Design and synthesis of novel series of 5-HT6 receptor ligands having indole, a central aromatic core and 1-amino-4 methyl piperazine as a positive ionizable group

Article abstract of DOI:10.1016/j.bmc.2013.05.051

The exclusive distribution of 5-HT₆ receptor in the brain regions and high affinity for antipsychotic and antidepressant drugs makes 5-HT₆ receptor a promising target in treatment of CNS diseases. Based on a pharmacophore model reported in the literature, we designed and synthesized a novel series of 5-HT₆ receptor ligands having indole as a central aromatic core and 1-amino-4-methyl piperazine as positive ionizable group. Out of 32 compounds we have successfully identified 10 new compounds as 5-HT₆ receptor antagonists. The structure-activity relationship (SAR) studies have been carried out by mapping the compounds with the 3D QSAR model.

Full text of DOI:10.1016/j.bmc.2013.05.051

Accepted Manuscript
Design and synthesis of novel series of 5-HT receptor ligands having indole, a
6
central aromatic core and 1-amino-4methyl piperazine as a positive ionizable
group
Faisal Hayat, Sungjin Cho, Hyewhon Rhim, I.V. Ambily Nath, Ae Nim Pae, Jae
Yeol Lee, Dong Joon Choo, Hea-Young Park Choo
PII:
S0968-0896(13)00500-2
DOI:
http://dx.doi.org/10.1016/j.bmc.2013.05.051
BMC 10877
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
27 March 2013
24 May 2013
24 May 2013
Please cite this article as: Hayat, F., Cho, S., Rhim, H., Ambily Nath, I.V., Pae, A.N., Lee, J.Y., Choo, D.J., Choo,
H.P., Design and synthesis of novel series of 5-HT receptor ligands having indole, a central aromatic core and 1-
6
amino-4methyl piperazine as a positive ionizable group, Bioorganic & Medicinal Chemistry (2013), doi: http://
dx.doi.org/10.1016/j.bmc.2013.05.051
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Design and synthesis of novel series of 5-HT6 receptor ligands having indole,
a central aromatic core and 1-amino-4methyl piperazine as a positive
ionizable group
Faisal Hayat a, Sungjin Cho b, Hyewhon Rhim b, Ambily Nath I.Vc,d, Ae Nim Paec,d, Jae Yeol
Leee, Dong Joon Choo e, Hea-Young Park Choo a
a College of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans
University, Seoul 120-750, Republic of Korea
b Center for Neuroscience, Korea Institute of Science & Technology, Seoul, 136-791, Korea
c Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 136-791,
Korea
d Department of Medicinal & Pharmaceutical Chemistry, School of Science, University of
Science and Technology, 52 Eoeun dong, Yuseong-gu, Daejeon 305-333, Republic of Korea
e
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences,
Kyung Hee University, Seoul 130-701, Korea
Abstract:
The exclusive distribution of 5-HT6 receptor in the brain regions and high affinity for
antipsychotic and antidepressant drugs makes 5-HT6 receptor a promising target in treatment
of CNS diseases. Based on a pharmacophore model reported in the literature, we designed
and synthesized a novel series of 5-HT6 receptor ligands having indole as a central aromatic
core and 1-amino-4-methyl piperazine as positive ionizable group. Out of 32 compounds we
have successfully identified 10 new compounds as 5-HT6 receptor antagonists. The structure-
activity relationship (SAR) studies have been carried out by mapping the compounds with the
3D QSAR model.
Keywords:
5-HT6 receptor antagonist, 1-amino-4-methylpiperazine, Sulfonyl indole, 3D QSAR,
pharmacophore mapping
Corresponding authors. Fax: +82 2 958 5923 (H.Rhim); fax: +82 2 3277 2821 (H.- Y. Park
Choo.).
E-mail addresses: hrhim@kist.re.kr (H. Rhim), hypark@ewha.ac.kr (H.-Y. Park Choo).

1. Introduction
5-Hydroxytryptamine (5-HT, serotonin) is a major neurotransmitter in both the central and
peripheral nervous system, which modulates a variety of important biological processes by
interaction with a family of receptors called 5-HT receptors. These receptors are divided into
seven subclasses (5-HT1-7), 5-HT6 being the most recently discovered and cloned member of
this class. The 5-HT6 receptor is almost exclusively expressed in the central nervous system,
especially in the areas associated with learning and memory. A thorough literature search
reveals that several antipsychotic and antidepressant drugs have significant affinity for 5-HT6
receptors.1 The specific localization of 5-HT6 receptors in CNS and high affinity of
antipsychotic and antidepressant drugs have promoted interest in this receptor as a promising
target in treatment of CNS disorders.2-8 In recent years several studies and reviews show
that serotonergic neurotransmission is implicated in modulation of learning and memory.9
In particular, 5-HT6 receptor antagonists are in beneficial on cognition in several animal
models.10 In addition, 5-HT6 antagonists have been shown to reduce appetite and produce
11
weight loss, and are being investigated for the treatment of obesity. Therefore, agents such
as latrepirdine, Lu AE58054, and SB-742,457 are being developed as novel treatments for
Alzheimer's disease, while PRX-07034, BVT-5,182, and BVT-74,316 are being investigated
for the treatment of obesity.
In the last decade, a large number of 5-HT6 ligands have been synthesized, and many are
comprised of an indole core with a basic amine and an arylsulfonyl moiety as shown in Fig.1.
Piperazine nucleus also plays a very important role to enhance the activity of 5-HT6 receptor
ligands. A series of piperazinylbenzenesulfonamides, including SB-271046 and SB-357134
were developed by Smith Kline-Beecham.12, 13 Cole and co-workers showed 4-piperazinyl- 1-
sulfonylindoles as potential 5-HT6 receptor antagonist.14 The 3- as well as 2-sulfonylindole
derivatives with a basic amine such as piperazine or piperidine at positions 4 through 7 on an
indole nucleus have been claimed as potent 5-HT6 antagonists.15-17
As part of our continuous efforts to develop agents for CNS diseases, we have focused on the
5-HT6 receptor to identify potent ligands for cognitive enhancement. Prompted by the above
described 5-HT6 ligands having indole and piperazine nucleus, here we report a novel series
of 5-HT6 receptor antagonist having a central indole core with 1-amino-4 methyl piperazine
nucleus as positive ionizable group. This is certainly the first report of the use of 1-amino-4
methyl piperazine as a positive ionizable group at the C-3 position of the indol ring for

