Synthesis and biological evaluation of novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the treatment of cognitive disorders

Article abstract of DOI:10.3109/14756366.2015.1103233

A series of 1-[3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole and 1-[3-(4-ethyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole derivatives were designed and synthesized as 5-HT₆ receptor (5-HT₆R) ligands. The lead compound 1-[4-methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-1H-indole dihydrochloride (6b), in this series, has shown potent in vitro binding affinity, selectivity, good pharmacokinetics (PK) profile and activity in the animal models of cognition.

Full text of DOI:10.3109/14756366.2015.1103233

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Synthesis and biological evaluation of novel N1-
phenylsulphonyl indole derivatives as potent
and selective 5-HT6R ligands for the treatment of
cognitive disorders
Ramakrishna V. S. Nirogi, Thrinath Reddy Bandyala, Pamuletinarasimha
Reddy Gangadasari & Mukkanti Khagga
To cite this article: Ramakrishna V. S. Nirogi, Thrinath Reddy Bandyala, Pamuletinarasimha
Reddy Gangadasari & Mukkanti Khagga (2016): Synthesis and biological evaluation of
novel N1-phenylsulphonyl indole derivatives as potent and selective 5-HT6R ligands for the
treatment of cognitive disorders, Journal of Enzyme Inhibition and Medicinal Chemistry, DOI:
10.3109/14756366.2015.1103233
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ISSN: 1475-6366 (print), 1475-6374 (electronic)
J Enzyme Inhib Med Chem, Early Online: 1–15
2016 Taylor & Francis. DOI: 10.3109/14756366.2015.1103233
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RESEARCH ARTICLE
Synthesis and biological evaluation of novel N1-phenylsulphonyl indole
derivatives as potent and selective 5-HT6R ligands for the treatment of
cognitive disorders
Ramakrishna V. S. Nirogi1, Thrinath Reddy Bandyala1,2, Pamuletinarasimha Reddy Gangadasari1, and
Mukkanti Khagga2
2
1Discovery Research, Suven Life Sciences Limited, Hyderabad, India and Centre for Chemical Sciences and Technology, Institute of Science and
Technology, Jawaharlal Nehru Technological University Hyderabad, Hyderabad, India
Abstract
Keywords
A series of 1-[3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole and 1-[3-(4-ethyl
piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole derivatives were designed and synthesized as
5-HT6 receptor (5-HT6R) ligands. The lead compound 1-[4-methyl-3-(4-methyl piperazin-1-yl
methyl) phenylsulfonyl]-1H-indole dihydrochloride (6b), in this series, has shown potent in vitro
binding affinity, selectivity, good pharmacokinetics (PK) profile and activity in the animal
models of cognition.
5-Hydroxytryptamine-6 receptor, animal
models, central nervous system, cognition,
novel object recognition test,
structure–activity relationship
History
Received 15 May 2015
Revised 11 September 2015
Accepted 11 September 2015
Published online 28 October 2016
Introduction
of cognitive impairments associated with Alzheimer’s disease and
schizophrenia.
Alzheimer disease (AD), the most common cause of dementia in
the elderly, is clinically characterized by progressive cognitive
impairment associated with severe neuropsychiatric disturbances.
These behavioral and psychological symptoms of dementia
(BPSD) include hallucinations, delusions, aggressive behavior,
over activity, anxiety and affective disturbances1,2. Current
options for treating the cognitive symptoms associated with
Alzheimer’s are inadequate, giving urgency to the search for novel
therapeutic strategies3–5. The 5-HT6 receptor has been identified
as a potential target for the treatment of cognitive deficits in
Alzheimer’s disease and schizophrenia.
The serotonin-6 receptor (5-HT6) is a G-protein-coupled
receptor (GPCR) predominantly expressed in the central nervous
system (CNS). In particular, it is widely reported to be located in
brain regions associated with learning and memory such as the
cerebral cortex, the hippocampus and the striatum6. It has been
demonstrated that antagonism of the 5-HT6 receptor modulates
the release of a wide variety of neurotransmitters including
elevation of extracellular levels of both glutamate and acetylcho-
line in brain regions such as the medial prefrontal cortex and the
hippocampal formation7,8. This modulatory activity suggests
potential utility for 5-HT6 receptor antagonists in the treatment
Research efforts in this area have led to the discovery of a
number of potent and selective 5-HT6 receptor antagonists over
the past decade, some of which have successfully undergone
Phase-I clinical studies and some have been evaluated in clinical
Phase-II studies for the treatment of AD9. As part of our own
research program, we at Suven have designed and developed
selective 5-HT6 receptor competitive antagonist, SUVN-502
which has shown positive results in both preclinical and Phase-I
study for cognitive impairment in schizophrenia and Alzheimer’s
disease10. Currently, several 5-HT6R antagonists, for example
SYN-120 (Biotie therapies)11, SAM-760 (Pfizer)12, AVN-211
(Figure 1, Avineuro Pharmaceuticals)13, Lu AE58054 (Figure 1,
Lundbeck)14, SB-742457 (Figure 1, GlaxoSmithKline, Brentford,
England, UK)15 are the advanced stage clinical candidates for the
treatment of different cognitive and mental disorders including
Alzheimer’s disease and schizophrenia.
During this decade or so, there was a plenty of chemistry
developed around different nuclei including the indole-based ones
or even much simpler biphenyl sulfones and sulfonamides16–33,34
(Figure 2). Suven has reported several series of 1-sulfonylindoles
bearing the amino group at 3 or 4 or 5 position of the central
core31–33. As part of our continuing research efforts in the 5-HT6
area to identify potent and selective 5-HT6 receptor ligands as
potential treatments for cognitive dysfunction, we have attempted
structural modification of earlier reported piperazinyl methyl-N1-
phenylsulfonyl indole derivatives33. We wished to determine
whether introduction of piperazinyl methyl group on N1-
phenylsulfonyl moiety at C-30 position would have a desired
Address for correspondence: Ramakrishna V. S. Nirogi, Discovery
Research, Suven Life Sciences Limited, Serene Chambers, Road-5,
Avenue-7, Banjara Hills, Hyderabad, 500 034, India. Tel: +91-40-
23556038/23541142. Fax: +91-40-23541152. E-mail: nvsrk@suven.com

2
R. V. S. Nirogi et al.
J Enzyme Inhib Med Chem, Early Online: 1–15
F
Figure 1. Structures of 5-HT6R antagonists in
clinical trials for Alzheimer’s disease.
O
F
O
O
F
S
O
N
F
S
HN
O
N
CH3
H3C
N
N
S
N
N
H
N
CH3
AVN-211, Ki = 1.2 nM
F
H
SB-742457, Ki = 0.234 nM
Lu AE58054, Ki = 0.83 nM
CH3
N
CH3
N
Cl
HN
O
S
R2
O
O
N
NH
O
O
S
N
O
N
N
N
Cl
N
NH
Cl
S
N
H
R1
CH3
O
O
O
S
R
CH3
O
3: R1 = H, R2= CH3, Ki = 0.63 nM,
R1 = OCH3, R2 = H, SB-399885,
Ki = 0.8 nM
4: R = 2-Br-Ph, Ki =1.4 nM
2: Ki = 0.2 nM
1: Ki = 0.16 nM
O
O
H
N
R
N
S
R
N
N
X
N
Cl
N
H
X
N
CH3
N
S
O
HN
S
O
N
R
O
S
N
H
S
O
CH3
R
O
O
O
8: X = Cl, R = Ph, Ki = 1.0 nM,
X = Cl, R = 3-Cl-Ph, SB-699929,
Ki = 0.3 nM,
7: X = N, R = H, Ki = 0.5 nM,
X = N, R = CH3, RO-4368554,
Ki = 0.5 nM,
6: R = H, Ki = 0.2 nM,
R = CH3, Ki = 0.2 nM
5: R = H, SB-271046, Ki = 1.3 nM,
R = CH3, SB-258510, Ki = 0.63 nM
X = C, R = H, Ki = 0.3 nM
Figure 2. Structures of known 5-HT6 receptor ligands.
effect on the binding to 5-HT6R and aimed to investigate the 1H-indole and 1-[3-(4-ethyl piperazin-1-ylmethyl) phenylsulfo-
structure–activity relationship (SAR). Researchers have devel- nyl]-1H-indole derivatives (Compounds 6) was summarized in
oped a pharmacophore model (Figure 3) for 5-HT6 receptor Scheme I.
antagonists, based on reported chemically diverse 5-HT6 receptor
Commercially available substituted 3-chlorosulfonyl benzoic
antagonists35–42,34. In this pharmacophore model, four core acid 2 was reacted with substituted indoles 1 in the presence of
features were taken into consideration which include the positive sodium hydride as base at room temperature to obtain 3-(indole-1-
ionizable atom (PI, usually a secondary or tertiary amino group), sulfonyl) benzoic acid derivatives 3. The latter were treated
a hydrogen bond acceptor group (HBA, usually a sulfone or with lithium aluminum hydride at 0 to 5 ꢀC to obtain 1-(3-
sulfonamide group), a hydrophobic site (HYD) and ꢀ-electron hydroxymethyl phenylsulfonyl)-1H-indole derivatives 4 in an
donor aromatic or heterocyclic ring (AR). We have designed and overall yield of 33–55%.
synthesized a series of sulfonyl indoles bearing basic cyclic
The intermediates 4 were treated with manganese dioxide
amines (i.e. N1-CH3 and N1-C2H5 substituted piperazines) on under reflux to afford 1-(3-formyl phenylsulfonyl)-1H-indole
phenyl ring at C-30 position (Figure 4), this designed series of derivatives 5 in 75–85% yield. Finally, the aromatic aldehydes 5
compounds has all the required pharmacophoric features for were reacted with appropriate N1-alkyl piperazines (N1-CH3 and
binding to 5-HT6R, and hence, we expected these compounds to N1-C2H5) in the presence of sodium triacetoxy borohydride as
be potent 5-HT6R ligands. Herein, we report a series of 1-[3–(4- reducing agent, to obtain the targeted compounds 6. The latter
methyl piperazin-1-ylmethyl) phenylsulfonyl]-1H-indole and compounds were further treated with methanolic hydrochloric
1-[3-(4-ethyl
piperazin-1-ylmethyl)
phenylsulfonyl]-1H- acid (16% w/v) to obtained the desired compounds as HCl salts
indole derivatives as potent and selective 5-HT6R ligands (compounds 6) in 55–65% yield.
(Compounds-6, Figure 4).
The selected compound 6b from this series was active in 5-HT6R-binding data (in vitro)
animal models of cognition. The synthesis, in vitro activity,
selectivity, SAR, CYP liabilities in human liver microsomes,
Radioligand binding assay for human 5-HT6 receptor
pharmacokinetics and pharmacological activities of this series of The in vitro 5-HT6 receptor-binding assay was carried out on
compounds are discussed in this paper.
human recombinant receptor expressed in HEK293 cells;
Chemistry: The general synthetic strategy used for the prepar- radioligand used was [3H] LSD (60–80 Ci/mmol). Final ligand
ation of 1-[3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]- concentration was 1.5 nM, nonspecific determinant was

DOI: 10.3109/14756366.2015.1103233
N1-phenylsulphonyl indole derivatives
3
Figure 3. 5-HT6 receptor pharmacophore
model.
Hydrophobic site
C
Proton
donor
(HYD)
A
Z
(PI)
Z'
B
X
Y
S
X = N, C
Y = C, N
O
O
Z = N, C with Z' = C, N
Double
acceptor
D
Hydrophobic site
(HYD)
(HBA)
determined in duplicate and the average values are reported here.
5-HT6 receptor-binding studies were carried out at NovaScreen
Biosciences Corporation, (caliper life sciences), Hanover, MD, as
per their standard protocol.
AR HYD
R2
2
4
5
3
R1
PI
N
O2S
6
Determination of kb and IC50 values for 5-HT6 receptor
antagonists
1
2'
7
N
3'
1'
N
HBA
A stable CHO cell line expressing recombinant human 5-HT6
receptor and pCRE-Luc reporter system was used for cell-based
assay. The assay offers a nonradioactive-based approach to
determine potency of a compound to GPCRs. In this specific
assay, the level of intracellular cyclic AMP which is modulated
by the activation or inhibition of the receptor is measured. The
recombinant cells harbor luciferase reporter gene under the
control of cAMP response element. The above cells were plated
in 96-well clear bottom white plates at a density of 5 ꢁ 104
cells/well using Hams F12 medium containing 10% fetal bovine
serum (FBS) and incubated overnight at 37 ꢀC and 5% CO2
followed by serum starvation for 18–20 h. Increasing concen-
trations of test compounds were added along with 10 mM
serotonin in OptiMEM to the cells. The incubation was
continued at 37 ꢀC in CO2 incubator for 4 h. After 4 h, cells
were lysed using lyses buffer and luciface assay buffer was
added to each well and counts per second were recorded using
luminescence counter. From CPS obtained, percentage inhib-
ition was calculated for each well by normalizing CPS values
obtained in the presence of the compounds to those with 10 mM
5-HT (0% inhibition) and with vehicle (100% inhibition). The
percent inhibition was determined for all concentrations of the
antagonists (0.1 nM–10 mM range, half-log increment) and
plotted as a function of the antagonist concentration. The Kb
values were calculated with Prism (GraphPad Software Inc., La
Jolla, CA) using built-in one site competition equation, by
entering EC50 values for 5-HT obtained in the same experi-
ments (80–100 nM) and the 5-HT concentration 10 mM, as it
was used in all the experiments.
R4
R3
6'
4'
5'
HYD
Compounds-6
Figure 4. General structure of designed 5-HT6 receptor ligands.
methiothepin mesylate – [0.1 mM]; Methiothepin mesylate was
used as reference compound and positive control. The radioligand
binding study was carried out at NovaScreen, Hanover, MD.
Materials and methods
General considerations
Infrared spectra were recorded in KBr disc and in solid state using
Perkin-Elmer model 1600 FT-IR spectrophotometer (Perkin-
Elmer, Norwalk, CT). Electrospray ionization mass spectra were
recorded on API 4000 triple quadrupole instrument (MDSSCIEX,
1
Concord, Ontario, Canada). H-NMR spectra were obtained on a
Bruker proton NMR spectrometer (Fallanden, Switzerland) at
400 MHz. Deuterated reagents were used as solvents and were
commercially procured. Tetramethylsilane (TMS) was used as an
internal standard. Chemical shift values are expressed in parts per
million (d) and coupling constants are expressed in Hertz (Hz).
Chromatography refers to column chromatography performed
using 100–200 mesh silica gel and executed under nitrogen
pressure (flash chromatography) conditions. All the reagents and
chemicals used were of ‘‘reagent grade’’.
Rodent pharmacokinetic study
Male Wistar rats (225 25 gm) were used as experimental
animals. Three animals were housed in each cage. Two days
prior to dosing day, male Wistar rats (225–250 gm) were
Determination of % inhibition at 100 nM concentration, ki
and IC50 values for 5-HT6 receptor
The in vitro 5-HT6 receptor-binding assay was carried out on anesthetized with isoflurane for the surgical placement of jugular
human recombinant expressed receptor in HEK293 cells; vein catheter. Animals were fasted over night before oral dosing
Radioligand used was [3H]LSD (60–80 Ci/mmol). Final ligand (p.o) and food pellets were allowed 2-h postdosing, whereas
concentration was 1.5 nM, nonspecific determinant was during intravenous dosing, food and water were provided as ad
methiothepin mesylate – [0.1 mM]; methiothepin mesylate was libitum. Three rats were dosed with compounds (10 mg/kg) orally
used as reference compound and positive control. Ki values were and intravenously (10 mg/kg).

