3.85 (3H, s,
OCH3), 3.89 (2H, t, ─CH2─), 4.12 (2H, t, ─CH2─),
4.36 (2H, q, CO2CH2CH3), 6.91 (1H, d, Ar–H), 7.05–
7.16 (4H, m, Ar–H), 7.35 (1H, t, Ar–H), 7.54 (1H, s, Ar–
H), 7.60 (1H, d, Ar–H), 7.96 (2H, d, Ar–H). ESI-MS m/
z: 534 [M + H]+, 536 [M + 2 + H]+. Elemental Anal.
Calcd (%) for C29H24ClNO7: C, 65.23; H, 4.53; N, 2.62;
found: C, 65.08; H, 4.31; N, 2.39.
(3H, t, CO2CH2CH3), 2.11 (2H, t, ─CH2─), 3.87 (3H, s,
OCH3), 3.92 (2H, t, ─CH2─), 4.11 (2H, t, ─CH2─),
4.32 (2H, q, CO2CH2CH3), 6.92 (1H, d, Ar–H), 7.08–
7.30 (4H, m, Ar–H), 7.63–7.68 (3H, m, Ar–H), 8.01 (2H,
d, Ar–H), 13.45 (1H, brs, NOH). ESI-MS m/z: 593
[M + H]+, 595 [M + 2 + H]+. Elemental Anal. Calcd (%)
for C29H25BrN2O7: C, 58.70; H, 4.25; N, 4.72; found: C,
58.46; H, 4.06; N, 4.68.
Ethyl 2-(4-methoxyphenyl)-5-(3-(5-methyl-2,3-dioxoindolin-
1-yl)propoxy)benzofuran-3-carboxylate (5b).
Yield: 27%.
Ethyl
5-(3-(5-chloro-3-(methoxyimino)-2-oxoindolin-1-yl)
1H NMR (400 MHz, DMSO-d6) δ 1.37 (3H, t,
CO2CH2CH3), 2.13 (2H, t, ─CH2─), 2.29 (3H, s,
─CH3), 3.86 (3H, s, OCH3), 3.92 (2H, t, ─CH2─),
4.12 (2H, t, ─CH2─), 4.34 (2H, q, CO2CH2CH3), 6.91
(1H, d, Ar–H), 7.03 (1H, d, Ar–H), 7.08–7.16 (3H, m,
Ar–H), 7.20 (1H, d, Ar–H), 7.57 (1H, d, Ar–H), 7.64
(1H, d, Ar–H), 7.96 (2H, d, Ar–H). ESI-MS m/z: 514
[M + H]+. Elemental Anal. Calcd (%) for C30H27NO7:
C, 70.16; H, 5.30; N, 2.73; found: C, 69.97; H, 5.13;
N, 2.52.
propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
(5g). Yield: 54%.1H NMR (400 MHz, DMSO-d6) δ 1.36
(3H, t, CO2CH2CH3), 2.09 (2H, t, ─CH2─), 3.86 (3H, s,
OCH3), 3.94 (2H, t, ─CH2─), 4.14 (2H, t, ─CH2─),
4.22 (3H, s, NOMe), 4.34 (2H, q, CO2CH2CH3), 6.98
(1H, d, Ar–H), 7.03–7.20 (4H, m, Ar–H), 7.26 (1H, t,
Ar–H), 7.58 (1H, d, Ar–H), 7.68 (1H, d, Ar–H), 8.02
(2H, d, Ar–H). ESI-MS m/z: 563 [M + H]+, 565
[M + 2 + H]+. Elemental Anal. Calcd (%) for
C30H27ClN2O7: C, 64.00; H, 4.83; N, 4.98; found: C,
63.79; H, 4.62; N, 4.87.
Ethyl
5-(3-(5-bromo-2,3-dioxoindolin-1-yl)propoxy)-2-(4-
(5c).