synthesis of 5-HT6 receptor antagonists.
2. Results
2.1.
Chemistry
The synthesis of a novel series of 5-HT6 receptor antagonists (5-36) was performed as
outlined in scheme 1. Initially, the coupling of 2-methylindole-3-carboxaldehyde (1 mmol)
and 2-phenylindole-3-carboxaldehyde (1 mmol) with 1-amino-4-methyl piperazine (1.5
mmol) was chosen as a model reaction to establish the optimized reaction conditions. All
reactions were performed in the presence of various solvents using 2-3 drops of acetic acid as
a catalyst at different temperature ranges under anhydrous conditions. The desired products
were isolated in good yield (60-70%) when the reactions were carried out using anhydrous
ethanol at reflux temperature for 12-14 hrs. The reactions completed within 12-14 hrs. A
further improvement of yield was observed when anhydrous DMF was used in place of
ethanol and the products were isolated in very good yield (85-90%). These reactions were
performed in anhydrous DMF at refluxed temperature for 20 to 22 hrs. In conclusion, for the
synthesis of (2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-yl)methanimine and N-(4-methyl
piperazin-1-yl)(2-phenyl-1H-indol-3-yl)methanimine, the best reaction conditions are (a)
o
anhydrous DMF (b) high temperature up to 150-155 C and (c) 20-22 hrs refluxing. With
final products synthesis, three test reactions were performed in three different solvents (DCM,
THF and DMF) in different temperature ranges by using Et3N (1.5 to 3.0 mmol) and NaH
(1.2-1.5 mmol) as base. After 24 hours of stirring at room temperature, TLC did not
progress in the first test reaction using DCM as solvent and Et3N as a base In two other test
reactions with DMF and THF as solvents and NaH as base, TLC showed little progress in the
reactions but yield of the desired products was very poor. We also did not get the desire
products in good yield after heating the reactions up to reflux temperature. The desired
products were isolated in good yield when the reactions were carried out in presence of
anhydrous THF as solvent and KH as base at room temperature. The reactions were complete
within 13-15 hrs. Each compound synthesized was characterized by 1H NMR, 13C NMR and
high resolution MS.
2.2. Biological evaluation
All synthesized compounds were evaluated in vitro against the human recombinant serotonin

receptors. They were evaluated for their functional profile by determining the adenylate
cyclase activity. HEK293 cell line stably expressed 5-HT6 receptor (HEK293/6R) was used
for 5-HT6 receptor activities. For the selectivity, HEK 293 cells transiently transfected with
5-HT4 or 5-HT7 receptor were used for 5-HT4 or 5-HT7 receptor activities, respectively. The
known 5-HT6 antagonist, SB258585 was used as reference having IC50 = 19.9 5.5 nM in our
experiment. The results were estimated as the percentage inhibition compared with the
untreated controls.
Three out of thirteen compounds prepared in 3-methyl indole series (5-17) showed higher
than 70% inhibition activity at 10 uM. Compounds 5, 6, and 12 showed IC50 values in the
range 2.0 to 4.7 μM as shown in Table 1. Compound 12 with 2-naphthyl group showed
inhibitory activity with an IC50 value of 4.74 μM. Compounds 5 and 6 with 5-chloro-2-
methoxy-4-methylphenyl and 4-fluorophenyl showed inhibitory activity with IC50 values of
2.04 and 2.4 μM, respectively. Compounds 8 and 11 with 4-nitrophenyl and 4-methylphenyl
were marginally active with 52% and 49% inhibition, respectively, at 10 μM. In the case of
biphenyl, 4-chlorobiphenyl as Ar, compounds 10 and 11 showed no activity. Compounds 16
and 15, with substituted azobenzene and 2-(1-naphthyl)ethyl as Ar respectively, showed no
activity, either.
In 3-phenyl indole series (18-36), seven compounds (18, 19, 20, 29, 32, 33, and 35) showed
IC50 values in the range 1.4 to 7.4 μM as shown in Table 2. Compound 18 with phenyl
showed good inhibitory activity with an IC50 value of 1.4 μM. Various substitutions, such as
methyl, isopropyl, n-buthyl, methoxy, chloro, and iodo on phenyl group decreased the
activity. Only compounds 19 and 20 with 5-chloro-2-methoxy-4-methylphenyl and 4-
fluorophenyl showed slightly decreased inhibitory activity with IC50 values of 2.9 and 7.4 μM,
respectively.
Compound 29 with 1-naphthyl showed moderate activity with IC50 values of 6.6 μM, while
20 with 2-naphthyl showed lower activity. The compound 32 with 1-(5-
(dimethylamino)naphthyl showed the highest activity with IC50 values of 1.4 μM in this
series of compound prepared. However compound 31 with 1-(5-(dibuthylamino)naphthyl
showed much decreased activity. Compounds 33 and 35 containing heterocycles such as 1-
methylimidazole and 2,3-dihydro-1,4-benzodioxane, showed good activity with IC50 values
of 3.6 and 3.8 μM, respectively. Compounds 34 and 36, with substituted chromone and
dihydrobenzofuran as Ar respectively, showed no activity.
Ten compounds that showed good 5-HT6 inhibitory activity were selected to test selectivity

toward other serotonergic receptors in same Gs family, 5-HT4 and 5-HT7 receptor.
Compounds 5 and 29 showed excellent selectivity as shown in Table 3. Compound 29
showed only 9.4% and 5.0% inhibition at 10 μM for the 5-HT4 and 5-HT7 receptors,
respectively. Compound 5 showed 17.9% and 18.4% inhibition at 10 μM for the 5-HT4 and
5-HT7 receptors, respectively. SB258585 (a known 5-HT6 antagonist) and SB269970 (a
known 5-HT7 antagonist) were employed as positive control.
2.3 Pharmacophore mapping
The present design and synthesis approach was guided by a previously reported
pharmacophore model18. Hence, the statistical validation of our compounds has been carried
out by the regeneration and subsequent mapping of the model with active and inactive
compounds. The mapping study derived satisfactory correlation between fitvalue and activity
of compounds. The active compounds, with the proper fitting of all features showed higher
fitvalues whereas the inactive compounds missed some key features which resulted in lower
fitvalues.
Using HypoGen, we generated total ten hypotheses, all with same features as in the reported
model ie., AR, PI, HBA and HYD. The top ranked hypothesis Hypo1 outperformed other
hypotheses in the cost analysis procedure. The Fixed, Null and Total costs of Hypo1 were
177.04, 257.86 and 198.16 bits respectively. The highest cost difference (59.7), lowest error
cost (167.97), lowest root mean square divergence (0.95) and best correlation coefficient
(0.91) demonstrates good predictability of Hypo1 (Fig. 2).
The mapping of most active compounds 32, 18, 6 and inactive compounds 10 and 34 with
Hypo1 is visualized (Fig.3). Compounds 32, 18 and 6 showed reasonable fitting with
fitvalues of 7.08, 7.51 and 7.65 respectively. The inactive compounds 10 and 34 displayed
poor mapping with the features as it is evident from the low fitvalues of 4.21 and 1.00. The
pharmacophoric features are observed to match with the key structural moieties of the
compounds feasibly well.
3. Discussion
Indole and piperazine nucleus are one of the most explored chemical classes of 5-HT6

receptor ligands. The structural requirements for the 5-HT6 receptor ligands that are
postulated by several research groups are comprised of four key requirements, a central
aromatic/heterocyclic ring (AR) flanked by a positive ionizable group (PI, such as a basic
nitrogen) and a strong, multiple hydrogen bond acceptor (HBA, such as sulfonyl group)
attached to a hydrophobic group (HYD, such as phenyl ring).18 A large number of 5-HT6
ligands with an indole core have been synthesized.19-22 It is suggested that the basic amine
and arylsulfonyl moieties are the necessary receptor pharmacophores and the indole core
serves merely as a template to hold these pharmacophores in the necessary orientation that
effectively interacts with the 5-HT6 receptor active site residues.23 As arylsulfonyl moieties,
substituted benzene and naphthalene are most often reported. The nature and position of the
substituents in the aryl fragment strongly influenced activity, since a substitute group likely
served to constrain the arylsulfonyl moiety in an appropriate conformation that affected the
binding affinity.
As a basic amine (PI), piperazine, methyl piperazine, piperidine, aminoethyl or N,N-
dimethylaminoethyl, have been reported in 5-HT6 antagonists. The 5-HT6 receptors are
transmembrane-embedded G-protein coupled receptors containing an aspartate moiety in TM
helix 3 that, presumably, serves as a ligand–amine binding site.24 Recently, we reported novel
5-HT6 antagonists which contain N,N-dimethylformimidamide as a basic amine moiety.25
As part of our continuous efforts to develop 5-HT6 antagonists, here we introduced N-(4-
methylpiperazin-1-yl)methanimine as a basic amine moiety. None N-(4-methylpiperazin-1-
yl)methanimine on indole ring derivative was reported as 5-HT6 receptor antagonists yet.
Among the whole series of 32 compounds, 10 compounds were found to be a potent 5- HT6
receptor antagonist. In this series, it has been expected that 2-methyl and 2-phenyl indole
rings, a –SO2 group, and benzene or napthalene served as AR, HBA, or HYD, respectively.
In terms of structure activity relationship of arylsulfonyl moiety among the 2-methyl indole
series (5-17), compound 5, 6 and 12, substituted 3-chloro-6-methoxy-4-methylphenyl, 2-
naphtyl, and 4-fluorophenyl ring at the position number N-1 of the indole ring attached with
the –SO2- system showed good activity with 5-HT6 receptor. Both electron donating (-CH3)
or withdrawing (-NO2) substituent showed similar biological activity (8 and 11). Large
substituents such as biphenyl showed the decreased activity (10). Compounds 6, substituted
with fluoro group at para position of phenyl ring, showed good biological activity among the
series, probably due to the small size. For selectivity, compounds 5, substituted 3-chloro-6-
methoxy-4-methylphenyl, showed excellent selectivity for 5-HT6 over 5-HT4 and 5-HT7

receptors. Compound 6 showed good activity but showed poor selectivity over 5-HT4.
In case of 2-phenyl indole series (18-36), 5-(dimethylamino) naphthalene, 1-methylimidazole,
4-chlorophenyl, phenyl, 4-fluorophenyl, 5-chloro-2-methoxy-4 methyl phenyl and1-naphtyl
ring at the position N-1 of the indole ring attached with the –SO2- system also showed good
activity with 5-HT6 receptor (IC50 = 1.4 - 7.4 μM). Some compounds substituted with phenyl
ring at position number 2 of indole ring were noticeably less potent than their congeners with
methyl group at C-2 position of indole ring. (5>19, 12> 30). On the other hand, a significant
change in biological activity (32> 13) was observed in compounds 32 and 13, both the
compounds are substituted with dimethyl amino group at 5- position on naphthyl ring but
only compound 32 showed good biological activity. So in case of compound 32, the presence
of another amino binding site may fit with phenyl group at C-2 position of indole ring. For
selectivity, compounds 29, substituted 1-naphthyl, showed excellent selectivity over 5-HT4
and 5-HT7 receptors.
Pharmacophore mapping studies with Hypo1 have demonstrated that active compounds with
IC50 values under 5.0 µM are found to map all features with fitvalues of ≥ 7.0 whereas the
inactive compounds with ~22% inhibition showed lower values of ≤ 5.0. In the most active
compounds 32, 18 and 6 the indole, sulfonyl and piperazine moieties mapped with aromatic,
acceptor and positive ionizable features. The naphthyl, phenyl and fluorophenyl groups in 32,
18 and 6 possessed hydrophobic feature. The least active compound 11 failed to map with
Hypo1. In compounds 10 and 34, the pharmacophoric features does not fit well with the
structure and even showed variations in the mapping pattern of ring aromatic feature. The
indole ring which was supposed to merge with aromatic feature fitted with hydrophobic
feature in 10 whereas it occupied the aromatic feature in 34. The sulfonyl and piperazine
groups showed poor fitting with acceptor and positive ionizable features.
The present mapping analysis validated the potential of our synthetic compounds as good 5-
HT6 antagonists and this in turn strongly supported the inference that ring aromatic, positive
ionizable, hydrogen bond acceptor and hydrophobic features are the essential requirement for
the activity of 5-HT6 antagonists. Further research in this direction could lead to the design
and development of novel diverse scaffolds as potential 5-HT6 antagonists.
4. Conclusion

Novel 2-methyl/phenyl-1-(substituted arylsulfonyl)-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimines were designed and synthesized as 5-HT6 ligands using N-(4-
methylpiperazin-1-yl)methanimine as basic amine moiety. Compounds 5 and 32 significantly
inhibited the 5-HT-induced cAMP level ( IC50 = 2.4 μM and 1.4 μM, respectively), indicating
that these compounds are potent 5-HT6 receptor antagonists. Compounds 5 and 29 showed
good selectivity for 5-HT6 over 5-HT4 and 5-HT7 receptors. The mapping of aromatic,
positive ionizable, hydrogen bond acceptor and hydrophobic features of the 3D QSAR model
with key structural moieties showed good agreement with the activity profile of the
compounds.
5. Experimental
5.1. Materials and methods
All melting points of the synthesized compounds were taken in Pyrex capillaries using
electrothermal digital melting point apparatus (Buchi) and were not corrected. 1H NMR
spectra were recorded on a 400 MHz Varian FT-NMR using tetramethylsilane as an internal
standard. Chemical shifts are expressed in ppm (δ), and peaks are listed as singlet (s), doublet
(d), triplet (t), quintet (q), multiplet (m), with coupling constants (J) expressed in Hertz. Mass
spectra data were obtained on a Agilent 6220 Accerate -Mass TOF LC/MS. Most of the
reagents were purchased from Aldrich Chemical Company and Merck Company. TLC was
run on the silica gel coated plastic sheets (Silica Gel 60, 230–400 mesh, Merck, Germany)
and visualized in UV light (254 or 365 nm).
5.2. General procedure for the preparation of (2-methyl-1H-indol-3-yl)-N-(4-
methylpiperazin-1-yl)methanimine and -N-(4-methylpiperazin-1-yl)(2-phenyl-1H-indol-
3-yl)methanimine (3 and 4)
A mixture of substituted indole 3-carboxaldehydes (1 mmol), the respective 1-amino-4-
methyl piperazine (1.5 mmol) in 5 mL dry DMF was heated to reflux under N2 until no
starting material could be detected by TLC. The resulting mixture was allowed to cool at
room temperature and poured into water and extracted with EtOAc. The combined organic

layers were washed with aqueous HCl (1 N), saturated aqueous NaHCO3 and brine solution
and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product
was purified by column chromatography using hexane: ethyl acetate (7:3) as eluent.
5.2. 1. (2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-yl)methanimine (3)
Brown solid (78%), mp 153–156 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.25 (m, 1H), 7.98
(s, 1H), 7.89 (s, 1H), 7.28-7.23 (m, 1H), 7.17-7.11 (m, 2H), 3.20 (t, J = 5.0 Hz, 4H), 2.65 (t, J
= 5.0 Hz, 4H), 2.53 (s,3H), 2.37 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 135.67 (Ar-
C=N), 135.47, 135.46, 126.38, 122.16, 121.57, 120.76, 110.23 (aromatic), 77.23, 54.86,
52.26 (N-C-C-N), 46.15 (N-C), 12.36 (C-C), HR-EI Calcd for C15H21N4 (M+H) +: 257.1761
found: 257.1766.
5.2. 2. N-(4-methylpiperazin-1-yl)(2-phenyl-1H-indol-3-yl)methanimine (4)
o
1
Brown solid (85 %), mp 183–184 C: H NMR (chloroform-d6,400 MHz) δ 8.47 (m, 1H),
8.38 (s, 1H), 7.58-7.55 (m, 2H), 7.50-7.46 (m, 2H),7.43-7.35 (M, 2H), 7.26-7.18 (m, 3H),
3.19 (t, J = 5.0 Hz, 4H), 2.65 (t, J = 5.0 Hz, 4H), 2.34 (s, 3H). 13C NMR (chloroform-d6,100
MHz): δ 138.65, 136.44(Ar-C=N), 135.36, 133.52, 129.18, 128.96, 128.55, 126.54, 123.46,
123.30, 121.33, 110.90, 110.75 (aromatic), 77.23, 54.78, 51.97 ( N-C-C-N), 46.15 (1C, N-C).
5.3. General procedure for the preparation of (2-methyl-1-(Ar-sulfonyl)-1H-indol-3-yl)-
N-(4-methylpiperazin-1-yl)methanimine (5-17) and N-(4-methylpiperazin-1-yl)(2-
phenyl-1-( Ar-sulfonyl)-1H-indol-3-yl)methanimine (18-36)
(2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-yl)methanimine
(3)
or
N-(4-
methylpiperazin-1-yl)(2-phenyl-1H-indol-3-yl)methanimine (4) (0.5 mmol) dissolved in 5
mL THF, was added slowly to 25 mL flask containing a suspension of potassium hydride
(1.17 mmol) in 15 mL THF under nitrogen atmosphere, while maintaining the mass
o
o
temperature below 10 C. The reaction mixture was then stirred for a period of 1 h at 25 C.
Ar-sulfonylchloride (1 mmol) was added slowly to the above well-stirred solution
maintaining the mass temperature below 10 oC. The reaction mixture was further stirred over
night. After completion of the reaction, the reaction mixture was poured on to ice-water and
extracted with ethyl acetate (3 x 20 mL). The combined ethyl acetate extracts were then
washed with water (20 mL), brine (20 mL) and dried over anhydrous sodium sulphate. The
volatiles were removed under the reduced pressure and the resulting thick syrupy mass was

purified over silica gel column using hexane: ethyl acetate (8:2) as eluent.
5.3.1.
(1-(5-chloro-2-methoxy-4-methylphenylsulfonyl)-2-methyl-1H-indol-3-yl)-N-(4-
methylpiperazin-1-yl)methanimine (5)
Brown solid (11%), mp 179–181 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.30-8.28 (m, 1H),
8.05 (s, 1H), 7.93-7.90 (m, 1H), 7.78 (s, 1H), 7.25-7.20 (m, 2H), 6.66 (s, 1H), 3.42 (s, 3H),
3.24 (t, J = 5.0 Hz, 4H), 2.66 (t, J = 4.4 Hz, 4H), 2.62 (s, 3H), 2.38 (s, 3H), 2.35 (s, 3H). 13C
NMR (chloroform-d6,100 MHz): δ 155.85, 144.81(Ar-C=N), 137.29, 137.01, 131.39, 130.60,
127.24, 125.97, 125.75, 124.27, 123.58, 122.08, 115.84, 114.98, 114.38 (aromatic), 56.10,
54.67, 51.26 (N-C-C-N), 46.09 (N-C), 29.11 (O-C), 21.10, 13.28 (C-C). HR- MS Calcd for
C23H28N4O3SCl (M+H)+: 475.1565 found: 475.1576.
5.3.2.
(1-(4-fluorophenylsulfonyl)-2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (6)
Dark brown oil (23%): 1H NMR (chloroform-d6,400 MHz) δ 8.29 (d, J = 6.4Hz, 1H), 8.16 (d,
J = 5.6 Hz, 1H), 7.78-7.75 (m, 2H), 7.72 (s, 1H), 7.31-7.28 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H),
3.22 (t, J = 5.0 Hz, 4H), 2.67 (s, 3H), 2.63 (t, J = 4.8 Hz, 4H), 2.36 (s, 3H). 13C NMR
(chloroform-d6,100 MHz): δ 167.03, 164.47, 162.73 (Ar-F), 136.66 (Ar-C=N), 135.45,
130.29, 129.39, 128.02, 124.94, 124.38, 122.42, 117.71, 116.93, 116.72, 114.29 (aromatic),
54.63, 51.11 (N-C-C-N), 46.11 (N-C), 13.26 (C-C). HR-MS Calcd for C21H24N4O2SF
(M+H)+: 415.1599 found: 415.1605.
5.3.3.
(1-(4-iodophenylsulfonyl)-2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (7)
Light brown solid (52%), mp 123–125 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.29-8.26 (m,
1H), 8.14 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.70 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H),
7.29-7.27 (m, 3H), 3.23 (t, J = 4.8 Hz, 4H), 2.65 (s, 3H), 2.63 (s, 4H), 2.36 (s, 3H). 13C NMR
(chloroform-d6,100 MHz): δ 162.74 (Ar-I), 138.73, 138.68, 136.63(Ar-C=N), 135.39, 130.23,
128.04, 127.69, 124.97, 124.45, 122.46, 117.83, 114.30, 101.71 ( aromatic), 54.61, 51.07 ( N-
C-C-N), 46.09 (N-C), 13.26 (C-C). HR-MS Calcd for C21H24N4O2SI (M+H)+: 523.0659
found:523.0658.
5.3.4.
(1-(4-nitrophenylsulfonyl)-2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-

yl)methanimine (8)
o
1
Dark brown solid (28%), mp 174–176 C: H NMR (chloroform-d6,400 MHz) δ 8.28 (d, J =
4.8Hz, 1H), 8.22 (d, J = 8.8 Hz, 2H), 8.14 (d, J =5.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.68 (s,
1H), 7.35-7.26 (m, 2H), 3.24 (t, J = 5.0 Hz, 4H), 2.68 (s, 3H), 2.65 (t, J = 4.8 Hz, 4H), 2.38 (s,
3H). 13C NMR (chloroform-d6,100 MHz): δ 150.70 (Ar-NO2), 144.22 (Ar-C=N), 136.54,
135.01, 129.65, 128.26, 127.81, 125.34, 124.93, 124.72, 124.47, 122.75, 118.69, 114.31
(aromatic), 54.55, 50.92 (N-C-C-N), 46.05 (N-C), 13.40 (C-C). HR-MS Calcd for
C21H24N5O4S (M+H) +: 442.1544 found: 442.1550
5.3.5.
(1-(p-tolylsulfonyl)-2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (9)
Red oil (34%): 1H NMR (chloroform-d6,400 MHz) δ 8.27 (d, J = 5.6 Hz, 1H), 8.19 (d, J = 6.4
Hz, 1H), 7.73 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.31-7.23 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H),
3.22 (t, J = 5.0 Hz, 4H), 2.67 (s, 3H), 2.63 (t, J = 5.0 Hz, 4H), 2.36 (s, 3H), 2.33 (s, 3H). 13C
NMR (chloroform-d6,100 MHz): δ 162.38 (Ar-SO2), 144.77 (Ar-C=N), 136.31, 135.78,
135.39, 130.29, 129.73, 127.52, 124.32, 123.72, 121.95, 116.86, 113.88 (aromatic), 54.22,
50.74 (N-C-C-N), 45.66 (N-C), 21.29, 12.77 (C-C). HR-MS Calcd for C22H27N4O2S (M+H)+:
411.1849 found: 411.1857.
5.3.6.
(2-methyl-1-(biphenylsulfonyl)-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (10)
Brown solid (56%), mp 163–165 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.29 (d, J = 6.0Hz,
1H), 8.23 (d, J = 6.4 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.75 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H),
7.50-7.47 (m, 2H), 7.45-7.36 (m, 3H), 7.34-7.25 (m, 2H), 3.24 (t, J = 4.8 Hz, 4H), 2.71 (s,
3H), 2.66 (t, J = 4.8 Hz, 4H), 2.38 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 162.73 (Ar-
Ar), 146.88 (Ar-C=N), 139.01, 137.64, 136.75, 135.72, 130.63, 129.20, 128.84, 128.04,
127.94, 127.43, 127.02, 124.83, 124.23, 122.31, 117.36, 114.36 (aromatic), 54.61, 51.12 ( N-
C-C-N), 46.07 (N-C), 13.27 (C-C). HR-MS Calcd for C27H29N4O2S (M+H)+: 473.2006
found: 473.2008.
5.3.7.
(1-(4-chlorobiphenylsulfonyl)-2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (11)
o
1
Brown solid (38%), mp 211–213 C: H NMR (chloroform-d6,400 MHz) δ 8.29 (d, J = 5.6

Hz, 1H), 8.22 (d, J = 6.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H), 7.54 (d, J = 8.8 Hz,
2H), 7.43-7.38 (m, 4H), 7.34-7.27 (m, 2H), 3.23 (t, J = 4.8 Hz, 4H), 2.71 (s, 3H), 2.63 (t, J =
4.8 Hz, 4H), 2.36 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 145.56 (Ar-Cl), 137.99,
137.46, 136.76 (Ar-C=N), 135.66, 135.18, 130.48, 129.45, 128.69, 128.01, 127.90, 127.14,
124.89, 124.32, 122.36, 117.52, 114.41 (aromatic), 54.64, 51.13 (N-C-C-N), 46.12 (N-C),
13.32 (C-C). HR- MS Calcd for C27H28N4O2SCl (M+H)+: 507.1616 found: 507.1620.
5.3.8.
(2-methyl-1-(naphthalensulfonyl)-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (12)
Brown solid (10%), mp 189–190 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.42 (s, 1H), 8.29-
8.26 (m, 2H), 7.91 (d, J = 7.6 Hz,1H), 7.80 (t, J = 8.0 Hz, 2H), 7.71 (s,1H), 7.63-7.55 (m, 2H),
7.33-7.23 (m, 3H), 3.20 (t, J = 5.0 Hz, 4H), 2.71 (s, 3H), 2.61 (t, J = 5.0 Hz, 4H), 2.35 (s, 3H).
13C NMR (chloroform-d6,100 MHz): δ 136.87 (Ar-C=N), 136.17, 135.76, 135.39, 132.04,
130.71, 129.63, 129.53, 128.20, 128.10, 127.98, 127.90, 124.86, 124.21, 122.34, 121.28,
117.29, 114.37 (aromatic), 54.61, 51.11 (N-C-C-N), 46.09 (N-C), 13.30 (C-C). HR-MS Calcd
for C25H27N4O2S (M+H)+: 447.1849 found: 447.1856.
5.3.9.
5-((3-(4-methylpiperazin-1-ylimino)methyl)-2-methyl-1H-indol-1-yl)sulfonyl)-
N,N-dimethylnaphthalen-1-amine (13)
o
1
Yellow solid (42%), mp 162–164 C: H NMR (chloroform-d6,400 MHz) δ 8.49 (d, J = 6.0
Hz, 1H), 8.38-8.36 (m, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.79-8.15 (s, 1H), 7.77 (m, 1H), 7.46 (t,
J = 8.0 Hz, 1H), 7.40-7.26 (m, 4H), 7.14 (d, J = 7.6 Hz, 1H), 3.25 (s, 4H), 2.84 (s, 6H), 2.65
(s, 4H), 2.56 (s, 3H), 2.38 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 149.85, 137.39, 136.
50, 136.13(Ar-C=N), 132.45, 130.86, 129.75, 128.71, 127.09, 126.90, 124.83, 124.05, 123.24,
122.40, 119.91, 119.13, 116.31, 114.43 (aromatic), 54.67, 54.43, 51.18 (N-C-C-N), 46.11 (N-
C), 29.28, 20.61 (N-C), 13.05 (C-C). HR-MS Calcd for C27H32N5O2S (M+H)+: 490.2271
found: 490.2273.
5.3.10.
5-((3-(4-methylpiperazin-1-ylimino)methyl)-2-methyl-1H-indol-1-yl)sulfonyl)-
N,N-dibutylnaphthalen-1-amine (14)
o
1
Light green solid (14%), mp 171–174 C: H NMR (chloroform-d6,400 MHz) δ 8.59-8.56
(m,1H), 8.39-8.37 (m,1H),8.29(d, J = 8.8 Hz, 1H), 8.18-8.16 (m, 1H), 7.79 (s,1H), 7.49 (t, J =
8.2 Hz, 1H), 7.33-7.27 (m, 4H),7.26-7.23 (m, 1H), 3.26 (t, J = 4.6 Hz, 4H), 3.07-3.04 (m, 6H),
2.65 (s, 4H), 2.58 (s, 3H) , 2.37 (s, 3H), 1.45-1.37 (m, 6H), 1.28-1.18 (m, 6H).13C NMR

(chloroform-d6,100 MHz): δ 152.09, 137.40, 136.40, 136.28 (Ar-C=N), 131.29, 130.85,
130.16, 129.78, 129.00, 127.06, 124.85, 124.06, 123.24, 122.44, 118.70, 116.37, 115.88,
114.44 (aromatic), 54.69, 51.20 (N-C-C-N), 45.55 (N-C), 13.03 (C-C). HR-MS Calcd for
C33H44N5O2S (M+H)+: 574.321 found: 574.3213.
5.3.11.
(1-(2-(naphthalen-1-yl)ethylsulfonyl)-2-methyl-1H-indol-3-yl)-N-(4-
methylpiperazin-1-yl)methanimine (15)
o
1
Brown solid (31%), mp 195–197 C: H NMR (chloroform-d6,400 MHz) δ 8.28 (d, J = 5.6
Hz, 1H), 8.20 (d, J = 6.4 Hz, 1H), 7.74 (s, 1H),7.32-7.27 (m, 2H), 7.26-7.23 (m, 1H), 7.18
(d, J = 8.4 Hz,3H), 3.23 (s, 4H), 2.71 (s, 3H), 2.68 (s, 3H) , 2.64 (s, 4H), 2.57 (t, J = 7.8 Hz,
4H), 2.37 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 149.87, 136. 77, 136.51 (Ar-C=N),
135.84, 130.82, 129.43, 127.85, 126.57, 124.73, 124.10, 122.23, 117.08, 114.35 (aromatic),
54.65, 51.18 (N-C-C-N), 46.11 (N-C), 22.41, 13.98 (S-C-C), 13.22 (C-C). HR- MS Calcd for
C27H31N4O2S (M+H)+: 475.2162 found: 475.2156.
5.3.12.
5-((3-((E)-(4-methylpiperazin-1-ylimino)methyl)-2-methyl-1H-indol-1-
yl)sulfonyl)-N,N-dimethyl (1, 2-diphenyldiazene)-1-amine (16)
o
1
Red solid (17%), mp 153–155 C: H NMR (chloroform-d6,400 MHz) δ 8.30-8.24 (m, 1H),
7.85-7.76 (m, 3H), 7.73 (s, 1H), 7.33-7.24 (m, 7H), 6.72 (d, J = 9.2 Hz, 1H), 3.22 (t, J = 5.0
Hz, 4H), 3.10 (s, 6H), 2.69 (s, 3H) 2.62 (t, J = 5.0 Hz, 4H), 2.35 (s, 3H).13C NMR
(chloroform-d6,100 MHz): δ 156.46, 153.43, 143.79 (Ar-C=N), 138.27, 136.82, 135.71,
130.64, 128.00, 127.59, 126.07, 124.86, 124.26, 122.87, 121.39, 117.48, 114.41, 111.62
(aromatic), 54.68, 51.19 (N-C-C-N), 46.16, 40.47 (N-C), 13.28 (C-C). HR-MS Calcd for
C29H34N7O2S (M+H)+: 544.2489 found: 544.2494.
5.3.13.
(1-(4-chlorobenzo[c][1,2,5]oxadiazol-7-sulfonyl)-2-methyl-1H-indol-3-yl)-N-(4-
methylpiperazin-1-yl)methanimine (17)
Brown solid (43%), mp 188–191 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.24-8.22 (m, 1H),
7.99 (s, 1H), 7.92 (s, 1H), 7.27-7.24 (m, 2H), 7.16-7.13 (m, 2H), 3.21 (t, J = 4.8 Hz, 4H), 2.68
(t, J = 5.0 Hz, 4H), 2.52 (s, 3H), 2.38 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 135.65
(Ar-C=N), 135.57, 135.52, 126.38, 122.20, 121.58, 120.79, 110.22, 109.88 (aromatic), 54.81,
52.23 (N-C-C-N), 46.11 (N-C), 12.38 (C-C). HR-MS Calcd for C21H22N6O3SCl (M+H)+:
473.1157 found:473.1166.