4
R. V. S. Nirogi et al.
J Enzyme Inhib Med Chem, Early Online: 1–15
R2
Scheme I. Reagents and conditions: (a) NaH,
tetrahydrofuran, RT, 20–24 h; (b) LiAlH4,
0–5 ꢀC, 4–5 h; (c) MnO2, Ethylene
Dichloride, reflux, 3–4 h; (d) N-methyl (or)
N-ethyl piperazine, Ethylene Dichloride,
Na(OAC)3BH, RT, 6–7 h; (e) Methanolic
HCl (16% w/v), Diethylether, RT, 1 h.
O
R2
a
R1
ClO2S
OH
R1
N
O
+
R3
N
O2S
OH
H
2
1
3
R3
(
33-55%)
b
over two steps
R2
R2
R1
R1
N
c
N
O
O2S
OH
4
O2S
(75-85%)
H
R3
5
R3
d,
e
(55-65%)
R1 = H, 5-OCH3, 5-OC2H5, 5-OiPr, 5-F, 5-Br
R2 = H, CH3
R3 = H, CH3, Cl, Br
R4 = CH3, C2H5
R2
R1
N
O2S
.2HCl
N
N
R3
R4
Compounds-6a to 6ac
At each time point, blood was collected through jugular vein concentrations, brian and blood was collected and estimated.
and immediately replenish with an equivalent volume of normal The animals were sacrificed to collect the plasma and brain tissue
saline from freely moving rats. Collected blood was transferred and thenhomogenized using milli-Q water (20%). Plasma and
into a labeled appendorf containing 10 mL of heparin as brain was stored frozen at ꢂ20 ꢀC until analysis. The concentra-
anticoagulant. Blood samples were collected at following time tions of the test compound in plasma and brain were determined
points: pre dose, 0.08 (only i.v.), 0.25-, 0.5-, 1-, 2-, 4-, 6-, 8- and using LC-MS/MS method.
24-h postdose (n ¼ 3). Blood was centrifuged at 4000 rpm for
The test compound was quantified in plasma and brain
10 min. Plasma was prepared and stored at ꢂ20 ꢀC until analysis. homogenate by validated LC-MS/MS method using solid-phase
The concentrations of the compounds were quantified in plasma extraction technique. The compound was quantified in the
by qualified LC-MS/MS method using suitable extraction tech- calibration range of 1–500 ng/mL in plasma and brain homogen-
nique. The compounds were quantified in the calibration range ate. Study samples were analyzed using calibration samples in the
around 2–2000 ng/mL in plasma. Study samples were analyzed batch and quality control samples spread across the batch. Extent
using calibration samples in the batch and quality control samples of brain-plasma ratio was calculated (Cb/Cp).
spread across the batch.
Pharmacokinetic parameters, Cmax, AUC0-t, t1/2 and bioavail- Protocol for NORT
ability, were calculated by noncompartmental model using stand-
For object recognition test, male Wistar rats 10–12 weeks old were
ard noncompartmental model by using WinNonLin 5.0.1 version
used. Arena was 50 ꢁ 50 ꢁ 50 cm. Open field was made up of
Software package (Pharsight corporation, Mountain view, CA).
acrylic. Twnety-four hours prior to testing, rats were habituated to
individual test arenas for 20 min in the absence of any objects.
Rodent brain penetration study
Twnety-four hours after the habituation, during the familiarization
Male Wistar rats (225 25 gm) were used as experimental phase (T1), rats were placed individually in the open field for
animals. Three animals were housed in each cage. Animals 3 min, containing two identical objects (a1 and a2). T2 trial was
were given water and food ad libitum throughout the experiment carried out after 24 h after the T1 trial. Rats were allowed to explore
and maintained on a 12-h light/dark cycle.
the open field for 3 min in the presence of one familiar object (a3)
Brain penetration was determined at steady state in rat. One and one novel object (b). Discriminative index was calculated.
day prior to dosing day, male wistar rats (225 25 gm) were
anesthetized with halothane for the surgical placement of jugular Experimental
and femoral vein catheters. After surgery, the rats were housed in
Experimental procedures and analytical characterization
individual rat infusion cage connected with infusion components
data of compounds 3a–3ab, 4a–4ab, 5a–5ab and 6a–6ac
and allowed free access to food and water.
The test compound was dissolved in water and administered at General (representative) procedure for the synthesis of compound
a constant infusion rate (5 mL/kg/h) upto 6 h at a target dose rate 6 g (Di HCl Salt)
1.0 mg free base/kg/h. Blood samples were removed during the Preparation of 2-bromo-5-(indole-1-sulfonyl) benzoic acid
latter part of the infusion to confirm steady-state blood (3 g). A solution of indole (6.24 g, 53.33 mmol) in 25 mL

DOI: 10.3109/14756366.2015.1103233
N1-phenylsulphonyl indole derivatives
5
tetrahydrofuran (THF) was slowly added to a cooled (20 ꢀC) Ar-H), 6.93–6.99 (m, 2H, Ar-H), 7.52–7.57 (m, 2H, Ar-H), 7.88–
suspension of sodium hydride (6.59 g, 164.74 mmol) in 20 mL of 7.90 (d, 1H, J ¼ 9.16 Hz, Ar-H), 8.05–8.09 (d, 1H,
THF, over a period of 10 min maintaining the mass temperature at J ¼ 7.88 Hz, Ar-H), 8.21–8.23 (d, 1H, J ¼ 7.80 Hz, Ar-H), 8.56
25 ꢀC under nitrogen atmosphere. The mass was further diluted (s, 1H, Ar-H).
with tetrahydrofuran (20 mL). The reaction mixture was further
3-(5-Isopropoxy indole-1-sulfonyl) benzoic acid (3j,
stirred for 1 h at the same temperature. Then, added a solution of R1 ¼ 5-OCH(CH3)2, R2 ¼ H, R3 ¼ H): ESIMS (m/z): 358.2
2-bromo-5-chlorosulfonyl benzoic acid (20.01 g, 66.81 mmol) in [M ꢂ H]ꢂ; 1H-NMR (400 MHz, CDCl3): d 1.31–1.32 (d, 6H,
THF (30 mL) slowly over a period of 10 min. The progress of the J ¼ 6.04 Hz, Ar-OCH(CH3)2), 4.42–4.54 (sept, 1H, Ar-
reaction was monitored by thin-layer chromatography (TLC). OCH(CH3)2), 6.60 (d, 1H, J ¼ 3.56 Hz, Ar-H), 6.91–6.94 (dd,
After completion of the reaction, the reaction mixture was 1H, J ¼ 8.96, 2.40 Hz, Ar-H), 6.97 (d, 1H, J ¼ 2.36 Hz, Ar-H),
quenched onto 600 mL cold water. The reaction mass was 7.52–7.53 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.54–7.58 (m, 1H, Ar-H),
acidified with concentrated hydrochloric acid to pH 2 and 7.87–7.89 (d, 1H, J ¼ 8.92 Hz, Ar-H), 8.06–8.09 (m, 1H, Ar-H),
extracted the product with ethyl acetate (2 ꢁ 200 mL). The 8.23–8.25 (m, 1H, Ar-H), 8.58 (d, 1H, J ¼ 1.61 Hz, Ar-H).
combined organic layer was washed with brine solution
3-(5-Fluoro indole-1-sulfonyl) benzoic acid (3k, R1 ¼ F,
(2 ꢁ 50 mL), water (2 ꢁ 100 mL), dried over anhydrous sodium R2 ¼ H, R3 ¼ H): ESIMS (m/z): 318.1 [M ꢂ H]ꢂ; 1H-NMR
sulfate and concentrated under reduced pressure to obtain 17.81 g (400 MHz, CDCl3): d 6.65–6.66 (d, 1H, J ¼ 3.08 Hz, Ar-H),
technical product. The material was used as such in the next step, 7.05–7.11 (m, 1H, Ar-H), 7.17–7.20 (dd, 1H, J ¼ 8.64, 2.52 Hz,
with out further purification.
Ar-H), 7.59–7.62 (m, 2H, Ar-H), 7.94–7.98 (m, 1H, Ar-H), 8.07–
Melting range: 188.7–191.4 ꢀC (dec); IR spectra (cmꢂ1): 1710, 8.09 (m, 1H, Ar-H), 8.25–8.27 (m, 1H, Ar-H), 8.57 (d, 1H,
1683, 1579, 1440, 1371, 1255, 1180, 1124, 744; ESIMS (m/z): J ¼ 1.64 Hz, Ar-H).
1
378.1, 380.0 [M ꢂ H]ꢂ; H-NMR (400 MHz, CDCl3): d 6.6–6.61
5-(5-Methoxy indole-1-sulfonyl)-2-methyl benzoic acid, (3 l,
(d, 1H, J ¼ 3.88 Hz, Ar-H), 7.13–7.24 (m, 2H, Ar-H), 7.43–7.45 R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ CH3): Melting range (ꢀC): 190.2–
(m, 2H, Ar-H), 7.61–7.64 (m, 2H, Ar-H), 7.83–7.85 (d, 1H, 194.9 (dec); IR (cmꢂ1): 3151, 1728, 1440, 1369, 1219, 1145;
1
J ¼ 8.24, Ar-H), 8.23 (d, 1H, J ¼ 2.04 Hz, Ar-H).
ESIMS (m/z): 344.1 [M ꢂ H]ꢂ; H-NMR (400 MHz, CDCl3): d
Similarly, compounds 3a–3ab were prepared from respective 2.69 (s, 3H, Ar-CH3), 3.81 (s, 3H, Ar-OCH3), 6.60–6.61 (d, 1H,
starting materials 1 (commercially available substituted indoles) J ¼ 3.08 Hz, Ar-H), 6.93 (d, 1H, J ¼ 2.48 Hz, Ar-H), 6.95–6.97
and 2 (commercially available substituted 3-chlorosulfonyl ben- (dd, 1H, J ¼ 6.68, 2.20 Hz, Ar-H), 7.32–7.34 (d, 1H, J ¼ 8.24, Ar-
zoic acids) by using the method described previously, for example H), 7.52–7.53 (d, 1H, J ¼ 3.60 Hz, Ar-H), 7.86–7.90 (m, 2H, Ar-
3 g with some noncritical variations. The analytical data of H), 8.52–8.53 (d, 1H, J ¼ 2.12 Hz, Ar-H).
compounds 3a–3ab are presented below. The obtained technical
5-(5-Fluoro indole-1-sulfonyl)-2-methyl benzoic acid (3m,
product was used as such in the next step, with out further R1 ¼ 5-F, R2 ¼ H, R3 ¼ CH3): Melting range (ꢀC): 198.7–200.7
purification.
(dec); IR (cmꢂ1): 3500, 3111, 1693, 1452, 1369, 1267, 1128;
3-(Indole-1-sulfonyl) benzoic acid (3a, R1 ¼ H, R2 ¼ H, ESIMS (m/z): 331.9 [M ꢂ H]ꢂ; H-NMR (400 MHz, DMSO-d6):
R3 ¼ H): ESIMS (m/z): 300.1 [M ꢂ H]ꢂ; 1H-NMR (400 MHz, d 2.49 (s, 3H, Ar-CH3), 6.83–6.84 (d, 1H, J ¼ 3.24 Hz, Ar-H),
CDCl3): d 6.69–6.70 (d, 1H, J ¼ 3.08 Hz, Ar-H), 7.23–7.27 (m, 7.18–7.23 (m, 1H, Ar-H), 7.40–7.43 (dd, 1H, J ¼ 9.08, 2.60 Hz,
2H, Ar-H), 7.33–7.37 (m, 1H, Ar-H), 7.52–7.61 (m, 2H, Ar-H), Ar-H), 7.51–7.53 (d, 1H, J ¼ 8.24, Ar-H), 7.90–7.92 (m, 2H, Ar-
8.00–8.02 (m, 1H, Ar-H), 8.09–8.12 (m, 1H, Ar-H), 8.23–8.26 H), 8.00–8.03 (dd, 1H, J ¼ 8.16 & 2.24 Hz, Ar-H), 8.24–8.25
1
(m, 1H, Ar-H), 8.60 (d, 1H, J ¼ 1.60 Hz, Ar-H).
(d, 1H, J ¼ 2.20 Hz, Ar-H), 13.46–13.49 (bs, 1H, Ar-COOH).
2-Chloro-5-(5-fluoro indole-1-sulfonyl) benzoic acid (3o,
5-(Indole-1-sulfonyl)-2-methyl benzoic acid (3b, R1 ¼ H,
R2 ¼ H, R3 ¼ 40-CH3): Melting range (ꢀC): 173.60–174.7 R1 ¼ F, R2 ¼ H, R3 ¼ Cl): Melting range (ꢀC): 189.6–191.5
(Clear); IR (cmꢂ1): 3126, 2924, 1699, 1440, 1375, 1261, 1172, (Clear); ESIMS (m/z): 352.5, 354.5 [M ꢂ H]ꢂ; 1H-NMR
1120; ESIMS (m/z): 314.4 [M ꢂ H]ꢂ; 1H-NMR (400 MHz, (400 MHz, CDCl3): d 6.67–6.68 (d, 1H, J ¼ 3.18 Hz, Ar-H),
CDCl3): d 2.62 (s, 3H, Ar-CH3), 6.67–6.68 (d, 1H, J ¼ 3.6 Hz, 7.06–7.11 (m, 1H, Ar-H), 7.18–7.20 (dd, 1H, J ¼ 8.60, 2.52 Hz,
Ar-H), 7.21–7.25 (m, 1H, Ar-H), 7.30–7.34 (m, 2H, Ar-H), 7.51– Ar-H), 7.55–7.56 (d, 1H, J ¼ 2.34 Hz, Ar-H), 7.58–7.60 (d, 1H,
7.53 (d, 1H, J ¼ 7.8 Hz, Ar-H), 7.56–7.57 (d, 1H, J ¼ 3.68 Hz, Ar- J ¼ 8.48 Hz, Ar-H), 7.89–7.90 (dd, 1H, J ¼ 8.50, 2.41 Hz, Ar-H),
H), 7.89–7.91 (dd, 1H, J ¼ 8.16, 2.04 Hz, Ar-H), 7.98–8.00 (d, 7.91–7.94 (m, 1H, Ar-H), 8.48–8.49 (d, 1H, J ¼ 2.36 Hz, Ar-H).
1H, J ¼ 8.32 Hz, Ar-H), 8.55–8.56 (d, 1H, J ¼ 1.96 Hz, Ar-H).
2-Bromo-5-(5-fluoro indole-1-sulfonyl) benzoic acid (3q,
2-Chloro-5-(indole-1-sulfonyl) benzoic acid (3d, R1 ¼ H, R1 ¼ F, R2 ¼ H, R3 ¼ Br): Melting range (ꢀC): 193.6–196.5
R2 ¼ H, R3 ¼ Cl): Melting range (ꢀC): 177.7–182.1 (dec); IR (Clear); IR (cmꢂ1): 3140, 2922, 1701, 1456, 1375, 1294, 1174,
(cmꢂ1): 3138, 1695, 1442, 1375, 1259, 1178, 1124; ESIMS (m/z): 1130; ESIMS (m/z): 397, 399 [M ꢂ H]ꢂ; 1H-NMR (400 MHz,
334.1, 336.1 [M ꢂ H]ꢂ; 1H-NMR (400 MHz, CDCl3): d 6.71–6.72 CDCl3): d 6.66 (d, 1H, J ¼ 3.40 Hz, Ar-H), 6.66–7.09 (m, 1H, Ar-
(d, 1H, J ¼ 3.64 Hz, Ar-H), 7.24–7.28 (m, 1H, Ar-H), 7.33–7.37 H), 7.17–7.20 (dd, 1H, J ¼ 8.60, 2.52 Hz, Ar-H), 7.56–7.57
(m, 1H, Ar-H), 7.54–7.56 (m, 3H, Ar-H), 7.90–7.93 (dd, 1H, (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.76–7.77 (m, 2H, Ar-H), 7.90–7.93
J ¼ 8.52, 2.40 Hz, Ar-H), 7.97–7.99 (d, 1H, J ¼ 8.16 Hz, Ar-H), (dd, 1H, J ¼ 9.12, 2.41 Hz, Ar-H), 8.40–8.41 (d, 1H, J ¼ 1.32 Hz,
8.50–8.51 (d, 1H, J ¼ 2.36 Hz, Ar-H).
Ar-H).
2-Bromo-5-(5-bromo indole-1-sulfonyl) benzoic acid (3s,
3-(5-Methoxy indole-1-sulfonyl) benzoic acid (3 h,
R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ H): ESIMS (m/z): 330.3 [M ꢂ H]ꢂ; R1 ¼ Br, R2 ¼ H, R3 ¼ Br):
1H-NMR (400 MHz, CDCl3): d 3.80 (s, 3H, Ar-OCH3), 6.62–6.63
(d, 1H, J ¼ 3.63 Hz, Ar-H), 6.93–6.94 (d, 1H, J ¼ 2.50 Hz, Ar-H),
ESIMS (m/z): 456.1, 458.2, 460.2 [M ꢂ H]ꢂ.
2-Chloro-5-(5-methoxy indole-1-sulfonyl) benzoic acid (3t,
6.96–6.97 (m, 1H, Ar-H), 7.53–7.58 (m, 2H, Ar-H), 7.89–7.91 (d, R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ Cl): Melting range (ꢀC): 156.75–
1H, J ¼ 8.76 Hz, Ar-H), 8.05–8.08 (m, 1H, Ar-H), 8.22–8.25 (m, 157.45 (Clear); IR (cmꢂ1): 3115, 1705, 1462, 1373, 1217, 1135;
1H, Ar-H), 8.56–8.57 (d, 1H, J ¼ 1.72 Hz, Ar-H).
ESIMS (m/z): 364.2, 366.2 [M ꢂ H]ꢂ; 1H-NMR (400 MHz,
3-(5-Ethoxy indole-1-sulfonyl) benzoic acid (3i, R1 ¼ 5- CDCl3):
d 3.81 (s, 3H, Ar-OCH3), 6.63–6.64 (d, 1H,
OCH2CH3, R2 ¼ H, R3 ¼ H): ESIMS (m/z): 344.3 [M ꢂ H]ꢂ; J ¼ 3.16 Hz, Ar-H), 6.94–6.98 (m, 2H, Ar-H), 7.49–7.54
1H-NMR (400 MHz, CDCl3): d 1.38–1.42 (t, 3H, Ar-OCH2CH3), (m, 2H, Ar-H), 7.86–7.89 (m, 2H, Ar-H), 8.47 (d, 1H,
3.98–4.04 (q, 2H, Ar-OCH2CH3), 6.60–6.61 (d, 1H, J ¼ 3.60 Hz, J ¼ 2.40 Hz, Ar-H).