methoxyphenyl)benzofuran-3-carboxylate
Yield:
Ethyl
5-(3-(3-(methoxyimino)-5-methyl-2-oxoindolin-1-yl)
27%. 1H NMR (400 MHz, DMSO-d6) δ 1.38 (3H, t,
CO2CH2CH3), 2.10 (2H, t, ─CH2─), 3.85 (3H, s,
OCH3), 3.93 (2H, t, ─CH2─), 4.08 (2H, t, ─CH2─),
4.36 (2H, q, CO2CH2CH3), 6.93 (1H, d, Ar–H), 7.08–
7.22 (3H, m, Ar–H), 7.31 (1H, d, Ar–H), 7.60–7.68 (3H,
m, Ar–H), 7.96 (2H, d, Ar–H). ESI-MS m/z: 578
[M + H]+, 580 [M + 2 + H]+. Elemental Anal. Calcd (%)
for C29H24BrNO7: C, 60.22; H, 4.18; N, 2.42; found: C,
propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
1
(5h). Yield: 66%. H NMR (400 MHz, DMSO-d6) δ
1.37 (3H, t, CO2CH2CH3), 2.10 (2H, t, ─CH2─), 2.28
(3H, s, ─CH3), 3.86 (3H, s, OCH3), 3.90 (2H, t,
─CH2─), 4.12 (2H, t, ─CH2─), 4.24 (3H, s, NOMe),
4.37 (2H, q, CO2CH2CH3), 6.92 (1H, d, Ar–H), 7.04–
7.16 (4H, m, Ar–H), 7.25 (1H, d, Ar–H), 7.62 (1H, d,
Ar–H), 7.68 (1H, d, Ar–H), 8.01 (2H, d, Ar–H). ESI-
MS m/z: 543 [M + H]+. Elemental Anal. Calcd (%) for
C31H30N2O7: C, 68.62; H, 5.57; N, 5.16; found: C,
60.01; H, 4.07; N, 2.23.
Ethyl (Z)-5-(3-(5-chloro-3-(hydroxyimino)-2-oxoindolin-1-
yl)propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
(5d). Yield: 67%. 1H NMR (400 MHz, DMSO-d6) δ 1.38
68.41; H, 5.39; N, 4.91.
Ethyl (Z)-5-(3-(5-bromo-3-(methoxyimino)-2-oxoindolin-1-
yl)propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
(5i). Yield: 51%. 1H NMR (400 MHz, DMSO-d6) δ 1.37
(3H, t, CO2CH2CH3), 2.11 (2H, t, ─CH2─), 3.87 (3H, s,
OCH3), 3.93 (2H, t, ─CH2─), 4.16 (2H, t, ─CH2─),
4.24 (3H, s, NOMe), 4.37 (2H, q, CO2CH2CH3), 6.92
(1H, d, Ar–H), 7.06–7.28 (4H, m, Ar–H), 7.62–7.68 (3H,
m, Ar–H), 7.98 (2H, d, Ar–H). ESI-MS m/z: 607
(3H, t, CO2CH2CH3), 2.11 (2H, t, ─CH2─), 3.85 (3H, s,
OCH3), 3.89 (2H, t, ─CH2─), 4.12 (2H, t, ─CH2─),
4.36 (2H, q, CO2CH2CH3), 6.90 (1H, d, Ar–H), 7.04–
7.16 (3H, m, Ar–H), 7.28 (1H, t, Ar–H), 7.46 (1H, s, Ar–
H), 7.57 (1H, d, Ar–H), 7.90 (1H, d, Ar–H), 8.02 (2H, d,
Ar–H), 13.48 (1H, brs, NOH). ESI-MS m/z: 549
[M + H]+, 551 [M + 2 + H]+. Elemental Anal. Calcd (%)
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DOI 10.1002/jhet

Month 2018
Design, Synthesis, and In Vitro Anti-mycobacterial Activities of Propylene
Tethered Benzofuran–Isatin Hybrids
[M + H]+, 609 [M + 2 + H]+. Elemental Anal. Calcd (%)
REFERENCES AND NOTES
for C30H27BrN2O7: C, 59.32; H, 4.48; N, 4.61; found: C,
59.14; H, 4.29; N, 4.54.
Ethyl 5-(3-(3-(ethoxyimino)-2-oxoindolin-1-yl)propoxy)-2-(4-
methoxyphenyl)benzofuran-3-carboxylate (5j). Yield: 43%.
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1H NMR (400 MHz, DMSO-d6) δ 1.36–1.41 (6H, m,
NOCH2CH3 and CO2CH2CH3), 2.13 (2H, t, ─CH2─),
3.87 (3H, s, OCH3), 3.91 (2H, t, ─CH2─), 4.13 (2H, t,
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N, 4.87.
Minimum inhibitory concentration determination. The
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concentration of the compound required to give complete
inhibition of bacterial growth.
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FUNDING
This study was funded by Natural Science Fund of
Liaoning Province (2015020680).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet