Design, synthesis and biological evaluation of novel 2-sulfonylindoles as potential anti-inflammatory therapeutic agents for treatment of acute lung injury

Article abstract of DOI:10.1016/j.ejmech.2018.10.014

Acute lung injury (ALI) is primarily driven by inflammation that severely impacts lung function. Novel 2-sulfonylindoles were recently shown to exhibit anti-inflammatory activity through the inhibition of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. Here, we synthesized 31 compounds which contained 2-sulfonylindole structure. The compounds 8a, 9g, 9h and 9k exhibited dose-dependent anti-inflammatory activity in vitro. Structural-activity relationship analysis revealed that the introduction of sulfonyl group in indole nucleus may be successful to obtain new anti-inflammatory structures and leads. The compounds 9h and 9k also decreased liposaccharide (LPS)-induced IL-6, IL-1β and vascular cell adhesion molecule-1 (VCAM-1) mRNA expression, both in vitro and in an in vivo model of ALI. Furthermore, the compounds 9h and 9k at a high dose (20 mg/kg) significantly protected against LPS-induced ALI in mice. These results show that compounds 9h and 9k could be a promising lead structure for the treatment of ALI.

Full text of DOI:10.1016/j.ejmech.2018.10.014

Accepted Manuscript
Design, synthesis and biological evaluation of novel 2-sulfonylindoles as potential
anti-inflammatory therapeutic agents for treatment of acute lung injury
Qinqin Xia, Xiaodong Bao, Chuchu Sun, Di Wu, Xiaona Rong, Zhiguo Liu, Yugui Gu,
Jianmin Zhou, Guang Liang
PII:
S0223-5234(18)30876-6
10.1016/j.ejmech.2018.10.014
EJMECH 10800
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 17 July 2018
Revised Date: 11 September 2018
Accepted Date: 7 October 2018
Please cite this article as: Q. Xia, X. Bao, C. Sun, D. Wu, X. Rong, Z. Liu, Y. Gu, J. Zhou, G. Liang,
Design, synthesis and biological evaluation of novel 2-sulfonylindoles as potential anti-inflammatory
therapeutic agents for treatment of acute lung injury, European Journal of Medicinal Chemistry (2018),
doi: https://doi.org/10.1016/j.ejmech.2018.10.014.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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Graphical abstract:
R1
R1
O
S
O
N
N
+
R3
R2
S
R2
R3
ONa
O
Sulfonylindole derivatives
1a-10e
CH3
CH3
O
S
O
S
N
N
CF3
O
O
Compound 9h
Compound 9k
IC50 IL-6 = 8.01 µM
IC50 TNf-α = 1.82 µM
IC50 IL-6 = 3.08 µM
IC50 TNf-α = 1.10 µM

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Design, synthesis and biological evaluation of novel 2-sulfonylindoles
as potential anti-inflammatory therapeutic agents for treatment of
acute lung injury
a, 1
a
Qinqin Xia
Xiaodong Bao a, c, 1, Chuchu Sun a, 1, Di Wu , Xiaona Rong b, Zhiguo
Liu a, Yugui Gu b, Jianmin Zhou a, Guang Liang a, *
a Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou, Zhejiang, 325035, China
b College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
Zhejiang, 325035, China
c Department of Pharmacy, Jinhua People’s Hospital, Jinhua, Zhejiang, 321000,
China
1 These authors contribute equally to this work.
* Corresponding authors:
Guang Liang, Ph.D, Professor
Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou
Medical University. 1210 University Town, Wenzhou, Zhejiang 325035, China
Tel: (+86)-577-86699396; Fax: (+86)-577-86699396.
E-mail: wzmcliangguang@163.com

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Abstract:
Acute lung injury (ALI) is primarily driven by inflammation that severely
impacts lung function. Novel 2-sulfonylindoles were recently shown to exhibit
anti-inflammatory activity through the inhibition of tumor necrosis factor-α (TNF-α)
and interleukin-6 (IL-6) production. Here, we synthesized 31 compounds which
contained 2-sulfonylindole structure. The compounds 8a, 9g, 9h and 9k exhibited
dose-dependent anti-inflammatory activity in vitro. Structural-activity relationship
analysis revealed that the introduction of sulfonyl group in indole nucleus may be
successful to obtain new anti-inflammatory structures and leads. The compounds 9h
and 9k also decreased liposaccharide (LPS)-induced IL-6, IL-1β and vascular cell
adhesion molecule-1 (VCAM-1) mRNA expression, both in vitro and in an in vivo
model of ALI. Furthermore, the compounds 9h and 9k at a high dose (20 mg /kg)
significantly protected against LPS-induced ALI in mice. These results show that
compounds 9h and 9k could be a promising lead structure for the treatment of ALI.
Keywords: 2-sulfonylindoles, SAR, macrophage, anti-inflammatory, acute lung
injury.

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1. Introduction
Acute lung injury (ALI) is caused by various direct or indirect insults which damage
alveolar epithelial and capillary endothelial cells, leading to pulmonary edema and
respiratory failure.[1-3] Mortality associated with ALI remains high (40%).[4] In
recent years, anti-inflammatory treatment has emerged as a reasonable approach to
managing patients with ALI.[5] Targeting of two key pro-inflammatory cytokines,
tumor necrosis factor alpha (TNF-α) and lnterleukin-6 (IL-6),[3, 6, 7] has been
successful in providing an effective strategy for treatment of inflammatory diseases.[8]
Therefore, the need to develop drugs that inhibit the production and release of
pro-inflammatory cytokines for treatment of ALI is urgent.
The indole nucleus is a very important element of naturally occurring compounds and
pharmacologically important agents. In the clinic, indole-containing agents have a
wide range of applications including anti-inflammatory,[9] antibacterial,[10, 11]
anti-convulsion [12] and antitumor [13]. The diversity of indoles has drawn the
attention of pharmacologists and chemists, and a large number of compounds
containing indole structures have been studied for treatment of specific diseases
(Figure 1). Indomethacin (a),[14] an inhibitor of cyclooxygenase-2 (COX-2), is well
documented to show anti-inflammatory activity. Based on the structure of indole, a
series compounds are explored as anti-inflammatory drugs such as PD-146176 (b)[15]
and Tenidap (c).[16] However, their potential role in the inhibition of cytokine release
has not been reported. We hypothesized that the indole ring is the structure that
contributes to the anti-inflammatory activity of the compounds.
Sulfonyl groups have been introduced to small molecules to maintain or enhance the
biological activity. With increasing the hydrogen bonding interaction between the
drug and the target, the introduction of sulfonyl groups may potentially increase the
biological activity.[17] The introduction of sulfonyl groups can also improve the
metabolic stability of drugs,[18] prolong the duration of action[19] and increase
bioavailability.[20] Sulfonyl groups in some drugs can also increase the polarity of the

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molecules and thus reduce human Ether-a-go-go Related Gene (hERG) toxicity.[21]
Currently, many drugs used clinically contain sulfonyl groups (Figure 1). For example,
Celecoxib (d)[22] and Nimesulide (e)[23] are two very successful nonsteroidal
anti-inflammatory drugs (NSAID). Tryptamine sulfonamides (f) [24] have also shown
inhibitory potency against reticulocyte 12/15-lipoxygenase.
With our continuing interest in the development of novel anti-inflammatory
therapeutics, we assumed that 2-sulfonylindoles compounds may play an important
functional role (Figure 1). Utilizing simple and efficient chemical synthesis methods,
we have synthesized 31 compounds which contain a 2-sulfonylindole structure.
Compared to indomethacin, some of 2-sulfonylindoles showed greater inhibition of
TNF-α
and
IL-6
release.
Compounds
and
9h
9k
(2-((4-(tert-butyl)phenyl)sulfonyl)-1-methyl-indole)
(1-methyl-2-((4-(trifluoromethyl)phenyl)sulfonyl)-indole) were further tested as novel
anti-inflammatory agents for treatment of ALI in cultured cells and an animal model
of ALI.
Please insert Figure 1 here
2. Chemistry
In order to obtain the 2-methylsulfonyl indoles, we have adopted an uncommon and
convenient method for synthesis as shown in Scheme 1. The N-methyl indoles 2a-i
were prepared using NaH as catalyst and CH3I as a nucleophilic substitution reagent
from 1a-i, purchased from Energy Chemical Company (Shanghai, China). The 2j
were prepared using the NaH as catalyst and C4H9Br as a nucleophilic substitution
reagent from 1a. Compounds 2k and 2l were also purchased from Energy Chemical
Company. Compared with the traditional sulfonylation, this method yields stable
sulfonic acid sodium salt. We have utilized a simple method to get a series of sodium
sulfinates as shown in Scheme 2. For preparation of sodium sulfinates, we used
differently substituted sulfonyl chlorides 3a-l, sodium sulfite and sodium bicarbonate
at 80°C in distilled water. The residue was further extracted with ethanol and the

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corresponding aryl sulfinates 4a-l were obtained with20%-80% yield. As shown in
Scheme 3, in a solution of 1H-indoles, sodium aryl sulfinates, I2 and tert-butyl
hydroperoxide in C2H5OH were used at 80°C for 12 h to obtain compounds 5a-e. It is
remarkable that the sulfonylation reaction occurred exclusively at the C-2 position.
However, we could use the same to get compounds 6a, 7a and 7b, in which the
sulfonylation reaction occurred at the C-3 position as seen in Scheme 4. Furthermore,
as is evident in Scheme 5, by using the same catalyst in MeOH as solvent, we
obtained compounds 8a-h, 9a-k, 10a-d. The afforded 2-arylsulfonyl indoles produced
high yields. Pure compounds were obtained by column chromatography.
Please insert Scheme 1, Scheme 2, Scheme 3, Scheme 4 and Scheme 5 here
3. Results and discussion
3.1. Anti-inflammatory screening and cytotoxicity of 2-sulfonylindoles
TNF-α and IL-6 have been shown to contribute to the initiation and progression of an
inflammation-induced ALI.[25] We utilized an enzyme-linked immunosorbent assay
(ELISA) to screen for changes in LPS-induced TNF-α and IL-6 release by the
synthesized compounds in mouse primary peritoneal macrophages (MPMs).
Macrophages were pre-treated with 10 µM compounds for 30 min. DMSO was the
vehicle control and Indomethacin was used as a positive control. Subsequently,
MPMs were challenged with 0.5 µg/mL LPS for 24 h at 37°C. The ability (%
inhibition) of the compounds to reduce pro-inflammatory cytokines IL-6 and TNF-α
is shown in Figure 2. Our results show that the skeleton of 2-sulfonyl indoles had
inhibitory effect on LPS-induced TNF-α and IL-6 by MPMs compared with the lead
compound indomethacin. We also evaluated the cytotoxicity of synthetic
2-sulfonylindoles in MPMs using the MTT assay. As shown in Supplementary Figure
S1, all compounds showed no significant cytotoxicity at the concentration of 10 µM,
indicating that their anti-inflammatory activity is not mediated by cytotoxic effect.
Among these compounds, compound 15 were found to inhibit the release of TNF-α to
a greater degree compared to indometacin (50-88% inhibition), and compound 14

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exhibited effective inhibitory on IL-6 release (67-90% inhibition). Compounds 8a, 9g,
9h, and 9k showed higher inhibition of both TNF-α and IL-6 than indometacin. In
particular, compounds 8a, 9h and 9k were the most potent compounds against
LPS-induced TNF-α and IL-6 production with 82% and 88% inhibitory rates,
respectively.
Please insert Figure 2 here
3.2. Predictive structure-activity relationship study (SAR)
According to the results of our anti-inflammatory screening, we assessed the
structure-activity relationship analysis (SAR) of 2-sulfonyl indoles (Figure 3).
Nucleophilic substitution reactions could occur at multiple sites of indoles, such as
substitutions at the C2 and C3 positions.[26-28] Examining the anti-inflammatory
activity of compounds 7b and 8b, we found that C2 and C3 substitution did not alter
the activity. We then evaluated the effect of the N-substituents and the substituents on
the indole ring. We selected H, Me, Et, N-butyl to evaluate the relationship with the
anti-inflammatory effect. Compound 8a showed robust inhibition against
LPS-stimulated TNF-α and IL-6 release. Next, we assessed different substituents on
the indole ring to evaluate the inhibition of LPS-induced TNF-α and IL-6, including
4-Cl, 5-NO2, 5-Br, 5-OMe, 6-Me, and 6-F. We found that neither the
electron-withdrawing groups nor electron-donating groups contributed to the
inhibition of inflammatory factors. H substitution on the indole ring showed the best
anti-inflammatory activity. Finally, the effect of R2 substituents was analyzed. We
found that phenyl > 2-Naphthyl ≈ 4,4'-Biphenyldiboronic > 2-Thienyl, from
compounds 9f, 9c, 9d, 9b. We also found that the substitution at the 4-position on the
phenyl ring is more conducive to anti-inflammatory activity with 4-methylphenyl >
phenyl > 3-methylphenyl > 2-methylphenyl. It can be seen from activities of
compounds 8a, 9f, 9a, 9e. Surprisingly, the introduction of 4-methoxyphenyl (9g),
4-tert-Butyl (9h) and 4-trifluoromethylphenyl (9k) dramatically enhanced activities
against TNF-α and IL-6 release. Therefore, compounds 8a, 9g, 9h, 9k were selected
for further studies.

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Please insert Figure 3 here
3.3. Inhibition of LPS-induced cytokine release by the active compounds in a
dose-dependent manner
Our next objective was to determine whether their inhibitory effect on inflammatory
cytokine release follows a dose-dependent pattern. We pretreated MPMs with
compounds 8a, 9g, 9h and 9k at concentrations of 2.5, 5, and 10 µM for 30 min, and
subsequently incubated the cells with 0.5 mg/mL LPS for 24 h. The release of
inflammatory cytokines into the culture medium was measured by ELISA. Active
compounds 8a, 9h and 9k showed well-defined a dose-dependent inhibition on both
TNF-α and IL-6 releases (Figure 4A and 4B). Moreover, the IC50 values of these
tested compounds prompted us to examine compounds 9h and 9k further in an animal
model of ALI.
Please insert Figure 4 here
3.4. Compounds 9h and 9k ameliorate histopathological changes in lung tissues
following LPS challenge in a model of ALI
The active compounds 9h and 9k showed the most robust anti-inflammatory
activity as evidenced by IC50 values and were tested in C57BL/6 mice with ALI
induced by intratracheal instillation of LPS. To assess histological changes in
LPS-challenged mice following treatment with compounds 9h and 9k, we performed
hematoxylin and eosin (H&E）staining (Figure 5A). LPS instillation led to significant
pro-inflammatory alterations, including lung edema, alveolar hemorrhage,
inflammatory cell infiltration, and destruction of alveolar structure. These
histopathological changes were improved with treatment of either 10 and 20 mg/kg of
compounds 9h and 9k. As a further evaluation, total protein content of
bronchoalveolar lavage fluid (BALF) was also measured. A marked increase in the
total protein concentration in BALF samples was observed from LPS-challenged ALI
mice at 6 h following the challenge (Figure 5B). Pretreatment with either compounds

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at 10 and 20 mg/kg decreased total protein levels in BALF (Figure 5B). In addition,
the lung Wet/Dry ratio (W/D) increased in mice with ALI, while this change was
significantly reversed by treatment with 9h and 9k (Supplementary Figure S2),
indicating attenuated pulmonary edema. These studies showed that compounds 9h
and 9k had a protective effect on LPS-induced histopathological changes in a mouse
model of ALI.
Please insert Figure 5 here
3.5. Compounds 9h and 9k prevented inflammation in lung tissues following LPS
challenge
It is well known that pro-inflammatory cytokines are critical factors in the early phase
of ALI and lead to the severity of lung injury.[29, 30] To inspect the inhibitory
abilities of compounds 9h and 9k against cytokines production, we measured the
levels of pro-inflammatory cytokines and neutrophils in BALF and serum samples
from mice. Compared with naive mice, the release of cytokine were significantly
increased by LPS challenge. On the contrary, administration of compounds 9h and 9k
at 10 or 20 mg/kg decreased the levels of LPS-induced TNF-α and IL-6 in BALF and
serum remarkably (Figure 6A-C). Cellular analysis of BALF samples revealed that
compounds 9h and 9k significantly reduced the number of total cells in BALF (Figure
6D) compared with the LPS group. Myeloperoxidase (MPO) (Figure 6E) activity was
determined as a surrogate readout of tissue neutrophil infiltration. Our results
demonstrated that LPS challenge led to significant increases in lung neutrophil
infiltration, whereas compounds 9h and 9k significantly lowered neutrophil
infiltration. We also evaluated the inhibitory effect of 9h and 9k against macrophage
infiltration in the lung tissues by performing immunohistochemistry for macrophage
marker CD68 (Figure 6F). LPS induced a significant accumulation of CD68-positive
cells in the lung tissues. Pretreatment of mice with compounds 9h and 9k reduced this
accumulation.
Please insert Figure 6 here

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3.6. Compounds 9h and 9k prevented LPS-induced inflammatory cytokines and
adhesion molecules in both cultured macrophages and lung tissues
Our last objective was to investigate the effects of compounds 9h and 9k on the
inhibition of inflammatory gene expression at the mRNA level in LPS-stimulated
mouse macrophages and in lung tissues of mice challenged with LPS. MPMs were
exposed to 0.5 mg/mL LPS for 6 h and mRNA was extracted to measure the levels of
pro-inflammatory genes. LPS increased mRNA levels of pro-inflammatory cytokines,
including IL-6, IL-1β, and VCAM-1 in cultured MPMs, while pretreatment with
compounds 9h and 9k prevented these changes (Figure 7A-7C). Similar results were
observed in lung tissues of mice (Figure 7D-7E)
Please insert Figure 7 here
4. Conclusion
Combining sulfonyl groups with indole nucleus, we synthesized 31 novel
2-sulfonylindoles and evaluated their activities against LPS-induced TNF-α and IL-6.
Specifically, compounds 8a, 9g, 9h and 9k inhibited cytokine production in a
dose-dependent manner and displayed low IC50 values. We show that compounds 9h
and 9k effectively reduced LPS-induced pulmonary inflammation and acute lung
injury in mice. According to SAR, the introduction of sulfonyl group in indole
nucleus may be successful to obtain new anti-inflammatory structures and leads. We
believe that compounds 9h and 9k warrant further research in preclinical models and
may have broad clinical applications against inflammation-dependent diseases.
A limitation of this study may be the unknown molecular target and mechanism
of these anti-inflammatory 2-sulfonylindoles. Their molecular targets may be very
complicated and difficult to be found, since a large number of signaling pathways are
involved in inflammatory regulation in cells. We are planning to identify the direct
molecular target of biotin-labeled 9k using proteome microarray assay, which will
help us to find which proteins are able to directly bind to 9k. Future studies will focus
on the molecular mechanism and target for the anti-inflammatory actions of

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compounds 9h and 9k, as well as the pre-clinical evaluation of these two compounds
as anti-ALI candidates.
5. Experimental section
5.1. Chemistry
5.1.1. General
All chemicals were obtained from commercial sources and used without further
purification. Chromatographic purification was carried out on silica gel (200-300
1
mesh). HNMR and 13CNMR spectra data were recorded on a Bruker 500 MHz
instruments with tetramethylsilane(TMS) as an internal standard. High-resolution
mass spectra (m/z) were recorded on a microTOF-Q II instrument and electronspray
ionization mass spectra in positive mode (ESI-MS) data were recorded on a Bruker
Esquire 3000t spectrometer. Melting points were determined an electrothermal
melting apparatus and were uncorrected. , The purity of compounds was confirmed to
be >95% as determined by HPLC.
5.1.2. Synthesis of N-methylindole analogues 2a-i
To a solution of indoles 1a-i (10 mmol) in dry tetrahydrofuran (THF; 25 mL), NaH
(30 mmol) was added. After the mixture was stirred 30 min, CH3I (30 mmol) in 5 mL
o
THF was added dropwise under 0 C. The reaction mixture was stirred at room
temperature for 12h in the dark. Then the reaction mixture was cooled to room
temperature，diluted with 30 mL saturated NH4Cl solution，and extracted with EtOAc
(3 × 30 mL). The organic layer dried over anhydrous MgSO4 and concentrated in
vacuo. The pure products 2a-i was obtained by column chromatography on silica gel
(Petroleum ether /EtOAc = 20:1) with yield of 90%-99%.
5.1.3. Synthesis of 1-Butyl-1H-indole 2j
To a solution of indoles 1a-i (10 mmol) in dry tetrahydrofuran (THF; 25 mL), NaH
(30 mmol) was added. After the mixture was stirred 30 min, C4H9Br (15 mmol) in 5

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o
mL THF was added dropwise under 0 C. The reaction mixture was stirred at room
temperature for 12h in the dark. Then the reaction mixture was cooled to room
temperature, diluted with 30 mL saturated NH4Cl solution (25 mL) and extracted with
EtOAc (3 × 30 mL). The organic layer dried over anhydrous MgSO4 and concentrated
in vacuo. The pure products 2a-i was obtained by column chromatography on silica
gel (Petroleum ether /EtOAc = 20:1) with yield of 98%.
5.1.4. General Procedure for the Preparation of Sodium Aryl Sulfinates 4a-l
Sodium sulfite 3a-l (0.02 mol), aryl sulfonyl chloride (0.01 mmol), and sodium
bicarbonate (0.02 mol) were dissolved in distilled water (9.6 mL). The reaction
mixture was stirred at 80°C for 4 hand then cooled to room temperature. Water
was removed under vacuum and the residue was extracted by ethanol (25 mL) to
afford the desired aryl sulfinate with yield of 20%-80%.
5.1.5. Synthesis of Compounds 5a-e
To a solution of 1H-indoles 1a-c (1.0 mmol), sodium aryl sulfonates 4a, 4e and 4h
(0.5 mmol, 1.0 equiv), catalyst I2 (1.5 mmol) and tert-Butyl hydroperoxide (1.5 mmol)
in C2H5OH (2 mL) were added. The reaction mixture was stirred at 80°C for 12 h.
Then the reaction mixture was cooled to room temperature, diluted with brine (15 mL)
and extracted with EtOAc (3 × 25 mL). The organic layer dried over anhydrous
MgSO4 and concentrated in vacuo. The pure products 5a-e was obtained by column
chromatography on silica gel (Petroleum ether /EtOAc = 5:1) with yield of 31%-65%.
5.1.5.1. 3-iodo-2-tosyl-1H-indole (5a): Brown solid (123.1 mg, 64% yield),
mp:163.1-164.5 oC; 1H NMR (500 MHz, DMSO-d6): δ 12.79 (s, 1H, N-H), 7.91 (d, J
= 8.0 Hz, 2H, H-2’, H-6’), 7.47 (m, 3H, H-4, H-5, H-6),7.38 (t, J = 8.0 Hz, 2H, H-3’,
H-5’), 7.05 (t, J = 8.5 Hz, 1H, H-7), 2.41 (s, 3H, 6-CH3); 13C NMR (125 MHz,
DMSO-d6): δ 144.8, 137.8, 136.8, 134.0, 130.4*2, 127.0*2, 125.7, 123.3, 122.2,
122.1, 112.6, 66.6, 21.4; HR-ESI-MS m/z: 396.96 (M+H)+, calcd for C15H12INO2S:
397.98.

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5.1.5.2. 3-iodo-6-methyl-2-tosyl-1H-indole (5b): Purple solid (132.6 mg, 65% yield),
1
m.p:162.1-164.5 oC; H NMR (500 MHz, DMSO-d6): δ 9.84 (s, 1H, N-H), 7.98 (d, J
= 8.0 Hz, 2H, H-2’, H-6’), 7.32 (d, J = 8.0 Hz, 1H, H-4), 7.27 (d, J = 8.0 Hz, 2H, H-3’,
H-5’), 7.17 (s, 1H, H-7), 7.02 (d, J = 8.0 Hz, 1H, H-5), 2.42 (s, 3H, CH3-6), 2.37 (s,
3H, H-4’); 13C NMR (125 MHz, DMSO): δ 144.9, 137.6, 137.5, 136.5, 133.2 *2,
129.8, 129.3 127.9*2, 124.4, 122.6, 112.1, 64.7, 21.9, 21.6; HR-MS-ESI [M+Na]+ m/z
= 433.9679, calcd for C16H14INO2S, 410.9790.
5.1.5.3. 4-chloro-2-tosyl-1H-indole (5c): Black solid (225.8 mg, 79% yield); 1H NMR
(500 MHz, DMSO-d6): δ 12.78 (s, 1H, N-H), 7.92 (t, J = 8.0 Hz, 2H, H-2’, H-6’),
7.46-7.42 (m, 3H, H-3’, H-5’, H-5), 7.30 (t, J = 7.0 Hz, 1H, H-6), 7.21(t, J = 7.5 Hz,
13
1H, H-7), 7.15(t, J = 7.5 Hz, 1H, H-3), 2.37 (s, 3H, Ph-CH3); C NMR (125 MHz,
DMSO-d6): δ 144.7, 137.9, 135.9, 130.1*2, 127.2*2, 126.1, 126.0, 124.7, 122.9,
120.4, 112.0, 105.1, 21.0; HR-MS-ESI [M+Na]+ m/z = 308.0277, calcd for
C15H12ClNO2S, 285.0823.
5.1.5.4. 6-methyl-2-(naphthalen-1-ylsulfonyl)-1H-indole (5d): Yellow solid (141.2 mg,
31% yield), mp: 175.0-177.6 oC; 1H NMR (500 MHz, DMSO-d6): δ12.2 (s, 1H), 8.79
(d, J = 8.0 Hz, 1H, H-7), 8.43 (d, J = 7.5 Hz, 1H, H-7), 8.30 (d, J = 8.0 Hz, 1H, H-7),
8.07 (d, J = 8.5 Hz, 1H, H-7), 7.77 (d, J = 8.0 Hz, 1H, H-7), 7.71 (d, J = 8.5 Hz, 1H,
H-7), 7.63 (d, J = 7.0 Hz, 1H, H-7), 7.54 (d, J = 8.0 Hz, 1H, H-), 2.35 (s, 3H, H-4’);
13C NMR (125 MHz, DMSO-d6): δ 138.1, 135.8, 135.3, 135.0, 133.7, 133.6, 129.4*2,
129.2*2, 128.4, 127.4, 127.0, 124.8, 123.8, 123.7, 122.9, 121.9, 112.0, 21.4;
HR-MS-ESI [M+H]+ m/z = 322.0910, calcd for C19H15NO2S, 321.0823.
5.1.5.5. 3-iodo-2-((4-methoxyphenyl)sulfonyl)-6-methyl-1H-indole (5e): Brown solid
(106.7 mg, 49% yield), m.p:169.2-171.5 oC; 1H NMR (500 MHz, DMSO-d6): δ 12.61
(s, 1H, N-H), 7.96 (d, J = 8.5 Hz, 2H, H-3’, H-5’), 7.25 (d, J = 4.0 Hz, 2H, H-3’,
H-5’), 7.17 (d, J =8.5 Hz, 2H, H-7), 7.02 (d, J =8.5 Hz,1H, H-7), 3.82 (s, 3H,-O-CH3),

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2.40 (s, 3H, Ph-CH3); 13C NMR (125 MHz, DMSO-d6): δ 163.4, 137.1, 136.0, 133.8,
132.4*2, 129.3*2, 128.5, 123.7, 121.9, 114.8, 112.5, 55.8, 55.8, 21.4; HR-MS-ESI
[M+Na]+ m/z = 449.9648, Calcd for C16H14INO3S, 426.9739.
5.1.6. General procedure for synthesis of compounds 6a, 7a-b, 8a-h, 9a-k, 10a-d.
To a solution of N-methylindoles (1.0 mmol), sodium aryl sulfonates (0.5 mmol),
catalyst I2 (0.75 mmol) and tert-Butyl hydroperoxide (1.5 mmol) in methanol (2 mL)
were added. The reaction mixture was stirred at 80°C for 12 h. Then the reaction
mixture was cooled to room temperature, diluted with brine (15 mL) and extracted
with EtOAc (3 × 25 mL). The organic layer dried over anhydrous MgSO4 and
concentrated in vacuo. The residue was further purified by column chromatography
on silica gel (Petroleum ether /EtOAc=5:1) to afford the compounds 6a, 7a-b, 8a-h,
9a-k, 10a-d with yield of 9%-95%.
5.1.6.1. 1-butyl-2-tosyl-indole (6a): Yellow solid (155.6 mg, 95% yield), m.p:
1
75.2-78.1 oC; H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 7.5 Hz, 2H, H-2’, H-6’),
7.68 (d, J = 8.0 Hz, 1H, H-7), 7.32 (m, 5H, H-4, H-5, H-6, H-3’, H-5’), 7.16 (t, J = 7.0
Hz, 1H, H-3), 4.26 (t, J = 8.0 Hz, 2H, N-CH2-CH2-CH2-CH3), 2.40 (s, 3H, Ph-CH3),
1.47 (m, 2H, N-CH2-CH2-CH2-CH3), 1.29 (m, 2H, N-CH2-CH2-CH2-CH3), 0.86 (m,
2H, N-CH2-CH2-CH2-CH3); 13C NMR (125 MHz, CDCl3): δ 144.4, 138.8, 138.6,
134.9, 129.9*2, 127.7*2, 125.5, 125.4, 122.9, 121.0, 110.8, 110.7, 44.8, 31.9, 21.6,
20.2; HR-MS-ESI [M+Na]+ m/z = 350.1184, Calcd for C19H21NO2S, 327.1293.
5.1.6.2. 1-ethyl-2-phenyl-3-tosyl-indole (7a): White solid (33.5 mg, 9% yield),
1
m.p:128.6-130.4 oC; H NMR (500 MHz, CDCl3): δ 8.334 (t, J = 3.5 Hz, 1H, H-4),
7.54-7.46 (m, 5H, H-2’,H-6’,H-2’’,H-6’’,H-7), 7.37-7.29 (m, 5H, H-3’, H-5’, H-3’’,
H-5’’, H-4), 7.09 (d, J = 8.0 Hz, 2H, H-5, H-6), 3.92 (t, J = 7.0 Hz, 2H, N-CH2-CH3),
2.32 (s, 4’’-CH3), 1.21 (t, J = 7.0 Hz,3H, -CH2-CH3); 13C NMR (125 MHz, CDCl3): δ
142.9, 141.9, 141.8, 139.6, 136.9, 136.5, 136.3, 129.5*2, 126.1*2, 125.0, 124.5, 122.8,

ACCEPTED MANUSCRIPT
122.2, 119.9, 111.6, 109.4, 108.8, 107.5, 29.8, 21.4, 11.0; HR-MS-ESI [M+Na]+ m/z
= 398.1187, calcd for C23H21NO2S, 375.1293.
5.1.6.3. 1,3-dimethyl-2-tosyl-indole (7b): Yellow solid (125.7 mg, 84% yield), m.p:
135.3-137.7 oC; 1H NMR (500 MHz, CDCl3): δ 8.10 (m, 1H, H-4), 7.68 (d, J = 8.0 Hz,
1H, H-7), 7.84 (d, J = 7.5 Hz, 2H, H-2’, H-6’), 7.24 (s, 3H, H-5, H-6, H-7), 3.64 (s,
3H, N-CH3), 2.72 (s, 3H, Ph-CH3), 2.33 (s, 3H, 2-CH3); 13C NMR (125 MHz,
CDCl3): δ 142.9, 141.9, 141.8, 136.3, 129.5*2, 126.1*2, 125.0, 122.8, 122.2, 119.9,
111.6, 109.4, 29.8, 21.4, 11.0; HR-MS-ESI [M+Na]+ m/z = 322.0887, Calcd for
C17H17NO2S, 299.0980.
5.1.6.4. 1-methyl-2-tosyl-indole (8a): Black solid (112.9 mg, 79% yield), m.p:
1
150.8-153.1 oC. H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 7.5 Hz, 2H, H-2’, H-6’),
7.68 (d, J = 8.0 Hz, 1H, H-7), 7.40 (t, J = 8.0 Hz, 2H, H-3’, H-5’), 7.29 (d, J = 7.5 Hz,
3H, H-4, H-5, H-6), 7.16 (t, J = 7.0 Hz, 1H, H-3), 3.83 (s, 3H, N-CH3), 2.40 (s, 3H,
H-4’); 13C NMR (125 MHz, CDCl3): δ 144.5, 139.5, 138.3, 135.2*2, 129.9*2, 127.7,
125.6, 125.2, 122.8, 121.1, 110.4, 110.2, 31.0, 21.6; MS-ESI [M+H]+ m/z = 286.09,
calcd for C16H15NO2S, 285.08.
5.1.6.5. 1,2-dimethyl-3-tosyl-indole (8b): Green solid (81.6 mg, 27% yield), m.p: 200
1
oC; H NMR (500 MHz, CDCl3): δ 7.78 (d, J = 8.5 Hz, 2H, H-2’, H-6’), 7.67 (d, J =
7.5 Hz, 1H, H-4), 7.36 (d, J = 8.0 Hz, 3H, H-5, H-3’, H-5’), 7.27 (d, J = 7.0 Hz, 1H,
H-7), 7.16 (t, J = 7.0 Hz, 1H, H-6), 3.85 (s, 3H, N-CH3), 2.74 (s, 3H, Ph-CH3), 2.38 (s,
13
3H, 3-CH3), 2.40 (s, 3H, H-4’); C NMR (125 MHz, CDCl3): δ 144.3, 140.0, 138.6,
136.0, 134.5, 129.9*2, 127.6*2, 123.2, 123.1, 122.4, 110.5, 109.9, 31.4, 21.5, 9.9;
MS-ESI [M+H]+ m/z = 300.10, calcd for C17H17NO2S, 299.10.
5.1.6.6. 1-methyl-5-nitro-2-tosyl-indole (8c): Yellow solid (146.8 mg, 44% yield), m.p:
1
127.8-130.7 oC; H NMR (500 MHz, CDCl3): δ 7.85 (d, J = 8.0 Hz, 2H, H-2’, H-6’),
7.40 (s, 1H, H-3), 7.32 (d, J = 7.5 Hz, 2H, H-3’, H-5’), 7.25 (d, J = 7.0 Hz, 1H, H-5),

ACCEPTED MANUSCRIPT
13
7.18(m, J = 7.5 Hz, 2H, H-6, H-7), 3.85 (s, 3H, N-CH3), 2.41 (s, 3H, Ph-CH3); C
NMR (125 MHz, CDCl3): δ 144.3, 140.0, 138.6, 136.0, 134.5*2, 129.9, 127.6*2,
123.2, 123.1, 122.4, 110.5, 109.9, 31.4, 21.6; MS-ESI [M+H]+ m/z = 331.08, m/z:
calcd for C16H14N2O4S, 330.07.
5.1.6.7. 5-bromo-1-methyl-2-tosyl-indole (8d): Yellow solid (125.7 mg, 84% yield),
1
m.p:160.8-162.1 oC; H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 8.0 Hz, 2H, H-2’,
H-6’), 7.80 (s, 1H, H-4), 7.41 (d, J = 7.5 Hz, 1H, H-6), 7.31 (d, J = 7.0 Hz, 2H, H-3’,
H-5’), 7.22(s, 1H, H-3), 7.16 (d, J = 9.5 Hz, 1H, H-7), 3.82 (s, 3H, N-CH3), 2.40 (s,
13
3H, Ph-CH3); C NMR (125 MHz, CDCl3): δ 144.8, 138.0, 137.9, 136.6, 130.2*2,
128.6, 127.8*2, 126.7, 125.1, 114.3, 111.8, 109.4, 31.2, 21.6; HR-MS-ESI [M+Na]+
m/z = 385.9831, calcd for C16H14BrNO2S, 362.9929.
5.1.6.8. 4-chloro-1-methyl-2-tosyl-1H-indole (8e): Yellow solid (143.4 mg, 45% yield),
1
m.p: 158.0-160.3 oC; H NMR (500 MHz, CDCl3): δ 7.85 (d, J = 8.0 Hz, 2H, H-2’,
H-6’), 7.40 (s, 1H, H-3), 7.32 (d, J = 7.5 Hz, 2H, H-3’, H-5’), 7.25 (d, J = 7.0 Hz, 1H,
H-5), 7.18(m, J = 7.5 Hz, 2H, H-6, H-7), 3.85 (s, 3H, N-CH3), 2.41 (s, 3H, Ph-CH3);
13C NMR (125 MHz, CDCl3): δ 144.3, 140.0, 138.6, 136.0, 134.5*2, 129.9, 127.6*2,
123.2, 123.1, 122.4, 110.5, 109.9, 31.4, 21.6; HR-MS-ESI [M+Na]+ m/z = 342.0345,
calcd for C16H14ClNO2S, 319.0434.
5.1.6.9. 6-fluoro-1-methyl-2-tosyl-indole (8f):Yellow solid (117.6 mg, 36% yield), m.p:
1
150.6-152.2 oC; H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 7.5 Hz, 2H, H-2’, H-6’),
7.61 (d, J = 8.0 Hz, 1H, H-7), 7.32 (t, J = 7.5 Hz, 3H, H-3’, H-5’, H-4), 6.95 (d, J =
9.5 Hz, 2H, H-5, H-6), 3.78 (s, 3H, N-CH3), 2.42 (s, 3H, H-4’); 13C NMR (125 MHz,
CDCl3): δ 162.8, 160.9, 144.6, 139.8, 139.7*2, 138.2*2,135.9, 127.7, 124.2, 124.1,
121.7, 110.8, 96.5, 31.2, 21.6; HR-MS-ESI [M+Na]+ m/z = 326.0620, calcd for
C16H14FNO2S, 303.0729.

ACCEPTED MANUSCRIPT
5.1.6.10. 5-methoxy-1-methyl-2-tosyl-indole (8g): Yellow solid (160.8 mg, 52% yield),
o
1
m.p: 123.1-124.3 C; H NMR (500 MHz, CDCl3): δ 8.30 (d, J = 8.0 Hz, 2H, H-2’,
H-6’), 7.30 (d, J = 8.0 Hz, 2H, H-3’, H-5’), 7.25 (s, 1H, H-4), 7.19 (d, J =9.0 Hz, 1H,
H-7), 7.07 (s, 1H, H-3), 7.02 (d, J =9.5 Hz, 1H, H-6), 3.84 (s, 3H,-O-CH3), 3.81 (s,
3H, N-CH3), 2.41 (s, 3H, Ph-CH3); 13C NMR (125 MHz, CDCl3): δ 155.0, 144.3,
138.5, 135.2, 135.0*2, 129.9*2, 127.6, 125.5, 117.3, 111.2, 109.8, 102.8, 55.8, 31.1,
21.6; HR-MS-ESI [M+Na]+ m/z = 338.0827, calcd for C17H17NO3S, 315.0929.
5.1.6.11. 1,6-dimethyl-2-tosyl-indole (8h): Brown solid (260 mg, 87% yield), m.p:
134.8-139.8 oC; 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J = 8.0 Hz, 2H, H-2’, H-6’),
7.56 (d, J = 8.5 Hz, 1H, H-4), 7.29 (d, J = 4.5 Hz, 3H, H-5, H-3’, H-5’), 7.07(s, 1H,
H-7), 7.01 (d, J = 8.5 Hz, 1H, H-3), 3.80 (s, 3H, N-CH3), 2.47 (s, 3H, Ph-CH3), 2.40
(s, 3H, 6-CH3), 2.40 (s, 3H, H-4’); 13C NMR (125 MHz, CDCl3): δ 144.3, 140.0,
138.6, 136.0, 134.5, 129.9*2, 127.6*2, 123.2, 123.1, 122.4, 110.5, 109.9, 30.9, 22.1,
21.5; MS-ESI [M+H]+ m/z = 300.24, calcd for C17H17NO2S, 299.10.
5.1.6.12. 1-methyl-2-(methylsulfonyl)- indole (9a): Yellow solid (71 mg, 34% yield),
1
m.p:75.4-77.2 oC; H NMR (500 MHz, CDCl3): δ7.70 (d, J = 8.0 Hz, 1H, H-7), 7.40
(d, J = 7.0 Hz, 2H, H-4, H-6), 7.28 (s, 1H, H-3), 7.22 (t, J = 7.0 Hz, 1H, H-5), 4.03 (s,
3H, CH3-N), 3.18 (s, 3H,CH3-S); 13C NMR (125 MHz, CDCl3): δ 139.5, 134.6, 126.0,
125.1, 123.0, 121.3, 110.4, 110.3, 45.4, 31.1; MS-ESI [M+H]+ m/z = 210.04, calcd for
C10H11NO2S, 209.05.
5.1.6.13. 1-methyl-2-(thiophen-2-ylsulfonyl)-indole (9b):Yellow solid (83.1 mg, 60%
1
yield), m.p:101.6-104.5oC; H NMR (500 MHz, CDCl3): δ 7.73 (d, J = 4.0 Hz, 1H,
H-3’), 7.69 (d, J = 8.0 Hz, 1H, H-4’), 7.66 (d, J = 8.0 Hz, 1H, H-5’), 7.37 (t, J = 9.0
Hz, 2H, H-5, H-6), 7.33 (d, J = 8.0 Hz, 1H, H-4), 7.19 (t, J = 8.0 Hz, 1H, H-7) , 7.09
(d, J = 7.0 Hz, 1H, H-3’), , 3.95 (s, 3H, N-CH3); 13C NMR (125 MHz, CDCl3): δ
143.2, 139.6, 135.5, 134.0, 133.4, 127.9, 125.9, 125.2, 123.0, 121.3, 110.5, 110.3,
31.0; HR-MS-ESI [M+Na]+ m/z = 308.0712, Calcd for C16H15NO2S, 285.0823.

ACCEPTED MANUSCRIPT
5.1.6.14. 1-methyl-2-(naphthalen-2-ylsulfonyl)-indole (9c): Brown solid (121.7 mg,
1
73% yield), m.p: 129.6-131.4 oC; H NMR (500 MHz, CDCl3): δ 8.59 (s, 1H, H-8’),
7.96 (d, J = 8.0 Hz, 1H, H-4’), 7.91 (d, J = 9.0 Hz, 1H, H-5’), 7.86 (d, J = 6.5 Hz, 2H,
H-2’, H-6’), 7.69 (t, J = 8.5 Hz, 1H, H-3’), 7.60 (m, 2H, H-7’, H-4), 7.43 (s, 1H, H-6),
7.34(t, J = 7.5 Hz, 1H, H-7), 7.24 (d, J = 6.0 Hz, 1H, H-5), 7.17 (t, J = 7.0 Hz, 1H,
H-3), 3.84 (s, 3H, N-CH3); 13C NMR (125 MHz, CDCl3): δ 139.5, 138.2, 135.1, 134.8,
132.2, 129.7, 129.4, 129.3, 129.0, 128.0, 127.8, 125.8, 125.3, 122.9, 122.7, 121.2,
111.0, 110.3, 30.9; HR-MS-ESI [M+H]+ m/z = 322.0859, Calcd for C19H15NO2S,
321.0823.
5.1.6.15. 2-([1,1'-biphenyl]-4-ylsulfonyl)-1-methyl-indole (9d): Brown solid (44.7 mg,
26% yield), m.p: 140.9-142.6 oC; 1H NMR (500 MHz, CDCl3): δ 8.02 (d, J = 8.0 Hz,
2H, H-2’, H-6’), 7.71 (d, J = 8.5 Hz, 3H, H-2’’, H-6’’, H-7), 7.56 (d, J = 8.5 Hz, 2H,
H-3’, H-5’), 7.46 (t, J = 7.5 Hz, 2H, H-3’’, H-5’’), 7.41 (t, J = 7.5 Hz, 2H, H-4’’, H-6),
7.36 (d, J = 7.0 Hz, 1H, H-3’, H-5), 7.32 (d, J = 8.5 Hz, 1H, H-4), 7.19 (t, J = 7.5 Hz,
13
1H, H-3), 3.84 (s, 3H, N-CH3); C NMR (125 MHz, CDCl3): δ146.4, 139.8, 139.6,
139.1, 134.9, 129.1*2, 128.7, 128.2*2, 128.0*2, 127.4*2, 125.8, 125.3, 122.9, 121.2,
110.8, 110.3, 31.0; HR-MS-ESI [M+Na]+ m/z = 370.0884, calcd for C21H17NO2S
347.0980.
5.1.6.16. 1-methyl-2-(o-tolylsulfonyl)-indole (9e): Black solid (66.8 mg, 47% yield),
1
m.p: 135.4-137.2 oC; H NMR (500 MHz, CDCl3): δ 8.15 (d, J = 8.0 Hz, 1H, H-2’),
7.70 (d, J = 8.5 Hz, 1H, H-7), 7.49 (t, J = 8.0 Hz, 1H, H-4’), 7.38 (m, J = 7.5 Hz, 3H,
H-4, H-5, H-6), 7.30 (d, J = 9.0 Hz, 1H, H-3’), 7.26 (d, J = 8.0 Hz, 1H, H-5’) , 7.19 (t,
13
J = 7.0 Hz, 1H, H-3), 3.76 s, 3H, N-CH3), 2.57 (s, 3H, H-4’); C NMR (125 MHz,
CDCl3): δ 139.4, 138.8, 138.7, 134.6, 133.8, 132.9, 129.3, 126.4, 125.7, 125.0, 122.8,
121.1, 111.4, 110.2, 31.0, 20.0; HR-MS-ESI [M+Na]+ m/z = 308.0728, calcd for
C16H15NO2S, 285.0823.

ACCEPTED MANUSCRIPT
5.1.6.17. 1-methyl-2-(phenylsulfonyl)-indole (9f): Yellow solid (189.8 mg, 70% yield),
1
m.p: 122.7-124.9oC; H NMR (500 MHz, CDCl3): δ7.96 (d, J = 8.0 Hz, 2H, H-2’,
H-6’), 7.70 (d, J = 8.5 Hz, 1H, H-7), 7.58 (t, J = 8.0 Hz, 1H, H-4’), 7.52 (t, J = 7.0 Hz,
2H, H-3’, H-5’), 7.36 (d, J = 10 Hz, 2H, H-4, H-6), 7.30 (d, J = 8.0 Hz, 1H, H-5),
13
7.19 (d, J = 7.0 Hz, 1H, H-3), 3.85 (s, 3H, CH3-N); C NMR (125 MHz, CDCl3): δ
141.3, 139.5, 134.8, 133.4, 129.3, 127.6, 125.7, 125.2, 122.8, 121.2, 110.8, 110.3 ,
31.0; MS-ESI [M+H]+ m/z = 272.35, Calcd for C15H13NO2S, 271.33.
5.1.6.18. 2-((4-methoxyphenyl)sulfonyl)-1-methyl-indole (9g): Yellow solid (91.8 mg,
61% yield), m.p: 126.1-128.5 oC; 1H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 7.5 Hz,
2H, H-2’, H-6’), 7.68 (d, J = 8.0 Hz, 1H, H-7), 7.35 (t, J = 7.5 Hz, 1H, H-5), 7.29 (d,
J = 10.5 Hz, 2H, H-4, H-6), 7.17 (t, J = 7.0 Hz, 1H, H-3), 6.97 (d, J = 7.5 Hz, 2H,
13
H-3’, H-5’), 3.83 (s, 6H, N-CH3, -O-CH3); C NMR (125 MHz, CDCl3): δ 163.6,
139.4, 135.7, 132.7, 129.9*2, 125.5, 125.2, 122.8, 121.1, 114.5*2, 110.2, 110.0, 55.7,
31.0; HR-MS-ESI [M+Na]+ m/z = 324.0670, calcd for C16H15NO3S, 301.0773.
5.1.6.19. 2-((4-(tert-butyl)phenyl)sulfonyl)-1-methyl-indole (9h): Brown solid (67.8
mg, 42% yield), m.p: 188.4-190.8 oC; 1H NMR (500 MHz, CDCl3): δ 7.87 (d, J = 7.5
Hz, 2H, H-2’, H-6’), 7.69 (d, J = 8.0 Hz, 1H, H-7), 7.51 (d, J = 7.5 Hz, 2H, H-3’,
H-5’), 7.80 (d, J = 8.0 Hz, 1H, H-7), 7.61 (d, J = 8.5 Hz, 1H, H-7), 7.52 (t, J = 7.5 Hz,
2H, H-3’, H-5’), 7.35(s, 1H, H-3), 7.30(d, J = 8.0 Hz, 1H, H-5), 7.17 (t, J = 8.0 Hz,
1H, H-6), 3.68 (s, 3H, N-CH3), 1.31(s, 9H, -C-(CH3)3); 13C NMR (125 MHz, CDCl3):
δ157.4, 139.5, 138.3, 135.3, 127.5*2, 126.3*2, 125.6, 125.3, 122.8, 121.1, 110.4,
110.2, 35.2, 31.0; HR-MS-ESI [M+Na]+ m/z = 350.1185, calcd for C19H21NO2S,
327.1293.
5.1.6.20. 2-((4-fluorophenyl)sulfonyl)-1-methyl-indole (9i): Brown solid (100.5 mg,
1
69% yield), m.p: 139.9-141.2 oC; H NMR (500 MHz, CDCl3): δ 7.97 (m, 2H, H-2’,
H-6’), 7.69 (d, J = 8.0 Hz, 1H, H-7), 7.36 (m, 2H, H-3’, H-5’), 7.31 (d, J = 8.0 Hz, 1H,
H-3), 7.16 (m, 3H, H-4, H-5, H-6), 3.85 (s, 3H, N-CH3); 13C NMR (125 MHz, CDCl3):

ACCEPTED MANUSCRIPT
δ 166.5, 139.6, 134.6, 130.6*2, 130.5, 125.9, 125.2, 122.9, 121.3, 116.8*2, 116.6,
110.9, 31.0; HR-MS-ESI [M+Na]+ m/z = 312.0467, Calcd for C15H12FNO2S,
289.0573.
5.1.6.21. 2-((4-chlorophenyl)sulfonyl)-1-methyl-indole (9j): White solid (106.2 mg, 70%
1
yield), m.p: 135.0-137.2 oC; H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 9.0 Hz, 2H,
H-2’, H-6’), 7.69 (d, J = 8.0 Hz, 1H, H-7), 7.48 (d, J = 8.5 Hz, 2H, H-3’, H-5’), 7.37
(t, J = 4.0 Hz, 2H, H-4, H-6), 7.31 (d, J = 8.5 Hz, 1H, H-5), 7.19 (d, J = 8.0 Hz, 1H,
H-3), 3.84 (s, 3H, N-CH3); 13C NMR (125 MHz, CDCl3): δ 140.1, 139.8, 139.6, 134.2,
129.7*2, 129.1*2, 126.0, 125.2, 122.9, 121.3, 111.1, 110.3, 31.0; MS-ESI [M+Na]+
m/z = 327.12, calcd for C15H12ClNO2S, 305.03.
5.1.6.22. 1-methyl-2-((4-(trifluoromethyl)phenyl)sulfonyl)-indole (9k): White solid
1
(101.8 mg, 60% yield), m.p: 156.5-158.7-77.2 oC; H NMR (500 MHz, CDCl3): δ
8.08 (d, J = 8.0 Hz, 2H, H-2’, H-6’), 7.77 (d, J = 8.0 Hz, 2H, H-3’, H-5’), 7.71 (d, J =
8.0 Hz, 1H, H-7), 7.43 (s, 1H, H-3), 7.39 (t, J = 7.0 Hz, 1H, H-4), 7.31 (t, J = 8.5 Hz,
13
1H, H-6), 7.20 (t, J = 7.0 Hz, 1H, H-5), 3.85 (s, 3H, N-CH3); C NMR (125 MHz,
CDCl3): δ 145.0, 139.8, 128.1, 126.6*2, 126.5*2, 126.4, 126.3, 125.2, 123.0, 121.5,
110.9, 110.4, 31.1; MS-ESI [M+H]+ m/z = 340.03, calcd for C16H12F3NO2S, 339.05.
5.1.6.23. 2-((4-(tert-butyl)phenyl)sulfonyl)-1,3-dimethyl-indole (10a): White solid
(44.4 mg, 26% yield), m.p: 146.2-147.9 oC; 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J
= 8.5 Hz, 2H, H-2’, H-6’), 7.68 (d, J = 8.0 Hz, 1H, H-6), 7.49 (t, J = 8.5 Hz, 2H, H-3’,
H-5’), 7.36 (d, J = 7.5 Hz, 1H, H-6), 7.28 (t, J = 8.5 Hz, 1H, H-5), 7.17 (t, J = 8.5 Hz,
13
1H, H-4) , 3.88 (s, 3H, N-CH3), 2.75 (s, 3H, 3-CH3), 1.30 (s, 9H, H-4’); C NMR
(125 MHz, CDCl3): δ 157.1, 139.5, 138.3, 129.8*2, 126.8*2, 126.6, 126.3, 126.0,
120.9, 120.3, 110.0, 35.2, 31.5, 31.0, 10.0; HR-MS-ESI [M+Na]+ m/z = 364.1339,
calcd for C20H23NO2S, 341.1449.

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5.1.6.24. 1,3-dimethyl-2-((4-(trifluoromethyl)phenyl)sulfonyl)-indole (10b): Black
1
solid (112.8 mg, 64% yield), m.p: 145.2-146.4 oC; H NMR (500 MHz, CDCl3): δ
8.01 (d, J = 8.0 Hz, 2H, H-2’, H-6’), 7.75 (d, J = 8.5 Hz, 2H, H-3’, H-5’), 7.68 (d, J =
8.0Hz, 1H, H-7), 7.30 (t , J = 8.0Hz, 1H, H-6), 7.30 (d, J = 8.0 Hz, 1H, H-4), 7.19 (d,
J = 7.0 Hz, 1H, H-5), 3.88 (s, 3H, N-CH3), 2.85 (s, 3H, 3-CH3); 13C NMR (125 MHz,
CDCl3): δ 146.3, 134.9, 138.7, 134.6*2, 128.1*2, 127.2, 126.7, 126.5, 126.4, 124.2,
122.2, 121.1, 110.2, 31.6, 10.0; HR-MS-ESI [M+Na]+ m/z = 376.0624, calcd for
C17H14F3NO2S, 353.0697.
5.1.6.25. 2-((4-(tert-butyl)phenyl)sulfonyl)-5-methoxy-1-methyl-indole (10c): White
solid (51.2 mg, 29% yield), m.p: 192.3-194.8 oC; 1H NMR (500 MHz, CDCl3): δ 7.87
(d, J = 8.5 Hz, 2H, H-2’, H-6’), 7.51 (d, J = 8.5 Hz, 2H, H-3’, H-5’), 7.26 (d, J = 8.0
Hz, 1H, H-7), 7.20 (d, J = 9.0Hz, 1H, H-4), 7.07 (t, J = 2.5 Hz, 1H, H-6), 7.03 (m, 1H,
13
H-3) , 3.84 (s, 3H, N-CH3), 3.83(s, 3H, -O-CH3), 2.40 (s, 9H, H-4’); C NMR (125
MHz, CDCl3): δ 157.3, 155.0, 138.4, 135.2, 135.0, 127.5*2, 126.3*2, 125.5, 117.3*2,
111.2, 109.8, 102.7, 55.7 , 35.2, 31.2, 31.0; HR-MS-ESI [M+Na]+ m/z = 380.1291,
Calcd for C20H23NO3S, 357.1399.
5.1.6.26. 5-methoxy-1-methyl-2-((4-(trifluoromethyl)phenyl)sulfonyl)-indole (10d):
White solid (51.2 mg, 55% yield), m.p: 142.5-144.6 oC; 1H NMR (500 MHz, CDCl3):
δ 8.07 (d, J = 8.5 Hz, 2H, H-2’, H-6’), 7.78 (d, J = 9 Hz, 2H, H-3’, H-5’), 7.34 (s, 1H,
H-4), 7.21 (d, J = 9.0 Hz, 1H,H-7), 7.07 (t, J = 2.5 Hz, 2H, H-4 ,H-6), 3.84 (s, 3H,
13
N-CH3), 3.83(s, 3H, -O-CH3); C NMR (125 MHz, CDCl3): δ 155.2, 145.2, 135.3,
133.4, 128.0, 126.6*2, 126.5*2, 118.2, 111.4*2, 111.1, 102.7, 102.7, 55.7 , 35.2, 31.2,
31.0; HR-MS-ESI [M+Na]+ m/z = 392.0536, Calcd for C17H14F3NO3S, 369.0646.
5.2. Animal model of acute lung injury
The animal care and experimental procedures were approved by Wenzhou Medical
University Animal Policy and Welfare Committee. Male C57BL/6 mice weighing
18-22 g were purchased from the Animal Center of Wenzhou Medical University

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(Wenzhou, China). Mice were kept in standard conditions and maintained in a 12:12-h
light/dark cycle with food and water ad libitum.
5.3. Cells and reagents
Lipopolysaccharide (LPS) was purchased from Sigma-Aldrich and dissolved in PBS.
Other synthesized compounds were dissolved in DMSO before use. Total peritoneal
macrophages were harvested by washing the peritoneal cavity with 8 mL RPMI-1640
medium per mouse and resuspending the pellet following centrifugation in
RPMI-1640 medium with 10% FBS, 100 U/mL penicillin, and 100 mg/mL
streptomycin. The macrophages were cultured at 37 oC in 5% CO2-humidified air.
5.4. Determination of cytokines
The amounts of TNF-α and IL-6 were measured by ELISA and normalized to the total
proteins extracted from cells. After treatment of cells with compounds and LPS,
Levels of TNF-α and IL-6 in the media were determined with an ELISA kit according
to the manufacturer's instructions.
5.5. MTT assay
MPMs were seeded into 96-well plates at a concentration of 2.0 ×104 cells per well in
1640 medium, supplemented with 10% FBS, 100 U/ml penicillin, and 100 mg/ml
streptomycin. After treatment with the compounds, A fresh solution of MTT (5 mg/ml)
prepared in NaCl solution (0.9%) was added to each well and the plate was then
o
incubated in 5% CO2 at 37 C for 4 h. Absorbance at 490 nm was detected by the
multi-well-plate reader.
5.6. Real-time quantitative PCR
RNA was extracted from tissues and cells using TRIZOL (Thermo Fisher, Waltham,
MA). The reverse transcription and quantitative PCR were carried out via a two-step
M-MLV Platinum SYBR Green qPCR SuperMix-UDG kit (Thermo Fisher).
Eppendorf Mastercycler ep realplex detection system (Eppendorf, Hamburg, Germany)

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was used for q-PCR analysis. The primers of genes including TNF-α and IL-6 were
obtained from Invitrogen. The primer sequences are shown as follows:
Mouse IL-6 sense: 5′-GAGGATACCACTCCCAACAGACC-3′;
Mouse IL-6 antisense: 5′- AAGTGCATCATCGTTGTTCATACA-3′;
Mouse IL-1β sense:5′- ACTCCTTAGTCCTCGGCCA-3′;
Mouse IL-1β antisense:5′-CCATCAGAGGCAAGGAGGAA-3′;
Mouse VCAM-1 sense:5′-TGCCGAGCTAAATTACACATTG-3′;
Mouse VCAM-1 antisense:5′-CCTTGTGGAGGGATGTACAGA-3′;
Mouse β-Actin sense:5′-CCGTGAAAAGATGACCCAGA-3′;
Mouse β-Actin antisense:5′-TACGACCAGAGGCATACAG-3′;
The amount of each gene was determined and normalized by the amount of β-Actin.
5.7. LPS-induced inflammatory mortality in C57BL/6 mice
Compounds 9h and 9k were dissolved in in 5% DMSO, 40% PEG400 in 0.9% saline.
Male B6 mice were randomly divided into four groups: control (n = 6), LPS (n = 6),
and 9h (10 mg/kg and 20 mg/kg) + LPS (n = 6) and 9k (10 mg/kg and 20 mg/kg) +
LPS (n = 6). The mice were treated by intraperitoneal injection with 9h and 9k at a
dose of 10 mg/kg or 20 mg/kg 30 min before challenged with LPS intratracheally (5
mg/kg). As a control for compounds 9h and 9k, 0.9% saline was given. LPS (5 mg /
kg) was then injected into the trachea. Mice in the control group received a similar
volume of PBS (1 mL / kg). After 6 h of LPS challenge, mice were euthanized with
ketamine.
5.8.1. Inflammatory cytokine levels in BALF
The collected BALF was centrifuged at 1,000 rpm for 10 min, the supernatant was
used for protein concentration detection and cytokine determinations. The cell pellets
obtained from BALF were washed and re-suspended in 50 µL PBS, total number of

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cells in BALF counted. Neutrophils were counted from 200 cells using
Wright-Giemsa staining.
5.8.2. Lung wet/dry weight ratio
Pulmonary edema was evaluated by the lung wet/dry weight ratio. The superior lobes
of the right lungs were excised, blotted dry, and weighed to obtain the “wet” weight.
o
Then the lungs were placed in an oven at 60 C for more than 48 h until getting
constant weight as dry weight. The ratio of wet/dry lung weight was reported.
5.8.3. Histopathologic evaluation
Lung tissues were fixed in 4% paraformaldehyde solution, embedded in paraffin, and
cut into 5 µm sections. The sections were stained with hematoxylin and eosin (H&E)
staining. The stained cells were photographed by a Nikon microscope (Nikon, Japan).
5.8.4. Immunofluorescence for CD68 detection
After deparaffinization and rehydration, lung sections were treated with 3% H2O2 for
20 min, and with 1% BSA in PBS for 30 min. Slides were incubated overnight at 4 °C
with anti-CD68 antibody (Santa Cruz; 1:100). Horseradish peroxidase-labeled
secondary antibody (Santa Cruz;1:200) and diaminobenzidine were used for detection.
Slides were counterstained using hematoxylin.
5.9. Statistical analysis
Data are expressed as means ± SEM. Statistical comparisons of the results were made
using analysis of Student’s. Significant differences were established at P values less
than 0.05 (p < 0.05). All experiments were repeated at least three times.

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AUTHOR INFORMATION
Corresponding authors
G.L.: phone, (+86)-577-86699396; E-mail: wzmcliangguang@163.com
Author contributions
The manuscript was written with contributions from all of the authors. All authors
have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by National Key Research Project (2017YFA0506000),
National Natural Science Foundation of China (21602159 and 81622043), Natural
Science Foundation of Zhejiang Province (LY17B020008), and Public Welfare
Science and Technology Project of Wenzhou (Y20160164).

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Figure Legends
Scheme 1. Synthesis of indole derivatives 2a-ja.
aReagents and conditions: (a) NaH, dry THF, 0oC, 30min, added CH3I, r.t. 12h,
90-100%; (b) NaH, dry THF, 0oC, 30min, added C4H9Br, r.t. 12h, 98%.
Scheme 2. Synthesis of Sodium sulfinate derivatives 4a-la
aReagents and conditions: (a) NaS2O4, NaHCO3, 80oC, 4 h, 20-80%.
Scheme 3. Synthesis of N-H indole derivatives 5a-ea
aReagents and conditions: (a) I2, TBHP, CH3CH2OH, 80oC, 12 h.
Scheme 4. Synthesis of compound 6a, 7a-ba
aReagents and conditions: (a) I2, TBHP, MeOH, 80oC, 12 h.
Scheme 5. Synthesis of 2-sulfonyl indoles 8a-h, 9a-k, 10a-da
aReagents and conditions: (a) I2, TBHP, MeOH, 80oC, 12 h.
Figure 1. Structures of a-f and drug design conception.
Figure 2. Indomethacin and compounds 5a-d, 6a, 7a-b, 8a-h, 9a-k, 10a-d inhibited
LPS-induced TNF-a (A) and IL-6 (B) secretion in MPMs. Macrophages were plated
at a density of 4.0 x 105/plate and cultured overnight. Cells were pre-treated with
compounds (10 µM) for 30 minutes, then treated with LPS (0.5 mg/ml) for 24 h.
TNF-α and IL-6 levels in the culture media were measured by ELISA and were
normalized by the total protein. The results were expressed as the percent of LPS
control. Each bar represents mean ± SEM of 3-5 independent experiments. [*p < 0.05,
**p < 0.01 compared to LPS].

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Figure 3. Predictive structure-activity relationship analysis (SAR) of compounds 5a-d,
6a, 7a-b, 8a-h, 9a-k, 10a-d.
Figure 4. Active compounds 8a, 9g, 9h and 9k inhibited LPS-induced TNF-α (A)
and IL-6 (B) release in a dose-dependent manner. MPMs were plated at a density of
4.0 x 105/plate and cultured overnight. Cells were pre-treated with compounds at
indicated concentrations for 30 min, then treated with LPS (0.5 mg/ml) for 24 h.
TNF-α and IL-6 levels in the culture media were measured by ELISA and were
normalized by the total protein. Each bar represents mean ± SEM of 3-5 independent
experiments. [*p < 0.05, **p < 0.01 compared to LPS].
Figure 5. Effect of active compounds 9h and 9k on histopathological changes in lung
tissues of mice challenged with LPS. (A) H&E staining. (B) Total protein
concentration in BALF. [ns: no significance, *p < 0.05, **p < 0.01, ***p < 0.001 vs
LPS].
Figure 6. Application of active compounds 9h and 9k in a mouse ALI model.
(A)TNF-α in BALF, (B) IL-6 in BALF, (C) TNF-α in serum, (D) Total cells in BALF,
(E) MPO activity of lung tissues from each group, (F) lung CD68
immunohistochemistry. [ns: no significance, *p < 0.05, **p < 0.01, ***p < 0.001 vs
LPS].
Figure 7. Active compounds 9h and 9k inhibited LPS-induced inflammatory genes in
mouse macrophages (A-C) and mouse lung tissue (D-F). (A, D) IL-6 mRNA levels,
(B, E) IL-1β mRNA levels, (C, F) VACM-1 mRNA levels. [ns: no significance, *p <
0.05, **p < 0.01, ***p < 0.001 vs LPS].

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