6
R. V. S. Nirogi et al.
J Enzyme Inhib Med Chem, Early Online: 1–15
2-Bromo-5-(5-methoxy indole-1-sulfonyl) benzoic acid (3v, Melting range (ꢀC): 101.0–102.8 (Clear); IR (cmꢂ1): 3280, 1444,
R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ Br): Melting range (ꢀC): 177.50– 1365, 1163, 1126; ESIMS (m/z): 302.7 [M + H]+; 1H-NMR
177.80 (Clear); IR (cmꢂ1): 3130, 1714, 1467, 1373, 1222, 1147; (400 MHz, CDCl3): d 1.72 (bs, 1H, Ar-CH2OH), 2.27 (s, 3H, Ar-
ESIMS (m/z): 407.9, 409.8 [M ꢂ H]ꢂ; 1H-NMR (400 MHz, CH3), 4.64–4.65 (d, 2H, Ar-CH2OH), 6.64–6.65 (d, 1H,
CDCl3):
d
3.81 (s, 3H, Ar-OCH3), 6.63–6.64 (d, 1H, J ¼ 3.6 Hz, Ar-H), 7.19–7.30 (m, 3H, Ar-H), 7.51–7.52 (d, 1H,
J ¼ 3.12 Hz, Ar-H), 6.94–6.96 (dd, 1H, J ¼ 8.88, 2.48 Hz, Ar- J ¼ 6.56 Hz, Ar-H), 7.57–7.58 (d, 1H, J ¼ 3.64 Hz, Ar-H), 7.92–
H), 6.97–6.98 (d, 1H, J ¼ 2.2 Hz, Ar-H), 7.48–7.49 (d, 1H, 7.93 (d, 1H, J ¼ 1.92 Hz, Ar-H), 7.98 (d, 1H, J ¼ 0.72 Hz, Ar-H),
J ¼ 3.6 Hz, Ar-H), 7.74–7.79 (m, 2H, Ar-H), 7.85–7.87 (d, 1H, 8.05–8.07 (d, 1H, J ¼ 0.68 Hz, Ar-H).
J ¼ 8.84 Hz, Ar-H), 8.42 (d, 1H, J ¼ 1.32 Hz, Ar-H).
1-[4-Chloro-3-(hydroxymethyl) phenylsulfonyl]-1H-indole
2-Chloro-5-(3-methyl indole-1-sulfonyl) benzoic acid (3x, (4d, R1 ¼ H, R2 ¼ H, R3 ¼ Cl): Yield: 39% (over 2 steps);
R1 ¼ H, R2 ¼ CH3, R3 ¼ Cl): Melting range (ꢀC): 188.40–191.50 Melting range (ꢀC): 104.5–107.4 ꢀC (dec); IR (cmꢂ1): 3429,
(Clear); IR (cmꢂ1): 2921, 1714, 1444, 1372, 1276, 1182, 1121; 1446, 1371, 1261, 1166, 1126; ESIMS (m/z): 322.1 [M + H]+,
ESIMS (m/z): 348.0, 350.1 [M ꢂ H]ꢂ; 1H-NMR (400 MHz, 324.0 [M + H]+2; H-NMR (400 MHz, CDCl3): d 1.85 (bs, 1H,
1
CDCl3): d 2.25 (d, 3H, Ar-CH3), 7.28–7.30 (m, 2H, Ar-H), Ar-CH2OH), 4.72 (s, 2H, Ar-CH2OH), 6.67–6.68 (d, 1H,
7.33–7.38 (m, 1H, Ar-H), 7.46–7.48 (d, 1H, J ¼ 7.84 Hz, Ar-H), J ¼ 3.64 Hz, Ar-H), 7.21–7.25 (m, 1H, Ar-H), 7.32–7.37 (m,
7.51–7.53 (d, 1H, J ¼ 8.52 Hz, Ar-H), 7.88–7.91 (dd, 1H, 1H, Ar-H), 7.39–7.41 (m, 1H, Ar-H), 7.52–7.56 (m, 2H, Ar-H),
J ¼ 8.48, 2.40 Hz, Ar-H), 7.97–7.99 (d, 1H, J ¼ 8.20, Ar-H), 7.72–7.74 (dd, 1H, J ¼ 8.36, 2.28 Hz, Ar-H), 7.97–7.99 (d, 1H,
8.48–8.49 (d, 1H, J ¼ 2.32 Hz, Ar-H).
J ¼ 8.28 Hz, Ar-H), 8.06–8.07 (d, 1H, J ¼ 2.0 Hz, Ar-H).
2-Bromo-5-(3-methyl indole-1-sulfonyl) benzoic acid (3z,
5-Methoxy-1-[3-(hydroxymethyl)
phenylsulfonyl]-1H-
R1 ¼ H, R2 ¼ CH3, R3 ¼ Br): ESIMS (m/z): 392.2, 394.2 indole (4 h, R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ H): Yield: 48% (over 2
[M ꢂ H]ꢂ.
steps); ESIMS (m/z): 318.2 [M + H]+; 1H-NMR (400 MHz,
2-Chloro-5-(5-methoxy-3-methyl indole-1-sulfonyl) benzoic CDCl3): d 1.85–1.87 (bs, 1H, Ar-CH2OH), 3.80 (s, 3H, Ar-
acid (3ab, R1 ¼ 5-OCH3, R2 ¼ CH3, R3 ¼ Cl): ESIMS (m/z): OCH3), 4.69 (s, 2H, Ar-CH2OH), 6.58–6.59 (d, 1H, J ¼ 3.68 Hz,
378.2, 380.2 [M ꢂ H]ꢂ.
Ar-H), 6.91–6.93 (dd, 1H, J ¼ 8.8, 2.52 Hz, Ar-H), 6.96 (d, 1H,
J ¼ 2.36 Hz, Ar-H), 7.38–7.42 (m, 1H, Ar-H), 7.51–7.52 (m, 2H,
Ar-H), 7.75–7.77 (d, 1H, J ¼ 7.84 Hz, Ar-H), 7.85–7.89 (m, 2H,
Ar-H).
Preparation of 1-[4-bromo-3-(hydroxymethyl) phenylsul-
fonyl]-1H-indole (4g)
5-Ethoxy-1-[3-(hydroxymethyl) phenylsulfonyl]-1H-indole
(4i, R1 ¼ 5-OCH2CH3, R2 ¼ H, R3 ¼ H): Yield: 44% (over 2
steps); ESIMS (m/z): 332.3 [M + H]+; 1H-NMR (400 MHz,
CDCl3): d 1.80 (bs, 1H, Ar-CH2OH), 1.38 – 1.42 (t, 3H, Ar-
OCH2CH3), 3.98–4.04 (q, 2H, Ar-OCH2CH3), 4.69 (s, 2H, Ar-
CH2OH), 6.57–6.58 (d, 1H, J ¼ 3.16 Hz, Ar-H), 6.90–6.95 (m,
2H, Ar-H), 7.40–7.42 (m, 1H, Ar-H), 7.50–7.52 (m, 2H, Ar-H),
7.75–7.77 (d, 1H, J ¼ 7.84 Hz, Ar-H), 7.85–7.88 (m, 2H, Ar-H).
A
solution of 2-bromo-5-(indole-1-sulfonyl) benzoic acid
(17.64 g, 46.42 mmol) in 30 mL tetrahydrofuran was slowly
added to a cooled (0–5 ꢀC) suspension of lithium aluminum
hydride (2.3 g, 60.5 mmol) in 20 mL of THF. The reaction mass
was stirred at 0–5 ꢀC for 4 h. The progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction
mass was cooled to ꢂ10 ꢀC. Water (20 mL) was added slowly
under nitrogen atmosphere. The reaction mass was diluted further
with water (300 mL) and filtered through hyflow bed. The clear
filtrate was extracted with ethyl acetate (4 ꢁ 100 mL). The
combined organic layer was washed with brine solution
(2 ꢁ 50 mL), water (2 ꢁ 50 mL) and dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The
residual mass was purified by column chromatography, the eluent
system being ethyl acetate and hexane (2:8) to obtain 6.025 g of
the title product, Yield: 33% (over 2 steps).
Melting range: 102.6–103.4 ꢀC (dec); I.R (cmꢂ1): 3311, 1444,
1371, 1257, 1128, 879; ESIMS (m/z): 366 [M + H]+, 368
[M + H]+2 1H-NMR (400 MHz, CDCl3): d 4.69 (s, 2H, Ar-
;
CH2OH), 6.67–6.68 (dd, 1H, J ¼ 3.64, 0.68 Hz, Ar-H), 7.23–7.25
(m, 1H, Ar-H), 7.32–7.33 (m, 1H, Ar-H), 7.55–7.64 (m, 4H, Ar-
H), 7.97–7.99 (dd, 1H, J ¼ 4.28, 0.8 Hz, Ar-H), 8.04–8.05 (d, 1H,
Ar-H).
Similarly compounds 4a–4ab were prepared from respective
starting materials 3a–3ab by using the method described earlier
for the example 4 g with some noncritical variations. The
analytical data of compounds 4a–4ab are presented below.
5-Isopropoxy-1-[3-(hydroxymethyl)
phenylsulfonyl]-1H-
indole (4j, R1 ¼ 5-OCH(CH3)2, R2 ¼ H, R3 ¼ H): Yield: 43%
(over
2
steps); ESIMS (m/z): 346.0 [M + H]+; 1H-NMR
(400 MHz, CDCl3): d 1.98 (bs, 1H, Ar-CH2OH), 1.29–1.30 (d,
6H, J ¼ 5.84 Hz, Ar-OCH(CH3)2), 4.46–4.52 (sept, 1H, Ar-
OCH(CH3)2), 4.67 (s, 2H, Ar-CH2OH), 6.55–6.56 (d, 1H,
J ¼ 3.0 Hz, Ar-H), 6.88–6.91 (dd, 1H, J ¼ 9.0, 2.44 Hz, Ar-H),
6.95–6.96 (d, 1H, J ¼ 2.40 Hz, Ar-H), 7.36–7.40 (m, 1H, Ar-
H), 7.48–7.50 (m, 2H, Ar-H), 7.74–7.76 (d, 1H, J ¼ 7.84 Hz, Ar-
H), 7.84–7.86 (m, 2H, Ar-H).
5-Fluoro-1-[3-(hydroxymethyl) phenylsulfonyl]-1H-indole
(4k, R1 ¼ F, R2 ¼ H, R3 ¼ H): Yield: 51% (over 2 steps);
1
ESIMS (m/z): 306.2 [M + H]+; H-NMR (400 MHz, CDCl3): d
2.0 (bs, 1H, Ar-CH2OH), 4.68 (s, 2H, Ar-CH2OH), 6.61 (d, 1H,
J ¼ 3.08 Hz, Ar-H), 7.03–7.06 (m, 1H, Ar-H), 7.15–7.18 (m, 1H,
Ar-H), 7.41–7.43 (m, 1H, Ar-H), 7.51–7.54 (m, 1H, Ar-H), 7.58–
7.59 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.74–7.78 (m, 1H, Ar-H), 7.86
(s, 1H, Ar-H), 7.90–7.92 (m, 1H, Ar-H).
5-Methoxy-1-[4-methyl-3-(hydroxymethyl) phenylsulfonyl]-
1H-indole (4 l, R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ CH3): Yield: 47%
(over 2 steps); Melting range (ꢀC): 144.3–145.2 (Clear); IR
(cmꢂ1): 3422, 1606, 1467, 1365, 1224, 1136; ESIMS (m/z): 331.7
[M + H]+; 1H-NMR (400 MHz, CDCl3): d 1.75–1.78 (t, 1H,
J ¼ 5.75 Hz, Ar-CH2OH), 2.27 (s, 3H, Ar-CH3), 3.79 (s, 3H, Ar-
OCH3), 4.63–4.64 (d, 2H, J ¼ 5.51 Hz, Ar-CH2OH), 6.56–6.57 (d,
1H, J ¼ 3.08 Hz, Ar-H), 6.90–6.92 (dd, 1H, J ¼ 8.98, 2.50 Hz, Ar-
H), 6.95 (d, 1H, J ¼ 2.42 Hz, Ar-H), 7.18–7.20 (d, 1H,
J ¼ 8.02 Hz, Ar-H), 7.52–7.53 (d, 1H, J ¼ 3.59 Hz, Ar-H), 7.66–
7.68 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.86–7.89 (m, 2H, Ar-H).
5-Fluoro-1-[4-methyl-3-(hydroxymethyl) phenylsulfonyl]-
1H-indole (4m, R1 ¼ 5-F, R2 ¼ H, R3 ¼ CH3): Yield: 45%
[3-(Indole-1-sulfonyl)-phenyl]-methanol
(4a,
R1 ¼ H,
R2 ¼ H, R3 ¼ H): Yield: 55% (over 2 steps); ESIMS (m/z):
288.2 [M + H]+; 1H-NMR (400 MHz, CDCl3): d 1.80 (bs, 1H, Ar-
CH2OH), 4.69 (s, 2H, Ar-CH2OH), 6.66–6.67 (d, 1H,
J ¼ 3.60 Hz, Ar-H), 7.21–7.24 (m, 1H, Ar-H), 7.30–7.34 (m,
1H, Ar-H), 7.40–7.44 (m, 1H, Ar-H), 7.51–7.53 (m, 2H, Ar-H),
7.56–7.57 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.79–7.81 (d, 1H,
J ¼ 8.28 Hz, Ar-H), 7.88 (s, 1H, Ar-H), 7.78–8.00 (d, 1H,
J ¼ 8.32 Hz, Ar-H).
1-[4-Methyl-3-(hydroxymethyl) phenylsulfonyl]-1H-indole
(4b, R1 ¼ H, R2 ¼ H, R3 ¼ CH3): Yield: 48% (over 2 steps);

DOI: 10.3109/14756366.2015.1103233
N1-phenylsulphonyl indole derivatives
7
(over 2 steps); Melting range (ꢀC): 129.0–131.1 (Clear); IR [M + H]+2
;
1H-NMR (400 MHz, CDCl3): d 1.98 (bs, 1H, Ar-
(cmꢂ1): 3441, 1593, 1462, 1371, 1215, 1136; ESIMS (m/z): 319.9 CH2OH), 2.24 (s, 3H, Ar-CH3), 4.69 (s, 2H, Ar-CH2OH), 7.27–
[M + H]+; 1H-NMR (400 MHz, CDCl3): d 1.73 (bs, 1H, Ar- 7.30 (m, 2H, Ar-H), 7.31–7.33 (d, 1H, J ¼ 7.16 Hz, Ar-H), 7.45–
CH2OH), 2.29 (s, 3H, Ar-CH3), 4.66 (s, 2H, Ar-CH2OH), 6.60– 7.46 (d, 1H, J ¼ 7.72 Hz, Ar-H), 7.55–7.57 (d, 1H, J ¼ 8.36 Hz,
6.61 (d, 1H, J ¼ 3.12 Hz, Ar-H), 7.03–7.06 (m, 1H, Ar-H), 7.15– Ar-H), 7.61–7.67 (d, 1H, J ¼ 2.32 Hz, Ar-H), 7.96–7.99 (d, 1H,
7.18 (dd, 1H, J ¼ 8.76, 2.52 Hz, Ar-H), 7.20–7.22 (d, 1H, J ¼ 8.24 Hz, Ar-H), 8.02–8.03 (d, 1H, J ¼ 2.2 Hz, Ar-H).
J ¼ 8.04 Hz, Ar-H), 7.60–7.61 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.67–
5-Methoxy-1-[4-Chloro-3-(hydroxymethyl)
phenylsulfo-
7.70 (dd, 1H, J ¼ 8.04, 2.12 Hz, Ar-H), 7.91–7.92 (m, 2H, Ar-H). nyl]-3-methyl-1H-indole (4ab, R1 ¼ 5-OCH3, R2 ¼ CH3,
5-Fluoro-1-[4-chloro-3-(hydroxymethyl) phenylsulfonyl]- R3 ¼ Cl): Yield: 43% (over 2 steps); Melting range (ꢀC): 130.9–
1H-indole (4o, R1 ¼ F, R2 ¼ H, R3 ¼ Cl): Yield: 42% (over 2 133.4 (Clear); I.R (cmꢂ1): 3293, 1611, 1453, 1366, 1228, 1133;
steps); ESIMS (m/z): 340.2 [M + H]+, 342.2 [M + H]+2; IR ESIMS (m/z): 366.4 [M + H]+, 368.6 [M + H]+2
;
1H-NMR
(cmꢂ1): 3431, 1587, 1460, 1373, 1213, 1168, 1138; 1H-NMR (400 MHz, CDCl3): d 2.07 (bs, 1H, Ar-CH2OH), 2.19 (s, 3H,
(400 MHz, CDCl3): d 2.0 (bs, 1H, Ar-CH2OH), 4.75 (s, 2H, Ar- Ar-CH3), 3.82 (s, 3H, Ar-OCH3), 4.71 (s, 2H, Ar-CH2OH), 6.85–
CH2OH), 6.63–6.64 (d, 1H, J ¼ 3.08 Hz, Ar-H), 7.02–7.08 (m, 6.86 (d, 1H, J ¼ 2.44 Hz, Ar-H), 6.90–6.93 (dd, 1H, J ¼ 8.92,
1H, Ar-H), 7.16–7.19 (dd, 1H, J ¼ 8.68, 2.48 Hz, Ar-H), 7.39– 2.48 Hz, Ar-H), 7.24 (d, 1H, J ¼ 1.2 Hz, Ar-H), 7.33–7.35 (d, 1H,
7.41 (d, 1H, J ¼ 8.04 Hz, Ar-H), 7.58–7.59 (d, 1H, J ¼ 3.68 Hz, J ¼ 8.4 Hz, Ar-H), 7.64–7.67 (dd, 1H, J ¼ 8.40, 2.40 Hz, Ar-H),
Ar-H), 7.70–7.72 (dd, 1H, J ¼ 8.4, 2.36 Hz, Ar-H), 7.91–7.95 (m, 7.85–7.87 (d, 1H, J ¼ 9.0 Hz, Ar-H), 8.01–8.02 (d, 1H,
1H, Ar-H), 8.05–8.06 (d, 1H, J ¼ 2.36 Hz, Ar-H).
J ¼ 2.32 Hz, Ar-H).
5-Fluoro-1-[4-bromo-3-(hydroxymethyl) phenylsulfonyl]-
1H-indole (4q, R1 ¼ F, R2 ¼ H, R3 ¼ Br): Yield: 39% (over 2
steps); Melting range (ꢀC): 129.9–131.2 (Clear); ESIMS (m/z):
384 [M + H]+, 386 [M + H]+2; IR (cmꢂ1): 3431, 1585, 1462,
Preparation of 1–(4-bromo-3-formyl phenylsulfonyl)-
1H-indole (5g)
1
To a solution of 1-[4-bromo-3-(hydroxymethyl) phenyl sulfonyl]-
1H-indole (4.73 g, 12.92 mmol) in ethylene dichloride (75 mL)
was added manganese dioxide (8.92 g, 102.5 mmol). The reaction
mass was heated to reflux temperature and maintained under
reflux for 3 h, while monitoring the progress of the reaction by
TLC. After completion of the reaction, the reaction mass was
filtered through hyflow bed and the bed was washed with ethylene
dichloride (2 ꢁ 10 mL). The clear filtrate was concentrated under
reduced pressure to obtain the technical product. The technical
material was triturated with of n-hexane (2 ꢁ 15 mL), decanted
the solvent and dried under reduced pressure to obtain 3.42 g of
the title product, Yield: 73%.
Melting range: 106.4–107.9 ꢀC; I.R (cmꢂ1): 3074, 1691, 1571,
1440, 1371, 1253, 748; ESIMS (m/z): 364.0 [M + H]+, 366
[M + H]+2 1H-NMR (400 MHz, CDCl3): d 6.7–6.71 (d, 1H,
;
J ¼ 3.52 Hz, Ar-H), 7.23–7.28 (m, 1H, Ar-H), 7.33–7.38 (m, 1H,
Ar-H), 7.52–7.54 (m, 2H, Ar-H), 7.71–7.73 (d, 1H, J ¼ 8.4 Hz,
Ar-H), 7.88–7.90 (dd, 1H, J ¼ 8.44, 1.92 Hz, Ar-H), 7.96–7.98 (d,
1H, J ¼ 8.28 Hz, Ar-H), 8.35–8.36 (d, 1H, J ¼ 2.28 Hz, Ar-H),
10.27 (s, 1H, Ar-CHO).
1369, 1215, 1168, 1136; H-NMR (400 MHz, CDCl3): d 2.0 (bs,
1H, Ar-CH2OH), 4.71 (s, 2H, Ar-CH2OH), 6.63–6.64 (d, 1H,
J ¼ 3.72 Hz, Ar-H), 7.05 (d, 1H, J ¼ 2.40, Ar-H), 7.16–7.19 (dd,
1H, J ¼ 8.68, 2.52 Hz, Ar-H), 7.58–7.62 (m, 3H, Ar-H), 7.91–
7.94 (dd, 1H, J ¼ 8.80, 2.42 Hz, Ar-H), 8.03 (d, 1H, J ¼ 1.56 Hz,
Ar-H).
5-Bromo-1-[4-bromo-3-(hydroxymethyl) phenylsulfonyl]-
1H-indole (4s, R1 ¼ Br, R2 ¼ H, R3 ¼ Br): Yield: 41% (over 2
steps); 444.3 [M + H]+, 446.2 [M + H]+2, 448.2 [M + H]+4
5-Methoxy-1-[4-chloro-3-(hydroxymethyl) phenylsulfonyl]-
.
1H-indole (4t, R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ Cl): Yield: 43% (over
2 steps); ESIMS (m/z): 352.4 [M + H]+, 354.5 [M + H]+2 1H-
;
NMR (400 MHz, CDCl3): d 2.11 (bs, 1H, Ar-CH2OH), 3.80 (s,
3H, Ar-OCH3), 4.72 (s, 2H, Ar-CH2OH), 6.58–6.59 (d, 1H,
J ¼ 3.2 Hz, Ar-H), 6.91–6.96 (m, 2H, Ar-H), 7.36–7.38 (d, 1H,
J ¼ 8.0 Hz, Ar-H), 7.49–7.50 (d, 1H, J ¼ 3.64 Hz, Ar-H), 7.67–
7.68 (dd, 1H, J ¼ 8.36, 2.40 Hz, Ar-H), 7.85–7.87 (d, 1H,
J ¼ 8.96 Hz, Ar-H), 8.03–8.04 (d, 1H, J ¼ 2.32 Hz, Ar-H).
5-Methoxy-1-[4-bromo-3-(hydroxymethyl) phenylsulfonyl]-
1H-indole (4v, R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ Br): Yield: 38% (over
2 steps); Melting range (ꢀC): 112.7–114.0 (Clear); IR (cmꢂ1):
3348, 1612, 1471, 1375, 1224, 1141; ESIMS (m/z): 396.4
Similarly, compounds 5a–5ab were prepared from respective
starting materials 4a–4ab by using the method described previ-
ously for the example 5 g with some noncritical variations. The
analytical data of compounds 5a–5ab are presented below.
1-(3-Formyl phenylsulfonyl)-1H-indole (5a, R1 ¼ H, R2 ¼ H,
[M + H]+, 398.6 [M + H]+2 1H-NMR (400 MHz, CDCl3): d
;
1.99 (bs, 1H, Ar-CH2OH), 3.80 (s, 3H, Ar-OCH3), 4.68 (s, 2H,
Ar-CH2OH), 6.60–6.61 (d, 1H, J ¼ 3.08 Hz, Ar-H), 6.91–6.94
(dd, 1H, J ¼ 8.96, 2.52 Hz, Ar-H), 6.96–6.97 (d, 1H, J ¼ 2.40 Hz,
Ar-H), 7.50–7.51 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.56–7.61 (m, 2H,
Ar-H), 7.86–7.88 (d, 1H, J ¼ 9.0 Hz, Ar-H), 8.01 (d, 1H,
J ¼ 1.2 Hz, Ar-H).
R3 ¼ H): Yield: 82%; ESIMS (m/z): 286.1 [M + H]+; H-NMR
1
(400 MHz, CDCl3): d 6.69–6.70 (d, 1H, J ¼ 3.04 Hz, Ar-H), 7.24–
7.25 (m, 1H, Ar-H), 7.31–7.36 (m, 1H, Ar-H), 7.51–7.53 (d, 1H,
J ¼ 7.76 Hz, Ar-H), 7.56–7.57 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.60–
7.63 (m, 1H, Ar-H), 7.99–8.03 (m, 2H, Ar-H), 8.09–8.12 (m, 1H,
Ar-H), 8.35 (d, 1H, J ¼ 1.6 Hz, Ar-H), 9.98 (s, 1H, Ar-CHO).
1-[4-Chloro-3-(hydroxymethyl) phenylsulfonyl]-3-methyl-
1H-indole (4x, R1 ¼ H, R2 ¼ CH3, R3 ¼ Cl): Yield: 41% (over 2
steps); Melting range (ꢀC): 106.6–109.3 (Clear); IR (cmꢂ1): 3546,
3339, 1567, 1447, 1372, 1273, 1196, 1117; ESIMS (m/z): 336.1
1-(4-Methyl-3-formyl
phenylsulfonyl)-1H-indole
(5b,
R1 ¼ H, R2 ¼ H, R3 ¼ CH3): Yield: 85%; Melting range (ꢀC):
88.3–89.3 (Clear); IR spectra (cmꢂ1): 1708, 1440, 1373, 1122;
1
[M + H]+, 338.6 [M + H]+2; H-NMR (400 MHz, CDCl3): d 1.97
ESIMS (m/z): 300.1 [M + H]+; H-NMR (400 MHz, CDCl3): d
1
(bs, 1H, Ar-CH2OH), 2.24 (s, 3H, Ar-CH3), 4.72 (s, 2H, Ar-
CH2OH), 7.23–7.27 (m, 1H, Ar-H), 7.29–7.30 (m, 1H, Ar-H),
7.32–7.34 (m, 1H, Ar-H), 7.35–7.38 (d, 1H, J ¼ 8.40 Hz, Ar-H),
7.44–7.46 (d, 1H, J ¼ 7.73 Hz, Ar-H), 7.69–7.72 (dd, 1H,
J ¼ 8.40, 2.38 Hz, Ar-H), 7.96–7.98 (d, 1H, J ¼ 8.21 Hz, Ar-H),
8.05 (d, 1H, J ¼ 2.3 Hz, Ar-H).
2.65 (s, 3H, Ar-CH3), 6.68–6.69 (d, 1H, J ¼ 3.6 Hz, Ar-H), 7.21–
7.25 (m, 1H, Ar-H), 7.31–7.35 (m, 2H, Ar-H), 7.52–7.54 (d, 1H,
J ¼ 7.68 Hz, Ar-H), 7.56–7.57 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.92–
7.94 (dd, 1H, J ¼ 8.12, 1.96 Hz, Ar-H), 7.98–8.01 (dd, 1H,
J ¼ 8.28, 0.68 Hz, Ar-H), 8.29 (d, 1H, J ¼ 2.12 Hz, Ar-H), 10.21
(s, 1H, Ar-CHO).
1-[4-bromo-3-(hydroxymethyl) phenylsulfonyl]-3-methyl-
1H-indole (4z, R1 ¼ H, R2 ¼ CH3, R3 ¼ Br): Yield: 38% (over 2
steps); Melting range (ꢀC): 122.7–123.9 (Clear); I.R (cmꢂ1):
3541, 1148, 1373, 1166; ESIMS (m/z): 380.1 [M + H]+, 382.1
1-(4-Chloro-3-formyl
phenylsulfonyl)-1H-indole
(5d,
R1 ¼ H, R2 ¼ H, R3 ¼ Cl): Yield: 78%; Melting range (ꢀC):
85.8–87.7 (Clear); IR (cmꢂ1): 1699, 1448, 1379, 1259, 1166;

8
R. V. S. Nirogi et al.
J Enzyme Inhib Med Chem, Early Online: 1–15
ESIMS (m/z): 320.1 [M + H]+, 322.3 [M + H]+2
;
1H-NMR 7.57–7.58 (d, 1H, J ¼ 3.72 Hz, Ar-H), 7.90–7.94 (m, 1H, Ar-H),
(400 MHz, CDCl3): d 6.70 (d, 1H, J ¼ 3.64 Hz, Ar-H), 7.23– 7.95–7.97 (dd, 1H, 8.52, 2.44 Hz, Ar-H), 8.36–8.37 (d, 1H,
7.27 (m, 1H, Ar-H), 7.32–7.34 (m, 1H, Ar-H), 7.51–7.54 (d, 3H, J ¼ 2.40 Hz, Ar-H), 10.39 (s, 1H, Ar-CHO).
Ar-H), 7.96–7.99 (m, 2H, Ar-H), 8.38–8.39 (d, 1H, J ¼ 2.4 Hz,
Ar-H), 10.37 (s, 1H, Ar-CHO).
5-Fluoro-1-(4-bromo-3-formyl phenylsulfonyl)-1H-indole
(5q, R1 ¼ F, R2 ¼ H, R3 ¼ Br): Yield: 76%; Melting range (ꢀC):
5-Methoxy-1-(3-formyl phenylsulfonyl)-1H-indole (5 h, 96.5–98.6 (Clear); IR (cmꢂ1): 3143, 1699, 1583, 1454, 1381,
R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ H): Yield: 82%; ESIMS (m/z): 1215, 1170, 1138; ESIMS (m/z): 382.2 [M + H]+, 384.4
316.1 [M + H]+; 1H-NMR (400 MHz, CDCl3): d 3.80 (s, 3H, [M + H]+2 1H-NMR (400 MHz, CDCl3): d 6.66–6.67 (d, 1H,
;
Ar-OCH3), 6.62–6.63 (d, 1H, J ¼ 3.60 Hz, Ar-H), 6.93 (d, 1H, J ¼ 3.20 Hz, Ar-H), 7.07–7.10 (m, 1H, Ar-H), 7.18–7.20 (dd, 1H,
J ¼ 2.57 Hz, Ar-H), 6.95–6.97 (m, 1H, Ar-H), 7.52–7.53 (d, J ¼ 8.60, 2.50 Hz, Ar-H), 7.53–7.55 (d, 1H, J ¼ 8.50 Hz, Ar-H),
1H, J ¼ 3.66 Hz, Ar-H), 7.60–7.64 (m, 1H, Ar-H), 7.88–7.91 (d, 7.57–7.58 (d, 1H, J ¼ 3.72 Hz, Ar-H), 7.91–7.95 (m, 1H, Ar-H),
1H, J ¼ 8.88 Hz, Ar-H), 8.02–8.09 (m, 2H, Ar-H), 8.32–8.33 (d, 7.95–7.97 (dd, 1H, 8.50, 2.42 Hz, Ar-H), 8.36–8.37 (d, 1H,
1H, J ¼ 1.64 Hz, Ar-H), 9.99 (s, 1H, Ar-CHO).
J ¼ 2.40 Hz, Ar-H), 10.36 (s, 1H, Ar-CHO).
5-Ethoxy-1-(3-formyl phenylsulfonyl)-1H-indole (5i, R1 ¼ 5-
5-Bromo-1-(4-bromo-3-formyl phenylsulfonyl)-1H-indole
OCH2CH3, R2 ¼ H, R3 ¼ H): Yield: 79%; ESIMS (m/z): 330.1 (5s, R1 ¼ Br, R2 ¼ H, R3 ¼ Br): Yield: 74%; 442.3 [M + H]+,
1
[M + H]+; H-NMR (400 MHz, CDCl3): d 1.38–1.42 (t, 3H, Ar- 444.2 [M + H]+2, 446.2 [M + H]+4
.
OCH2CH3), 3.98–4.04 (q, 2H, Ar-OCH2CH3), 6.60–6.61 (d, 1H,
5-Methoxy-1-(4-chloro-3-formyl phenylsulfonyl)-1H-indole
J ¼ 3.62 Hz, Ar-H), 6.92–6.93 (d, 1H, J ¼ 2.47 Hz, Ar-H), 6.95– (5t, R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ Cl): Yield: 80%; Melting range
6.96 (m, 1H, Ar-H), 7.51–7.52 (d, 1H, J ¼ 3.64 Hz, Ar-H), 7.59– (ꢀC): 141.6–142.5 (Clear); IR (cmꢂ1): 3116, 1701, 1462, 1375,
7.63 (m, 1H, Ar-H), 7.87–7.89 (d, 1H, J ¼ 8.64 Hz, Ar-H), 8.02– 1224, 1136; ESIMS (m/z): 350.2 [M + H]+, 352.3 [M + H]+2; 1H-
8.08 (m, 2H, Ar-H), 8.32 (d, 1H, J ¼ 1.68 Hz, Ar-H), 9.99 (s, 1H, NMR (400 MHz, CDCl3): d 3.80 (s, 3H, Ar-OCH3), 6.62–6.63 (d,
Ar-CHO).
1H, J ¼ 3.62 Hz, Ar-H), 6.93–6.97 (m, 2H, Ar-H), 7.49–7.52 (m,
5-Isopropoxy-1-(3-formyl phenylsulfonyl)-1H-indole (5j, 2H, Ar-H), 7.85–7.87 (d, 1H, J ¼ 8.80 Hz, Ar-H), 7.93–7.96 (dd,
R1 ¼ 5-OCH(CH3)2, R2 ¼ H, R3 ¼ H): Yield: 79%; ESIMS (m/ 1H, J ¼ 8.84, 2.48 Hz, Ar-H), 8.35 (d, 1H, J ¼ 2.4 Hz, Ar-H),
z): 344.1 [M + H]+; 1H-NMR (400 MHz, CDCl3): d 1.31–1.32 (d, 10.38 (s, 1H, Ar-CHO).
6H, J ¼ 6.04 Hz, Ar-OCH(CH3)2), 4.47–4.53 (sept, 1H, Ar-
5-Methoxy-1-(4-bromo-3-formyl phenylsulfonyl)-1H-indole
OCH(CH3)2), 6.60 (d, 1H, J ¼ 3.52 Hz, Ar-H), 6.91–6.93 (dd, (5v, R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ Br): Yield: 78%; Melting range
1H, J ¼ 8.96, 2.40 Hz, Ar-H), 6.96–6.97 (d, 1H, J ¼ 2.36 Hz, Ar- (ꢀC): 145.5–148.6 (Clear); IR (cmꢂ1): 1699, 1465, 1377, 1222,
1
H), 7.51 (d, 1H, J ¼ 3.60 Hz, Ar-H), 7.62–7.64 (m, 1H, Ar-H), 1145; ESIMS (m/z): 394.2 [M + H]+, 396.3 [M + H]+2; H-NMR
7.86–7.88 (d, 1H, J ¼ 8.96 Hz, Ar-H), 8.02–8.09 (m, 2H, Ar-H), (400 MHz, CDCl3): d 3.80 (s, 3H, Ar-OCH3), 6.62 (d, 1H,
8.33 (d, 1H, J ¼ 1.6 Hz, Ar-H), 9.99 (s, 1H, Ar-CHO).
J ¼ 3.60 Hz, Ar-H), 6.93–6.96 (m, 2H, Ar-H), 7.49 (s, 1H, Ar-H),
5-Fluoro-1-(3-formyl
phenylsulfonyl)-1H-indole
(5k, 7.70–7.72 (d, 1H, J ¼ 8.32 Hz, Ar-H), 7.85–7.87 (m, 2H, Ar-H),
R1 ¼ F, R2 ¼ H, R3 ¼ H): Yield: 81%; ESIMS (m/z): 304 8.32 (s, 1H, Ar-H), 10.27 (s, 1H, Ar-CHO).
[M + H]+; 1H-NMR (400 MHz, CDCl3): d 6.66–6.67 (d, 1H,
1-[4-Chloro-3-formyl phenylsulfonyl]-3-methyl-1H-indole
J ¼ 3.68 Hz, Ar-H), 7.06–7.09 (m, 1H, Ar-H), 7.17–7.19 (dd, 1H, (5x, R1 ¼ H, R2 ¼ CH3, R3 ¼ Cl): Yield: 81%; Melting range
J ¼ 8.64, 2.52 Hz, Ar-H), 7.60–7.61 (d, 1H, J ¼ 3.64 Hz, Ar-H), (ꢀC): 142.8–144.9 (Clear); IR (cmꢂ1): 2870, 1701, 1583 1447,
7.64–7.66 (m, 1H, Ar-H), 7.93–7.98 (m, 1H, Ar-H), 8.04–8.09 1371, 1166, 1115; ESIMS (m/z): 334.3 [M + H]+, 336.5
(m, 2H, Ar-H), 8.34 (d, 1H, J ¼ 1.56 Hz, Ar-H), 10.0 (s, 1H, Ar- [M + H]+2
;
1H-NMR (400 MHz, CDCl3): d 2.24 (s, 3H, Ar-
CH3), 7.25–7.28 (m, 2H, Ar-H), 7.32–7.36 (m, 1H, Ar-H), 7.44–
CHO).
5-Methoxy-1-(4-methyl-3-formyl phenylsulfonyl)-1H-indole 7.46 (d, 1H, J ¼ 7.72 Hz, Ar-H), 7.49–7.51 (d, 1H, J ¼ 8.48 Hz,
(5 l, R1 ¼ 5-OCH3, R2 ¼ H, R3 ¼ CH3): Yield: 83%; Melting Ar-H), 7.95–7.97 (m, 2H, Ar-H), 8.37 (d, 1H, J ¼ 2.37 Hz, Ar-H),
range (ꢀC): 134.2–135.3 (Clear); IR (cmꢂ1): 3124, 1705, 1446, 10.37 (s, 1H, Ar-CHO).
1367, 1222, 1128; ESIMS (m/z): 330 [M + H]+; 1H-NMR
1-[4-Bromo-3-formyl phenylsulfonyl]-3-methyl-1H-indole
(400 MHz, CDCl3): d 2.60 (s, 3H, Ar-CH3), 3.72 (s, 3H, Ar- (5z, R1 ¼ H, R2 ¼ CH3, R3 ¼ Br): Yield: 76%; Melting range
OCH3), 6.76–6.77 (d, 1H, J ¼ 3.20 Hz, Ar-H), 6.92–6.95 (dd, 1H, (ꢀC): 156.5–159.6 (Clear); IR (cmꢂ1): 1700, 1578, 1371, 1167;
J ¼ 9.04, 2.56 Hz, Ar-H), 7.09 (d, 1H, J ¼ 2.52 Hz, Ar-H), 7.52– ESIMS (m/z): 378.2 [M + H]+, 380.2 [M + H]+2
;
1H-NMR
7.54 (d, 1H, J ¼ 8.20 Hz, Ar-H), 7.76–7.77 (d, 1H, J ¼ 3.64 Hz, (400 MHz, CDCl3): d 2.24 (s, 3H, Ar-CH3), 7.26–7.28 (m, 2H,
Ar-H), 7.80–7.82 (d, 1H, J ¼ 9.04 Hz, Ar-H), 8.03–8.06 (dd, 1H, Ar-H), 7.32–7.36 (t, 1H, J ¼ 7.44 Hz, Ar-H), 7.44–7.46 (d, 1H,
J ¼ 8.12, 2.24 Hz, Ar-H), 8.26–8.27 (d, 1H, J ¼ 2.16 Hz, Ar-H), J ¼ 7.04 Hz, Ar-H), 7.69–7.71 (d, 1H, J ¼ 8.36 Hz, Ar-H), 7.86–
10.19 (s, 1H, Ar-CHO).
7.88 (d, 1H, J ¼ 6.72 Hz, Ar-H), 7.95–7.97 (d, 1H, J ¼ 8.2 Hz, Ar-
5-Fluoro-1-(4-methyl-3-formyl phenylsulfonyl)-1H-indole H), 8.34 (d, 1H, J ¼ 1.28 Hz, Ar-H), 10.27 (s, 1H, Ar-CHO).
(5m, R1 ¼ 5-F, R2 ¼ H, R3 ¼ CH3): Yield: 79%; Melting range
5-Methoxy-1-[4-Chloro-3-formyl phenylsulfonyl]-3-methyl-
(ꢀC): 96.5–99.4 (Clear); IR (cmꢂ1): 3145, 1712, 1460, 1373, 1H-indole (5ab, R1 ¼ 5-OCH3, R2 ¼ CH3, R3 ¼ Cl): Yield: 80%;
1
1213, 1138; ESIMS (m/z): 318 [M + H]+; H-NMR (400 MHz, ESIMS (m/z): 364.2 [M + H]+, 366.3 [M + H]+2
;
1H-NMR
CDCl3): d 2.67 (s, 3H, Ar-CH3), 6.64–6.65 (d, 1H, J ¼ 3.16 Hz, (400 MHz, CDCl3): d 2.19 (s, 3H, Ar-CH3), 3.82 (s, 3H, Ar-
Ar-H), 7.03–7.09 (m, 1H, Ar-H), 7.16–7.19 (dd, 1H, J ¼ 8.68, OCH3), 6.85–6.86 (d, 1H, J ¼ 2.48 Hz, Ar-H), 6.92–6.95 (dd, 1H,
2.52 Hz, Ar-H), 7.34–7.36 (d, 1H, J ¼ 8.16 Hz, Ar-H), 7.60 (d, J ¼ 8.96, 2.52 Hz, Ar-H), 7.23 (d, 1H, J ¼ 1.16 Hz, Ar-H), 7.48–
1H, J ¼ 3.68 Hz, Ar-H), 7.89–7.94 (m, 2H, Ar-H), 8.26–8.27 (d, 7.50 (d, 1H, J ¼ 8.48 Hz, Ar-H), 7.84–7.86 (d, 1H, J ¼ 9.0 Hz, Ar-
1H, J ¼ 2.12 Hz, Ar-H), 10.22 (s, 1H, Ar-CHO).
H), 7.91–7.93 (dd, 1H, J ¼ 8.52, 2.40 Hz, Ar-H), 8.33–8.34 (d,
5-Fluoro-1-(4-chloro-3-formyl phenylsulfonyl)-1H-indole 1H, J ¼ 2.4 Hz, Ar-H), 10.37 (s, 1H, Ar-CHO).
(5o, R1 ¼ F, R2 ¼ H, R3 ¼ Cl): Yield: 78%; Melting range (ꢀC):
92.5–94.4 (Clear); IR (cmꢂ1): 3136, 1699, 1579, 1452, 1377,
Preparation of 1-[4-bromo-3–(4-ethyl piperazin-1-yl
1207, 1163, 1132; ESIMS (m/z): 338.2 [M + H]+, 340.4
methyl) phenylsulfonyl]-1H-indole (6 g)
[M + H]+2 1H-NMR (400 MHz, CDCl3): d 6.66–6.67 (d, 1H,
;
To a solution of 1–(4-bromo-3-formyl phenylsulfonyl)-1H-
indole (1.004 g, 2.758 mmol) in 20 mL ethylene dichloride was
J ¼ 3.20 Hz, Ar-H), 7.06–7.09 (m, 1H, Ar-H), 7.17–7.19 (dd, 1H,
J ¼ 8.60, 2.52 Hz, Ar-H), 7.53–7.55 (d, 1H, J ¼ 8.52 Hz, Ar-H),

DOI: 10.3109/14756366.2015.1103233
N1-phenylsulphonyl indole derivatives
9
added N-ethyl piperazine (0.3757 g, 3.295 mmol). Reaction mass (s, 2H, Ar-CH2-N), 6.72–6.73 (dd, 1H, J ¼ 3.69, 0.39 Hz, Ar-H),
was stirred at 25 ꢀC for 10 min. Sodium triacetoxy borohydride 7.20–7.24 (m, 1H, Ar-H), 7.31–7.35 (m, 1H, Ar-H), 7.41–7.43 (d,
(0.8842 g, 4.171 mmol) was added over a period of 10 min. The 1H, J ¼ 8.18 Hz, Ar-H), 7.52–7.54 (d, 1H, J ¼ 7.8 Hz, Ar-H),
reaction mass was stirred at 25 ꢀC for 6 h while monitoring the 7.67–7.68 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.83–7.85 (dd, 1H,
progress of the reaction by TLC. After completion of the reaction, J ¼ 8.14, 2.02 Hz, Ar-H), 8.02–8.04 (dd, 1H, J ¼ 8.28, 0.52 Hz,
reaction mass was quenched onto 5% sodium bicarbonate solution Ar-H), 8.12 (d, 1H, J ¼ 1.24 Hz, Ar-H); HRMS: [M + H]+
(100 mL) and extracted the product with chloroform (3 ꢁ 50 mL). C21H25N3O2S calc. 384.1667, found. 384.1663.
The combined organic layer was washed with brine solution
The compound 6c was prepared from starting materials 5b and
(2 ꢁ 50 mL), water (2 ꢁ 50 mL), dried over anhydrous sodium N-ethyl piperazine
sulfate and concentrated under reduced pressure. The technical
product was purified by column chromatography, eluent system 1-[4-Methyl-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-
being ethyl acetate and n-hexane (7:1) to obtain 0.9344 g of the 1H-indole dihydrochloride (6c)
title product.
Yield: 62%, after 2 steps; Melting point: 250.13 ꢀC; I.R (cmꢂ1):
Melting Range: 122.2–126.3 ꢀC; ESIMS (m/z): 462 [M + H]+;
1
3300, 2997, 1643, 1168, 752; ESIMS (m/z): 398.1 [M + H]+; H-
HRMS: [M + H]+ C21H24BrN3O2S calc. 462.0773, found.
NMR (400 MHz, D2O): d 1.35–1.39 (t, 3H, N-CH2CH3), 2.42 (s,
462.0775.
3H, Ar-CH3), 3.12–3.14 (bs, 6H, Piperazine-H), 3.23–3.29 (q,
Example 6 g (Di HCl salt): Preparation of 1-[4-bromo-3–(4-
2H, N-CH2CH3), 3.6 (bs, 2H, Piperazine-H), 4.05 (s, 2H, Ar-
ethyl
piperazin-1-yl
methyl)
phenylsulfonyl]-1H-indole
CH2-N), 6.72–6.73 (dd, 1H, J ¼ 3.12, 0.58 Hz, Ar-H), 7.20–7.24
(m, 1H, Ar-H), 7.30–7.34 (m, 1H, Ar-H), 7.38–7.40 (d, 1H,
J ¼ 8.17 Hz, Ar-H), 7.52–7.54 (d, 1H, J ¼ 7.82 Hz, Ar-H), 7.65–
7.66 (d, 1H, J ¼ 3.69 Hz, Ar-H), 7.80–7.82 (dd, 1H, J ¼ 8.11,
1.97 Hz, Ar-H), 8.0–8.02 (m, 2H, Ar-H); HRMS: [M + H]+
C22H27N3O2S calc. 398.1824, found. 398.1821.
dihydrochloride.
To a clear solution of 1-[4-bromo-3–(4-ethyl piperazin-1-yl
methyl) phenylsulfonyl]-1H-indole (252.4 mg, 0.5463 mmol) in
15 mL diethyl ether under nitrogen atmosphere, a solution of
methanolic hydrochloric acid (16% w/v, 0.32 mL, 1.402 mmol)
was added in 5 min under stirring. The above reaction mass was
further stirred at 25 ꢀC, for a period of 1 h and concentrated under
vacuum to obtain the above title product 262 mg, Yield: 65%,
after 2 steps.
The compound 6d was prepared from starting materials 5d and
N-methyl piperazine.
1-[4-Chloro-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
1H-indole dihydrochloride (6d)
Melting range: 208.4–210.4 ꢀC; IR spectra (cmꢂ1): 3429,
1
2935, 2245, 1440, 1172, 765; ESIMS (m/z): 462 [M + H]+; H-
NMR (400 MHz, D2O): d 1.20–1.24 (t, 3H, N-CH2CH3), 2.83 (bs, Yield: 59%, after 2 steps; Melting range: 210.6–213.90 ꢀC; I.R
4H, Piperazine-H), 3.10–3.15 (q, 2H, N-CH2CH3), 3.18 (bs, 4H, (cmꢂ1): 3415, 2987, 1591, 1444, 1373, 1174, 736; ESIMS (m/z):
1
Piperazine-H), 3.91 (s, 2H, Ar-CH2-N), 6.75 (d, 1H, J ¼ 3.70 Hz, 403.9 [M + H]+; H-NMR (400 MHz, D2O): d 2.84 (s, 3H, N-
Ar-H), 7.21 (m, 1H, Ar-H), 7.28–7.30 (m, 1H, Ar-H), 7.53–7.55 CH3), 3.05 (bs, 4H, Piperazine-H), 3.28 (bs, 4H, Piperazine-H),
(d, 1H, J ¼ 7.7 Hz, Ar-H), 7.58–7.59 (d, 1H, J ¼ 3.72 Hz, Ar-H), 4.10 (s, 2H, Ar-CH2-N), 6.72–6.78 (d, 1H, J ¼ 3.7 Hz, Ar-H),
7.69 (m, 2H, Ar-H), 7.78 (d, 1H, J ¼ 1.8 Hz, Ar-H), 7.9 (d, 1H, 7.18–7.22 (d, 1H, J ¼ 7.4 Hz, Ar-H), 7.26–7.30 (d, 1H, J ¼ 7.4 Hz,
J ¼ 8.2 Hz, Ar-H); HRMS: [M + H]+ C21H24BrN3O2S calc. Ar-H), 7.49–7.51 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.55–7.56 (d, 1H,
462.0773, found. 462.0775.
J ¼ 3.72 Hz, Ar-H), 7.82–7.84 (dd, 1H, J ¼ 8.52, 2.32 Hz, Ar-H),
7.86–7.88 (dd, 2H, J ¼ 7.92, 2.06 Hz, Ar-H); HRMS: [M + H]+
C20H22ClN3O2S calc. 404.1121, found. 404.1117.
The compound 6e was prepared from starting materials 5d and
N-ethyl piperazine.
Examples 6a–6ac
The compounds 6a–6ac were prepared from respective starting
materials by using the method described above for the example 6g
(Di HCl) with some noncritical variations. The analytical data of
compounds 6a–6ac are presented below. The compound 6a was
prepared from starting materials 5a and N-methyl piperazine.
1-[4-Chloro-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-
1H-indole dihydrochloride (6e)
Yield: 62%, after 2 steps; Melting range: 196.0–197.1 ꢀC; I.R
1-[3-(4-Methyl piperazin-1-yl methyl) phenylsulfonyl]-1H-
indole (6a)
(cmꢂ1): 3446, 2985, 2451, 1469, 1444, 1172, 740; ESIMS (m/z):
1
418.0 [M + H]+; H-NMR (400 MHz, D2O): d 1.17–1.21 (t, 3H,
N-CH2CH3), 3.04 (bs, 8H, Piperazine-H), 3.10–3.15 (q, 2H, N-
CH2CH3), 4.10 (s, 2H, Ar-CH2-N), 6.69–6.70 (d, 1H, J ¼ 3.61 Hz,
Ar-H), 7.15–7.19 (d, 1H, J ¼ 7.5 Hz, Ar-H), 7.23–7.27 (m, 1H,
J ¼ 7.3 Hz, Ar-H), 7.46–7.48 (d, 2H, J ¼ 8.34 Hz, Ar-H), 7.52–
7.53 (d, 1H, J ¼ 3.71 Hz, Ar-H), 7.79–7.81 (dd, 1H, J ¼ 8.5,
2.2 Hz, Ar-H), 7.84–7.86 (m, 2H, Ar-H); HRMS: [M + H]+
C21H24ClN3O2S calc. 418.1278, found. 418.1276.
Yield: 63%; I.R (cmꢂ1): 2936, 1445, 1168, 823; ESI-MS (m/z):
1
370.3 [M + H]+; H-NMR (400 MHz, CDCl3): d 2.29 (s, 3H, N-
CH3), 2.36 (bs, 8H, Piperazine-H), 3.47 (s, 2H, Ar-CH2-N), 6.65–
6.66 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.19–7.23 (m, 1H, Ar-H), 7.30
(m, 1H, Ar-H), 7.36–7.38 (m, 1H, Ar-H), 7.45–7.53 (m, 2H, Ar-
H), 7.56–7.57 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.73–7.75 (m, 1H, Ar-
H), 7.87 (m, 1H, Ar-H), 7.98–8.00 (d, 1H, J ¼ 8.32 Hz, Ar-H);
HRMS: [M + H]+ C20H23N3O2S calc. 370.1511, found. 370.1514.
The compound 6b was prepared from starting materials 5b and
N-methyl piperazine
The compound 6f was prepared from starting materials 5 g and
N-methyl piperazine.
1-[4-Bromo-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
1H-indole dihydrochloride (6f)
1-[4-Methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
1H-indole dihydrochloride (6b)
Yield: 59%, after 2 steps; Melting range: 214.1–216.0 ꢀC; I.R
(cmꢂ1): 3429, 2372, 1440, 1170, 740; ESIMS (m/z): 447.9
[M + H]+; 1H-NMR (400 MHz, D2O): d 2.26 (bs, 2H, Piperazine-
H), 2.79 (s, 3H, N-CH3 & 2H, Piperazine-H), 3.09–3.11 (bs, 2H,
Piperazine-H), 3.37–3.40 (bs, 2H, Piperazine-H), 3.7 (s, 2H, Ar-
CH2-N), 6.86 (dd, 1H, J ¼ 3.7, 0.57 Hz, Ar-H), 7.24–7.28 (m, 1H,
Yield: 65%, after 2 steps; Melting range: 180.4–183.0 ꢀC; I.R
(cmꢂ1): 3383, 2960, 1629, 1446, 1130, 948; ESIMS (m/z): 384.6
1
[M + H]+; H-NMR (400 MHz, D2O): d 2.45 (s, 3H, Ar-CH3),
2.97 (s, 3H, N-CH3), 3.29–3.58 (bs, 8H, Piperazine-H), 4.25

10 R. V. S. Nirogi et al.
J Enzyme Inhib Med Chem, Early Online: 1–15
Ar-H), 7.33–7.37 (m, 1H, Ar-H), 7.59–7.61 (d, 1H, J ¼ 7.67 Hz,
The compound 6l was prepared from starting materials 5 l and
Ar-H), 7.76–7.78 (dd, 1H, J ¼ 8.4, 2.4 Hz, Ar-H), 7.80–7.81 (d, N-methyl piperazine.
1H, J ¼ 3.6 Hz, Ar-H), 7.847.86 (d, 1H, J ¼ 8.44 Hz, Ar-H), 7.93–
7.95 (dd, 1H, J ¼ 8.0, 0.35 Hz, Ar-H), 8.09 (bs, 1H, Ar-H); 1-[4-Methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
HRMS: [M + H]+ C20H22BrN3O2S calc. 448.0616, found. 5-methoxy-1H-indole dihydrochloride (6l)
448.0611.
Yield: 63%, after 2 steps; Melting range: 198.1–199.3 ꢀC; I.R
The compound 6h was prepared from starting materials 5 h
(cmꢂ1): 3427, 2974, 2372, 1616, 1465, 1224, 950; ESIMS (m/z):
and N-methyl piperazine.
1
414.3 [M + H]+; H-NMR (400 MHz, D2O): d 2.37 (s, 3H, Ar-
CH3), 2.78 (s, 3H, N-CH3), 2.79–3.46 (bs, 8H, Piperazine-H),
5-Methoxy-1-[3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
3.73 (s, 3H, Ar-OCH3), 3.83–3.90 (s, 2H, Ar-CH2-N), 6.73–6.74
1H-indole (6h)
(d, 1H, J ¼ 3.6 Hz, Ar-H), 6.91–6.93 (dd, 1H, J ¼ 9.01, 2.5 Hz,
Yield: 64%; I.R (cmꢂ1): 2936, 2790, 1615, 1465, 1224, 996; Ar-H), 7.08 (d, 1H, J ¼ 2.46 Hz, Ar-H), 7.39–7.41 (d, 1H,
1
ESIMS (m/z): 400.3 [M + H]+; H-NMR (400 MHz, CDCl3): d J ¼ 8.13 Hz, Ar-H), 7.73–7.76 (m, 2H, Ar-H), 7.82–7.84 (d, 1H,
2.28 (s, 3H, N-CH3), 2.35 (bs, 8H, Piperazine-H), 3.46 (s, 2H, Ar- J ¼ 9.02 Hz, Ar-H), 8.11 (bs, 1H, Ar-H); HRMS: [M + H]+
CH2-N), 3.80 (s, 3H, Ar-OCH3), 6.57–6.58 (d, 1H, J ¼ 3.6 Hz, C22H27N3O3S calc. 414.1773, found. 414.1775.
Ar-H), 6.89–6.92 (dd, 1H, J ¼ 8.96, 2.52 Hz, Ar-H), 6.95 (d, 1H,
The compound 6m was prepared from starting materials 5m
J ¼ 2.44 Hz, Ar-H), 7.33–7.36 (m, 1H, Ar-H), 7.45–7.47 (m, 1H, and N-methyl piperazine.
Ar-H), 7.51–7.52 (d, 1H, J ¼ 3.6 Hz, Ar-H), 7.69–7.71 (m,
1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.86–7.89 (d, 1H, J ¼ 9.0 Hz, 1-[4-Methyl-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
Ar-H); HRMS: [M + H]+ C21H25N3O3S calc. 400.1617, found. 5-fluoro-1H-indole dihydrochloride (6m)
400.1619.
Yield: 57%, after 2 steps; Melting range: 220.3–223.4 ꢀC; I.R
The compound 6i was prepared from starting materials 5i and
(cmꢂ1): 3370, 2642, 1596, 1464, 1171, 949; ESIMS (m/z): 402.3
N-methyl piperazine.
1
[M + H]+; H-NMR (400 MHz, D2O): d 2.45 (s, 3H, Ar-CH3),
2.97 (s, 3H, N-CH3), 3.29–3.62 (bs, 8H, Piperazine-H), 4.19 (s,
5-Ethoxy-1-[3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
2H, Ar-CH2-N), 6.72–6.73 (d, 1H, J ¼ 3.6 Hz, Ar-H), 7.07–7.13
1H-indole (6i)
(m, 1H, Ar-H), 7.23–7.25 (dd, 1H, J ¼ 8.9, 2.52 Hz, Ar-H), 7.41
Yield: 62%; I.R (cmꢂ1): 3743, 2935, 1615, 1456, 1222, 900; 7.43 (d, 1H, J ¼ 8.18 Hz, Ar-H), 7.75–7.76 (d, 1H, J ¼ 3.67 Hz,
1
ESIMS (m/z): 414.4 [M + H]+; H-NMR (400 MHz, CDCl3): d Ar-H), 7.82–7.89 (dd, 1H, J ¼ 8.14, 1.96 Hz, Ar-H), 8.01–8.02
1.38–1.42 (t, 3H, Ar-OCH2CH3), 2.28 (s, 3H, N-CH3), 2.35 (bs, (m, 1H, Ar-H), 8.12 (bs, 1H, Ar-H); HRMS: [M + H]+
8H, Piperazine-H), 3.48 (s, 2H, Ar-CH2-N), 3.98–4.03 (q, 2H, Ar- C21H24FN3O2S calc. 402.1573, found. 402.1569.
OCH2CH3), 6.56–6.57 (d, 1H, J ¼ 3.60 Hz, Ar-H), 6.89–6.92 (dd,
The compound 6n was prepared from starting materials 5m
1H, J ¼ 8.96, 2.45 Hz, Ar-H), 6.93–6.94 (d, 1H, J ¼ 2.38 Hz, Ar- and N-ethyl piperazine.
H), 7.32–7.36 (m, 1H, Ar-H), 7.44–7.46 (m, 1H, Ar-H), 7.50–
7.51 (d, 1H, J ¼ 3.64 Hz, Ar-H), 7.69–7.71 (m, 1H, Ar-H), 7.83 1-[4-Methyl-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-5-
(s, 1H, Ar-H), 7.86–7.88 (d, 1H, J ¼ 8.98 Hz, Ar-H); HRMS: fluoro-1H-indole dihydrochloride (6n)
[M + H]+ C22H27N3O3S calc. 414.1773, found. 414.1778.
Yield: 59%, after 2 steps; Melting range: 203.4–206.2 ꢀC; I.R
The compound 6j was prepared from starting materials 5j and
(cmꢂ1): 3425, 2458, 1594, 1443, 1171, 799; ESIMS (m/z): 416.3
N-methyl piperazine.
[M + H]+; 1H-NMR (400 MHz, D2O): d 1.23–1.27 (t, 3H, N-
CH2CH3), 2.38 (s, 3H, Ar-CH3), 3.03–3.06 (bs, 8H, Piperazine-
5-Isopropoxy-1-[3-(4-methyl piperazin-1-yl methyl) phenylsulfo-
H), 3.35–3.37 (q, 2H, N-CH2CH3), 3.8 (s, 2H, Ar-CH2-N), 6.81–
nyl]-1H-indole (6j)
6.82 (d, 1H, J ¼ 3.56 Hz, Ar-H), 7.16–7.21 (dd, 1H, J ¼ 9.2,
Yield: 63%; I.R (cmꢂ1): 2974, 1612, 1455, 1221, 923; ESIMS (m/ 2.62 Hz, Ar-H), 7.397.41 (dd, 1H, J ¼ 9.16, 2.58 Hz, Ar-H), 7.41–
z): 428.3 [M + H]+; 1H-NMR (400 MHz, CDCl3): d 1.31–1.32 (d, 7.43 (d, 1H, J ¼ 7.86 Hz, Ar-H), 7.79–7.81 (d, 1H, J ¼ 6.98 Hz,
6H, J ¼ 6.04 Hz, Ar-OCH(CH3)2), 2.30 (s, 3H, N-CH3), 2.46 (bs, Ar-H), 7.87–7.88 (d, 1H, J ¼ 3.66 Hz, Ar-H), 7.94–7.98 (dd, 1H,
8H, Piperazine-H), 3.47 (s, 2H, Ar-CH2-N), 4.47 (sept, 1H, Ar- J ¼ 9.02, 4.42 Hz, Ar-H), 8.13 (bs, 1H, Ar-H); HRMS: [M + H]+
OCH(CH3)2), 6.55–6.56 (d, 1H, J ¼ 3.56 Hz, Ar-H), 6.87–6.90 C22H26FN3O2S calc. 416.1730, found. 416.1727.
(dd, 1H, J ¼ 8.96, 2.44 Hz, Ar-H), 6.95–6.96 (d, 1H, J ¼ 2.44 Hz,
The compound 6o was prepared from starting materials 5o and
Ar-H), 7.33–7.37 (m, 1H, Ar-H), 7.45–7.47 (m, 1H, Ar-H), 7.50– N-methyl piperazine.
7.51 (d, 1H, J ¼ 3.56 Hz, Ar-H), 7.7–7.72 (m, 1H, Ar-H), 7.84–
7.87 (m, 2H, Ar-H); HRMS: [M + H]+ C23H29N3O3S calc. 1-[4-Chloro-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
428.1930, found. 428.1936.
The compound 6k was prepared from starting materials 5k and
N-methyl piperazine.
5-fluoro-1H-indole dihydrochloride (6o)
Yield: 58%, after 2 steps; Melting range: 220.2–221.3 ꢀC; I.R
(cmꢂ1): 3429, 2983, 1591, 1463, 1377, 1138, 950; ESIMS (m/z):
1
422.0 [M + H]+; H-NMR (400 MHz, D2O): d 2.84 (s, 3H, N-
5-Fluoro-1-[3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
1H-indole (6k)
CH3), 3.05 (bs, 4H, Piperazine-H), 3.34–3.36 (bs, 4H, Piperazine-
H), 3.98 (s, 2H, Ar-CH2-N), 6.60–6.61 (d, 1H, J ¼ 3.67, Ar-H),
Yield: 62%; I.R (cmꢂ1): 2937, 1590, 1460, 1216, 998; ESIMS (m/ 6.91–6.96 (dd, 1H, J ¼ 9.18, 2.4 Hz, Ar-H), 7.04–7.07 (dd, 1H,
1
z): 388.3 [M + H]+; H-NMR (400 MHz, CDCl3): d 2.30 (s, 3H, J ¼ 8.99, 2.41 Hz, Ar-H), 7.26–7.28 (d, 1H, J ¼ 8.52 Hz, Ar-H),
N-CH3), 2.36 (bs, 8H, Piperazine-H), 3.48 (s, 2H, Ar-CH2-N), 7.53–7.54 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.63–7.66 (dd, 1H, J ¼ 8.5,
6.61–6.62 (d, 1H, J ¼ 3.64 Hz, Ar-H), 7.03 (m, 1H, Ar-H), 7.15– 1.9 Hz, Ar-H), 7.72–7.75 (m, 1H, J ¼ 4.34 Hz, Ar-H), 7.85–7.86
7.18 (m, 1H, Ar-H), 7.37–7.39 (m, 1H, Ar-H), 7.47 (m, 1H, Ar- (d, 1H, J ¼ 2.18 Hz, Ar-H); HRMS: [M + H]+ C20H21ClFN3O2S
H), 7.59–7.60 (d, 1H, J ¼ 3.64 Hz, Ar-H), 7.71 (m, 1H, Ar-H), calc. 422.1027, found. 422.1023.
7.84 (m, 1H, Ar-H), 7.92–7.94 (m, 1H, Ar-H); HRMS: [M + H]+
The compound 6p was prepared from starting materials 5o and
N-ethyl piperazine.
C20H22FN3O2S calc. 388.1417, found. 388.1421.

DOI: 10.3109/14756366.2015.1103233
N1-phenylsulphonyl indole derivatives 11
1-[4-Chloro-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-5-
fluoro-1H-indole dihydrochloride (6p)
N-CH3), 3.05 (bs, 4H, Piperazine-H), 3.23–3.28 (bs, 4H,
Piperazine-H), 3.60 (s, 3H, Ar-OCH3), 3.9 (s, 2H, Ar-CH2-N),
6.55–6.56 (d, 1H, J ¼ 3.64 Hz, Ar-H), 6.67–6.79 (dd, 1H,
J ¼ 9.03, 2.44 Hz, Ar-H), 6.88–6.89 (d, 1H, J ¼ 2.42 Hz, Ar-H),
7.20–7.22 (d, 1H, J ¼ 8.53 Hz, Ar-H), 7.42–7.43 (d, 1H,
J ¼ 3.65 Hz, Ar-H), 7.58–7.61 (dd, 1H, J ¼ 8.5, 2.1 Hz, Ar-H),
7.65–7.68 (d, 1H, J ¼ 9.04 Hz, Ar-H), 7.79 (d, 1H, J ¼ 2.21 Hz,
Ar-H); HRMS: [M + H]+ C21H24ClN3O3S calc. 434.1227, found.
434.1225.
Yield: 56%, after 2 steps; Melting range: 204.1–205.5 ꢀC; I.R
(cmꢂ1): 3414, 2976, 1622, 1458, 1139, 804; ESIMS (m/z): 436.0
[M + H]+; 1H-NMR (400 MHz, D2O): d 1.20–1.23 (t, 3H, N-
CH2CH3), 3.04 (bs, 4H, Piperazine-H), 3.13–3.18 (q, 2H, N-
CH2CH3), 3.32–3.34 (bs, 4H, Piperazine-H), 4.05 (s, 2H, Ar-
CH2-N), 6.65–6.66 (d, 1H, J ¼ 3.67 Hz, Ar-H), 6.99–7.03 (m, 1H,
Ar-H), 7.13–7.16 (dd, 1H, J ¼ 9.0, 2.5 Hz, Ar-H), 7.41–7.43 (d,
1H, J ¼ 8.55 Hz, Ar-H), 7.56–7.57 (d, 1H, J ¼ 3.7 Hz, Ar-H),
7.74–7.76 (dd, 1H, J ¼ 8.55, 2.26 Hz, Ar-H), 7.78–7.81 (dd, 1H,
J ¼ 9.0, 4.1 Hz, Ar-H), 7.86 (d, 1H, J ¼ 2.3 Hz, Ar-H); HRMS:
[M + H]+ C21H23ClFN3O2S calc. 436.1184, found. 436.1182.
The compound 6q was prepared from starting materials 5q and
N-methyl piperazine.
The compound 6u was prepared from starting materials 5t and
N-ethyl piperazine.
1-[4-Chloro-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-5-
methoxy-1H-indole dihydrochloride (6u)
Yield: 61%, after 2 steps; Melting range: 209.5–211.0 ꢀC; I.R
(cmꢂ1): 3448, 2983, 1585, 1465, 1222, 761; ESIMS (m/z): 448.0
1-[4-Bromo-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-5- [M + H]+; 1H-NMR (400 MHz, D2O): d 1.19–1.23 (t, 3H, N-
fluoro-1H-indole dihydrochloride (6q)
CH2CH3), 2.97 (bs, 4H, Piperazine-H), 3.11–3.16 (q, 2H, N-
CH2CH3), 3.23 (bs, 4H, Piperazine-H), 3.67 (s, 3H, Ar-OCH3),
4.0 (s, 2H, Ar-CH2-N), 6.61–6.62 (d, 1H, J ¼ 3.66 Hz, Ar-H),
6.83–6.86 (dd, 1H, J ¼ 9.0, 2.5 Hz, Ar-H), 6.98 (d, 1H,
J ¼ 2.47 Hz, Ar-H), 7.39–7.41 (d, 1H, J ¼ 8.54 Hz, Ar-H), 7.46–
7.47 (d, 1H, J ¼ 3.68 Hz, Ar-H), 7.71–7.74 (m, 2H, Ar-H), 7.80
(d, 1H, J ¼ 2.2 Hz, Ar-H); HRMS: [M + H]+ C22H26ClN3O3S
calc. 448.1383, found. 448.1378.
Yield: 55%, after 2 steps; Melting range: 219.4–221.6 ꢀC; I.R
(cmꢂ1): 3435, 2924, 2366, 1633, 1452, 1134, 943; ESIMS (m/z):
1
465.7 [M + H]+; H-NMR (400 MHz, D2O): d 2.83 (s, 3H, N-
CH3), 2.93 (bs, 4H, Piperazine-H), 3.2–3.26 (bs, 4H, Piperazine-
H), 3.96 (s, 2H, Ar-CH2-N), 6.70–6.71 (d, 1H, J ¼ 3.6 Hz, Ar-H),
7.02–7.07 (m, 1H, Ar-H), 7.19–7.22 (dd, 1H, J ¼ 9.02, 2.5 Hz, Ar-
H), 7.6–7.62 (d, 1H, J ¼ 3.72 Hz, Ar-H), 7.67–7.72 (bs, 2H, Ar-
H), 7.8 (s, 1H, Ar-H), 7.82–7.86 (m, 1H, Ar-H); HRMS:
[M + H]+ C20H21BrFN3O2S calc. 466.0522, found. 466.0519.
The compound 6r was prepared from starting materials 5q and
N-ethyl piperazine.
The compound 6v was prepared from starting materials 5v and
N-methyl piperazine.
1-[4-Bromo-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-5-
methoxy-1H-indole (6v)
1-[4-Bromo-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-5-
fluoro-1H-indole (6r)
Yield: 63%; Melting range: 115.2–117 ꢀC; I.R (cmꢂ1): 2929,
1
1606, 1371, 1217, 817; ESIMS (m/z): 477.9 [M + H]+; H-NMR
(400 MHz, CDCl3): d 2.33 (s, 3H, N-CH3), 2.35 (bs, 8H,
Piperazine-H), 3.50 (s, 2H, Ar-CH2-N), 3.80 (s, 3H, Ar-OCH3),
6.58 (dd, 1H, J ¼ 3.6, 0.48 Hz, Ar-H), 6.9 (dd, 1H, J ¼ 8.97,
2.50 Hz, Ar-H), 6.95 (d, 1H, J ¼ 2.43 Hz, Ar-H), 7.48 (d, 1H,
J ¼ 3.6 Hz, Ar-H), 7.56 (m, 2H, Ar-H), 7.85 (d, 1H, J ¼ 8.9 Hz,
Ar-H), 7.96 (d, 1H, J ¼ 1.33 Hz, Ar-H); HRMS: [M + H]+
C21H24BrN3O3S calc. 478.0722, found. 478.0715.
Yield: 58%; Melting range: 92.2–93.9 ꢀC; IR (cmꢂ1): 2939, 1589,
1458, 1138, 808; ESIMS (m/z): 479.8 [M + H]+; 1H-NMR
(400 MHz, CDCl3): d 1.11 (t, 3H, N-CH2CH3), 2.43–2.48 (bs,
8H, Piperazine-H & 2H, N-CH2CH3), 3.51 (s, 2H, Ar-CH2-N),
6.62–6.63 (dd, 1H, J ¼ 3.59, 0.44 Hz, Ar-H), 7.00–7.05 (m, 1H,
Ar-H), 7.16–7.19 (dd, 1H, J ¼ 8.66, 2.5 Hz, Ar-H), 7.5–7.6 (m,
3H, Ar-H), 7.917.95 (m, 1H, Ar-H), 7.97 (d, 1H, J ¼ 1.94 Hz, Ar-
H); HRMS: [M + H]+ C21H23BrFN3O2S calc. 480.0678, found.
480.0675.
The compound 6w was prepared from starting materials 5v
and N-ethyl piperazine.
The compound 6s was prepared from starting materials 5s and
N-ethyl piperazine.
1-[4-Bromo-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-5-
methoxy-1H-indole (6w)
1-[4-Bromo-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-5-
bromo-1H-indole dihydrochloride (6s)
Yield: 59%; Melting range: 196.1–198.6 ꢀC; I.R (cmꢂ1): 3444,
1
2430, 1614, 1438, 1224, 761; ESIMS (m/z): 491.9 [M + H]+; H-
NMR (400 MHz, CDCl3): d 1.22–1.27 (t, 3H, N-CH2CH3), 2.65–
2.66 (bs, 4H, Piperazine-H), 2.99–3.00 (bs, 2H, Piperazine-H),
3.12–3.14 (bs, 2H, Piperazine-H), 3.22–3.34 (q, 2H, N-CH2CH3),
3.35–3.37 (s, 2H, Ar-CH2-N), 3.79 (s, 3H, Ar-OCH3), 6.67–6.79
(d, 1H, J ¼ 3.69 Hz, Ar-H), 6.93–6.96 (dd, 1H, J ¼ 9.01, 2.52 Hz,
Ar-H), 7.10–7.11 (d, 1H, J ¼ 2.4 Hz, Ar-H), 7.71–7.72 (dd, 1H,
J ¼ 8.45, 2.42 Hz, Ar-H), 7.75–7.76 (d, 1H, J ¼ 3.65 Hz, Ar-H),
7.80–7.85 (m, 2H, Ar-H), 8.03 (bs, 1H, Ar-H); HRMS: [M + H]+
C22H26BrN3O3S calc. 491.0878, found. 491.0882.
Yield: 56%, after 2 steps; Melting range: 205.1–207.1 ꢀC; I.R
(cmꢂ1): 3435, 2346, 1439, 1172, 815; ESIMS (m/z): 540.2
[M + H]+; 1H-NMR (400 MHz, D2O): d 1.07–1.22 (t, 3H, N-
CH2CH3), 2.59–2.89 (bs, 6H, Piperazine-H), 3.04–3.07 (q, 2H,
N-CH2CH3), 3.10–3.12 (bs, 2H, Piperazine-H), 3.34 (s, 2H, Ar-
CH2-N), 6.50–6.51 (d, 1H, J ¼ 3.39 Hz, Ar-H), 7.15 (m, 2H,
Ar-H), 7.32 (m, 2H, Ar-H), 7.49 (dd, 1H, J ¼ 9.24, 3.49 Hz, Ar-
H), 7.61 (d, 1H, J ¼ 8.74 Hz, Ar-H), 7.70 (bs, 1H, Ar-H); HRMS:
[M + H]+ C21H23Br2N3O2S calc. 539.9878, found. 539.9881.
The compound 6t was prepared from starting materials 5t and
N-methyl piperazine.
The compound 6x was prepared from starting materials 5x and
N-methyl piperazine.
1-[4-Chloro-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
3-methyl-1H-indole dihydrochloride (6x)
1-[4-Chloro-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
5-methoxy-1H-indole dihydrochloride (6t)
Yield: 61%, after 2 steps; Melting range: 216.9–218.7 ꢀC; I.R
(cmꢂ1): 3493, 2673, 1627, 1450, 1174, 962; ESIMS (m/z): 418.4
Yield: 62%, after 2 steps; Melting range: 208.8–210.2 ꢀC; I.R
(cmꢂ1): 3446, 2981, 2372, 1585, 1465, 1222, 952; ESIMS (m/z):
434.1 [M + H]+; 1H-NMR (400 MHz, D2O): d 2.82 (s, 3H,
1
[M + H]+; H-NMR (400 MHz, D2O): d 2.01 (s, 3H, Ar-CH3),
2.83 (s, 3H, N-CH3), 3.00 (bs, 4H, Piperazine-H), 3.2–3.35

12 R. V. S. Nirogi et al.
J Enzyme Inhib Med Chem, Early Online: 1–15
(bs, 4H, Piperazine-H), 3.98 (s, 2H, Ar-CH2-N), 7.12–7.14 (m, 1-[4-Chloro-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-5-
1H, Ar-H), 7.15–7.31 (m, 4H, Ar-H), 7.62–7.63 (dd, 1H, J ¼ 8.54, methoxy-3-methyl-1H-indole dihydrochloride (6ac)
1.96 Hz, Ar-H), 7.65–7.84 (m, 2H, Ar-H); HRMS: [M + H]+
Yield: 59%, after 2 steps; Melting range: 217.5–220.8 ꢀC; I.R
C21H24ClN3O2S calc. 418.1278, found. 418.1275.
(cmꢂ1): 3456, 2983, 1612, 1448, 1172, 962; ESIMS (m/z): 462.2
The compound 6y was prepared from starting materials 5x and
[M + H]+; 1H-NMR (400 MHz, D2O): d 1.10–1.14 (t, 3H,
N-ethyl piperazine.
N-CH2CH3), 1.91 (s, 3H, Ar-CH3), 3.07–3.12 (bs, 10H,
Piperazine-H & 2H, N-CH2CH3), 3.60 (s, 3H, Ar-OCH3), 4.18
1-[4-Chloro-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-3-
methyl-1H-indole dihydrochloride (6y)
(s, 2H, Ar-CH2-N), 6.74–6.8 (m, 2H, Ar-H), 7.11 (s, 1H, Ar-H),
7.37–7.39 (d, 1H, J ¼ 8.76 Hz, Ar-H), 7.61–7.67 (m, 2H, Ar-H),
Yield: 63%, after 2 steps; Melting range: 218.9–220.5 ꢀC; I.R 7.74 (s, 1H, Ar-H); HRMS: [M + H]+ C23H28ClN3O3S calc.
(cmꢂ1): 3417, 2436, 1631, 1442, 1166, 966; ESIMS (m/z): 432.3 462.1540, found. 462.1543.
[M + H]+; 1H-NMR (400 MHz, D2O): d 1.19–1.22 (t, 3H, N-
CH2CH3), 2.00 (s, 3H, Ar-CH3), 2.93 (bs, 4H, Piperazine-H)
Results and discussion
3.11–3.16 (q, 2H, N-CH2CH3), 3.33–3.35 (bs, 4H, Piperazine-H),
Structure–activity relationship (SAR)
4.01 (s, 2H, Ar-CH2-N), 7.10–7.14 (m, 1H, Ar-H), 7.23–7.30
(m, 4H, Ar-H), 7.61 (dd, 1H, J ¼ 8.64, 1.74 Hz, Ar-H), 7.82–7.84
(m, 2H, Ar-H); HRMS: [M + H]+ C22H26ClN3O2S calc.
432.1434, found. 432.1436.
The compound 6z was prepared from starting materials 5z and
N-methyl piperazine.
Several analogs of 1-[3–(4-methyl piperazin-1-ylmethyl) phenyl-
sulfonyl]-1H-indoles and 1-[3–(4-ethyl piperazin-1-ylmethyl)
phenylsulfonyl]-1H-indoles were synthesized and their radioli-
gand binding affinities at the human 5-HT6R at 100 nM concen-
tration are given in Table 1.
The binding data of these compounds at 100 nM concentra-
tion indicated that the compounds have high to moderate
affinity to the 5-HT6R. Among the compounds synthesized 6a,
6b, 6c, 6d, 6e, 6x, 6y, 6z and 6aa have shown good binding
affinity at human 5-HT6R, when compared to other compounds
in the series. Unsubstituted indole derivatives 6a, 6b, 6c and
6d have shown higher 5-HT6R-binding affinities than those of
the corresponding 5-substituted compounds, suggesting that the
substitution at 5th position of indole ring is not well tolerated.
This can be seen by comparing the in vitro binding affinities of
the compound 6a with 6 h, 6i, 6j and 6k, compound 6b with
6 l and 6m, compound 6c with 6n or compound 6d with 6o
and 6t. Compounds with electron donating and/or bulky groups
(viz. OCH3, OC2H5, OCH(CH3)2) at C5 of indole showed
moderate potency toward 5-HT6R (compounds 6 h, 6i and 6j).
One-fourth of the activity was lost when electron-donating
groups like methoxy group was introduced at C5 of indole as
can be seen by comparing the binding affinities of the
compound 6a with 6 h, compound 6d with 6t, compound 6e
with 6u, compound 6f with 6v, compound 6 g with 6w,
compound 6x with 6ab or compound 6y with 6ac.
More or less a very similar trend was observed in the case of
electron withdrawing and/or bulky halogen groups (viz. F, Br) as
can be seen by comparing the binding affinities of the compound
6 g with 6r and 6s. The C5 halo substituted indole derivatives
exhibited moderate affinity toward 5-HT6R as can be seen
from 6k–6s. In terms of in vitro affinity, the preferred order of
substitution on phenylsulfonyl ring at C-40 position was found to
be CH3, H, Cl over Br as can be seen by comparing the binding
affinities of the compounds 6b with 6a, 6d and 6f, compound 6k
with 6m, 6o and 6q. In terms of activity, almost similar trend was
observed in compounds with N1-methyl or N1-ethyl substitution
on piperazine ring, as can be seen from comparing the binding
affinities of the compound 6b with 6c, compound 6d with 6e,
compound 6f with 6 g, compound 6t with 6u, compound 6v with
6w, compound 6x with 6y or compound 6z with 6aa.
1-[4-Bromo-3-(4-methyl piperazin-1-ylmethyl) phenylsulfonyl]-3-
methyl-1H-indole dihydrochloride (6z)
Yield: 56%, after 2 steps; Melting range: 210.5–213 ꢀC; I.R
(cmꢂ1): 3429, 2370, 1631, 1174, 948; ESIMS (m/z): 462.2
1
[M + H]+; H-NMR (400 MHz, D2O): d 1.97 (s, 3H, Ar-CH3),
2.78 (s, 3H, N-CH3), 2.79 (bs, 4H, Piperazine-H), 3.10–3.17
(bs, 4H, Piperazine-H), 3.72 (s, 2H, Ar-CH2-N), 7.06–7.08 (m,
1H, Ar-H), 7.17–7.21 (m, 4H, Ar-H), 7.37 (m, 1H, Ar-H),
7.72 (bs, 1H, Ar-H), 7.79–7.82 (d, 1H, J ¼ 8.20 Hz, Ar-H);
HRMS: [M + H]+ C21H24BrN3O2S calc. 462.0773, found.
462.0778.
The compound 6aa was prepared from starting materials 5z
and N-ethyl piperazine
1-[4-Bromo-3-(4-ethyl piperazin-1-yl methyl) phenylsulfonyl]-3-
methyl-1H-indole dihydrochloride (6aa)
Yield: 62%, after 2 steps; Melting range: 204.1–206.5 ꢀC; I.R
(cmꢂ1): 3439, 2434, 1566, 1442, 1174, 966; ESIMS (m/z):
1
476.2 [M + H]+; H-NMR (400 MHz, D2O): d 1.16–1.19 (t, 3H,
N-CH2CH3), 1.96 (s, 3H, Ar-CH3), 2.77–2.94 (bs, 4H,
Piperazine-H), 3.04 (q, 2H, N-CH2CH3), 3.08 (bs, 4H,
Piperazine-H), 3.69 (s, 2H, Ar-CH2-N), 7.04–7.20 (m, 4H,
Ar-H), 7.22 (bs, 1H, Ar-H), 7.35–7.37 (d, 1H, J ¼ 8.2 Hz, Ar-
H), 7.72 (bs, 1H, Ar-H), 7.8–7.82 (d, 1H, J ¼ 8.16 Hz, Ar-H);
HRMS: [M + H]+ C22H26BrN3O2S calc. 476.0929, found.
476.0931.
The compound 6ab was prepared from starting materials 5ab
and N-methyl piperazine.
1-[4-Chloro-3-(4-methyl piperazin-1-yl methyl) phenylsulfonyl]-
5-methoxy-3-methyl-1H-indole dihydrochloride (6ab)
Yield: 61%, after 2 steps; Melting range: 213.3–214.2 ꢀC; I.R
(cmꢂ1): 3479, 2963, 2441, 1608, 1454, 1172, 883; ESIMS (m/z):
1
448.3 [M + H]+; H-NMR (400 MHz, D2O): d 2.16 (s, 3H, Ar-
Generally, replacement of the hydrogen atom at the indole-C3
with the small methyl group is well tolerated and produced good
in vitro potency, as can be seen by comparing affinities of the
methyl-substituted derivatives 6x, 6y, 6z and 6aa with those of the
corresponding C3-unsubstituted compounds 6d, 6e, 6f and 6g.
The compounds showing 490% inhibition at 100 nM concen-
tration at 5-HT6R were further assessed for their Ki (nM) values
by performing complete dose response from 10 mM to 0.1 nM in
semilogarithmic concentrations (Table 1).
CH3), 2.77 (s, 3H, N-CH3), 2.95–2.99 (bs, 6H, Piperazine-H),
3.45 (bs, 2H, Piperazine-H), 3.94 (s, 3H, Ar-OCH3), 4.29 (s, 2H,
Ar-CH2-N), 6.92–6.96 (dd, 1H, J ¼ 8.96, 2.52 Hz, Ar-H), 7.01 (d,
1H, J ¼ 2.44 Hz, Ar-H), 7.54 (d, 1H, J ¼ 1.04 Hz, Ar-H), 7.66–
7.68 (d, 1H, J ¼ 8.52 Hz, Ar-H), 7.79–7.83 (m, 2H, Ar-H), 8.22
(s, 1H, Ar-H); HRMS: [M + H]+ C22H26ClN3O3S calc. 448.1383,
found. 448.1387.
The compound 6ac was prepared from starting materials 5ab
and N-ethyl piperazine.

DOI: 10.3109/14756366.2015.1103233
N1-phenylsulphonyl indole derivatives 13
Table 1. 5-HT6R binding datay for compounds 6.
% Inhibition at 100 nM
concentration*
Comp. No
R1
R2
R3
R4
Ki (nM)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
Cl
CH3
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
CH3
C2H5
CH3
C2H5
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
92.41
95.11
95.48
92.36
92.06
88.79
87.68
67.58
63.73
61.48
79.20
62.18
86.18
78.54
72.97
64.82
70.45
62.52
55.86
57.03
55.68
54.21
50.53
96.63
92.91
93.23
91.51
71.53
68.10
7.50 0.42
7.01 0.26
3.96 0.28
18.4 0.84
15.6 0.70
–
Cl
H
H
Br
Br
H
H
H
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
5-OCH3
5-OC2H5
5-OiPr
5-F
5-OCH3
5-F
5-F
5-F
5-F
5-F
5-F
5-Br
5-OCH3
5-OCH3
5-OCH3
5-OCH3
H
H
CH3
CH3
CH3
Cl
Cl
Br
Br
Br
Cl
6s
6t
6u
6v
6w
6x
6y
6z
6aa
6ab
6ac
Cl
Br
Br
Cl
–
5.45 0.28
7.85 0.35
9.11 0.24
12.8 0.63
–
H
H
H
Cl
Br
Br
Cl
5-OCH3
5-OCH3
Cl
–
*The data represent average of two determinations.
y5-HT6 receptor-binding studies were carried out at NovaScreen Biosciences Corporation, (caliper life sciences),
Hanover, MD, USA. Human recombinant/HEK293 cells; Radioligand: [3H] LSD (60–80 Ci/mmol).
‘‘_’’ means not tested for Ki (nM) determination.
The compound 6b was also evaluated in 5-HT6 reporter gene This greatly limits the potential of a compound to become a
cell-based functional assay43,44. The tested compound 6b has successful CNS agent.
shown antagonistic activity by inhibiting the 5-HT-stimulated
cAMP accumulation, with a Kb value of 4.92 0.13 nM and IC50 their PK parameters (Table 2). Brain and plasma levels were
value of 548.2 3.6 nM. calculated in male Wistar rats after 6 h i.v. continuous infusion of
We have profiled the selected compounds (6b, 6c and 6x) for
Selected compounds that displayed satisfactory potency compounds 6b, 6c and 6x at 1 mg/kg/h dose. Among these
towards 5-HT6R in in vitro binding assay were further profiled compounds, 6b has shown adequate brain to plasma ratio of
in selectivity assays, against a panel of related serotonin receptors 2.03 0.42 (brain and plasma concentrations are 510 145 ng/g,
like 5-HT4b, 5-HT3, 5-HT2A and 5-HT2C, histamine H1, 286 80 ng/mL), whereas compounds 6c and 6x were having
dopamine D2, adrenergic a1B and the transporters such as lower to moderate brain to plasma ratio of 0.53 0.13 (brain and
SERT, NET and DAT.
plasma concentrations are 312 82 ng/g, 59 37 ng/mL) and
We were also pleased to find that the tested compounds (6b, 6c 1.61 0.39 (brain and plasma concentrations are 486 250 ng/g,
and 6x) demonstrated 530% inhibition at maximum tested 293 102 ng/mL), respectively. The pharmacokinetic profile of
concentration of 10 mM, indicating that the tested compounds 6b, 6c and 6x was assessed in male Wistar rats (Table 2).
have very less activity toward these off targets and are highly Following i.v. administration of 10 mg/kg, the compounds 6b, 6c
selective toward 5HT6 receptor (data not shown).
and 6x have shown good mean half-life of 2.69 1.51 h,
In drug discovery, a major challenge of CNS therapy is the 6.25 0.35 h and 5.84 2.21 h, respectively. Following oral
blood–brain barrier (BBB). 5-HT6 receptor antagonists should administration at 10 mg/kg, the compounds 6b and 6c have
cross the blood brain barrier for treating cognitive dysfunction. shown good plasma concentrations of 1375 427 ng/mL,

14 R. V. S. Nirogi et al.
J Enzyme Inhib Med Chem, Early Online: 1–15
Table 2. Pharmacokinetic profile of compounds 6b, 6c, and 6x in male
wistar rats*.
Open column - familiar object
Filled column - novel object
16
14
12
10
8
Compound
6b
6c
6x
D.I.=0.73
D.I.=0.56
i.v. (n ¼ 3)
Dose (mg/kg)
t1/2 (h)
*
10
10
6.25 0.35
6.9 4.3
10
5.84 2.21
7.5 1.0
2.69 1.51
3.6 1.2
34 12
Vz (L/kg)
Cl (mL/min/kg)
p.o. (n ¼ 3)
Dose (mg/kg)
t1/2 (h)
Cmax (ng/mL)
Tmax (h)
40
7
52
7
10
10
10
1.73 0.56
106
0.38 0.18
342 152
6
7.85 2.62
1375 427
0.38 0.18
3194 1748
3.18 1.71
749 836
0.50 0.43
1171 1046
14 10
1
4
AUC (ng.h/mL)
F (%)
2
30
7
10
6
Brain (ng/g)
Plasma (ng/mL)
Cb/Cp
570 145
286 80
2.03 0.42
312 82
592 37
0.53 0.13
486 250
293 102
1.61 0.39
0
Vehicle
10 mg/kg
Compound 6b
*Fasted male wistar rats, vehicle used: water for injection for both oral Figure 5. Novel object recognition test data for compound 6b in rats.
and intravenous routes. Dosing volumes: 10 mL/kg p.o. and 2 mL/kg for Compound 6b versus vehicle (paired t-test), n ¼ 9–10/group, p.o., dosing
i.v.; values are mean SD.
drug: 60 min prior to test (p.o.). Vehicle PEG 400 50% v/v; 1 mL/kg, p.o.
i.v. ¼ intravenous, p.o. ¼ per oral, t1/2 ¼ half-life, Vz ¼ volume of distri- *p50.05 Student’s t-test. D.I. ¼ discriminative index.
bution, Cl ¼ clearance, Cmax ¼ The peak plasma concentration of a drug
after administration, Tmax ¼ Time of maximum drug concentration,
attractive task for testing compounds for their potential against
AUC ¼ Area Under the Curve, F (%) ¼ bioavailability, Cb/Cp ¼ brain to
cognitive deficits in Alzheimer’s disease and schizophrenia.
Oral administration of compound 6b (10 mg/kg) has signifi-
cantly improved performance of rats in animal models of
cognition like novel object recognition test46 (NORT, Figure 5).
Discriminative index of vehicle-treated group between familiar
and novel object is 0.56, where as in compound 6b treated group
is 0.73 (Figure 5).
plasma ratio.
Table 3. Human CYP45045 inhibitory data and microsomal metabolic
stability for compound 6b*.
% Metabolism in liver
IC50 (mM)
microsomes
Human
94
Compound
CYP 3A4
6.9
CYP 2D6
4.3
Rat
100
Conclusion
6b
We have identified a new series of 1-[3-(4-alkyl piperazin-1-
ylmethyl)- phenylsulfonyl]-1H-indoles (Compounds 6) as potent,
selective, orally available and brain penetrant 5-HT6 receptor
ligands. The lead compound, 1-[4-methyl-3-(4-methyl piperazin-
1-yl methyl) phenylsulfonyl]-1H-indole dihydrochloride (6b)
from this series has shown desired pharmacokinetic properties
and is active in animal models of cognition such as NORT in
preclinical trials. Based on its overall profile, the compound 6b
was selected for further development.
*The cytochrome P450 inhibitory potential was determined using
isoform-selective assays and heterologously expressed human CYP
2D6 and CYP 3A4. These values are the mean of duplicate determin-
ations. Microsomal metabolic stability in wistar rat and human at 0.5 h,
conc. 2.5 mM.
749 836 ng/mL, respectively, whereas compound 6x has shown
low plasma concentration of 106 1 ng/mL.
The clearance was low (34 12 mL/min/kg) for compound 6b
as compared to those of 6c and 6x. The compounds 6b, 6c and 6x
have shown the volume of distributions (Vz, L/kg), that is,
3.6 1.2, 6.9 4.3 and 7.5 1.0, respectively, at 10 mg/kg, i.v.
dose.
The mean oral bioavailability for compound 6b was better
(30 7%) as compared to that of 6c (14 10%) and 6x (10 6%).
The moderate-to-low oral bioavailability of these compounds may
be because of their poor metabolic stability in rat liver
microsomes.
Acknowledgements
Mr. Venkateswarlu Jasti, CEO, Suven Life Sciences Ltd., Hyderabad,
India is gratefully acknowledged.
Declaration of interest
The study is supported by discovery analytical, DMPK, In vitro,
In vivo departments.
References
The in vitro metabolic stability of compound 6b in rat and
human liver microsomes was carried out for 30 minutes.
Additional screening in in vitro ADME assays demonstrated
that the compound 6b has extensively metabolized (100% and
94%) in rat and human liver microsomes, respectively.
Based on above pharmacokinetic profile data, the compound
6b was further evaluated for its CYP liabilities in human liver
microsomes, the IC50 values for compound 6b was found to be
6.9 mM for CYP 3A4 enzymes and 4.3 mM for CYP 2D6 enzymes
(Table 3).
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