5.3.14.
N-(4-methylpiperazin-1-yl)(2-phenyl-1-(phenylsulfonyl)-1H-indol-3-
yl)methanimine (18)
Brown solid (33%), mp 188–190 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.37-8.33 (m. 2H),
7.48-7.35 (m, 10H), 7.33-7.26 (m, 3H), 3.13 (t, J = 5.0 Hz, 4H), 2.63 (t, J = 5.0 Hz, 4H), 2.38
(s, 3H).13C NMR (chloroform-d6,100 MHz): δ 139.72 (Ar-C=N), 138.14, 137.75, 133.87,
132.08, 131.92, 130.60, 129.30, 128.95, 128.11, 127.77, 126.98, 125.80, 124.92, 123.34,
120.12, 115.90 (aromatic), 54.36, 50.59 (N-C-C-N), 45.81 (N-C). HR-MS Calcd for
C26H27N4O2S (M+H)+: 459.1849, found: 459.1846.
5.3.15. (1-(5-chloro-2-methoxy-4-methylphenylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-
methylpiperazin-1-yl)methanimine (19)
Light brown solid (17%), mp 139–141 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.44 (s, 1H),
8.20 (d, J = 8.4 Hz, 1H), 7.43-7.26 (m, 7H), 7.08-7.06 (m, 2H), 6.60 (s, 1H), 3.26 (s, 3H),
3.06 (t, J = 5.0 Hz, 4H), 2.53 (t, J = 5.0 Hz, 4H), 2.32 (s, 3H), 2.30 (s, 3H).13C NMR
(chloroform-d6,100 MHz): δ 155.97, 144.44 (Ar-C=N), 139.53, 139.09, 132.13, 132.05,
131.21, 129.64, 129.18, 128.93, 127.51, 126.70, 126.16, 125.32, 125.25, 123.89, 123.07,
118.72, 115.87, 114.34 (aromatic), 56.18, 54.59, 51.02 (N-C-C-N), 46.07 (N-C), 21.06
(methoxy). HR-MS Calcd for C28H30N4O3SCl (M+H)+: 537.1722, found: 537.1713.
5.3.16.
(1-(4-fluorophenylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (20)
o
1
Brown solid (53%), mp 177–179 C: H NMR (chloroform-d6,400 MHz) δ 8.47 (d, J = 8.8
Hz, 1H), 8.39 (d, J = 6.4 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 7.58-
7.56 (m, 1H), 7.51-7.47 (m, 2H), 7.47-7.36 (m, 3H), 7.34-7.19 (m, 2H), 6.93 (t, J = 7.6 Hz,
13
1H), 5.29 (s, 1H), 3.09 (t, J = 5.0 Hz, 4H), 2.54 (t, J = 5.0 Hz, 4H), 2.31 (s,3H). C NMR
(chloroform-d6,100 MHz): δ 167.04, 164.49 (C-F aromatic), 139.81 (Ar-C=N), 138.72,
137.73, 136.42, 135.71, 131.86, 131.24, 130.61, 129.90, 129.53, 128.95, 128.58, 128.32,
127.83, 125.90, 125.09, 123.52, 123.27, 121.33, 120.58, 110.77 (aromatic), 54.64, 50.52,
51.80, 50.85 (N-C-C-N), 46.06 (N-C). HR-MS Calcd for C26H26N4O2SF (M+H) +: 477.1755
found: 477.1763.

5.3.17.
(1-(4-chlorophenylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (21)
o
1
Brown solid (38%), mp 169–171 C: H NMR (chloroform-d6,400 MHz) δ 8.39 (d, J = 6.0
Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H),7.48-7.30 (m, 10H), 7.22 (d, J = 8.8 Hz, 2H), 3.08 (t, J = 5.0
Hz, 4H), 2.53 (t, J = 5.0 Hz, 4H), 2.31 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 140.54,
139.21, 137.70, 136.36 (Ar-C=N), 131.86, 131.05, 130.60, 129.37,129.25, 128.41, 127.85,
125.93, 125.16, 123.58, 120.74, 115.95 (aromatic), 54.56, 50.89 (N-C-C-N), 46.11 (N-C).
HR-MS Calcd for C26H26N4O2SCl (M+H) +: 493.1460 found: 495.1458.
5.3.18.
(1-(4-iodophenylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (22)
White solid (42%), mp 178–181 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.38 (d, J = 6.4 Hz,
1H), 8.28 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 7.47-7.33 (m, 7H), 7.31 (s, 1H), 7.07
(d, J = 8.8 Hz, 2H), 3.07 (t, J = 5.0 Hz, 4H), 2.52 (t, J = 5.0 Hz, 4H), 2.30 (s, 3H).13C NMR
(chloroform-d6,100 MHz): δ 139.19, 138.19, 137.67, 137.55 (Ar-C=N), 131.86, 131.04,
130.60, 129.36, 128.39, 128.22, 127.85, 125.93, 125.16, 123.58, 120.75, 115.94, 101.82
(aromatic), 54.56, 50.89 (N-C-C-N), 46.12 (N-C). HR-MS Calcd for C26H26N4O2SI (M+H) +:
585.0816 found:585.0813.
5.3.19.
(1-(p-tolylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (23)
o
Lihgt brown solid (78%), mp 159–162 C:1H NMR (chloroform-d6,400 MHz) δ 8.37 (d, J =
6.8 Hz, 1H), 8.33 (d, J = 7.2 Hz, 1H),7.72 (dd, J = 5.6 Hz, 3.2 Hz, 1H), 7.52 (dd, J = 14.8
Hz, 3.6 Hz, 1H), 7.46-7.44 (m, 2H), 7.40-7.37 (m, 2H), 7.34-7.27 (m, 4H), 7.04 (d, J = 8.0 Hz,
2H), 3.08 (t, J = 5.0 Hz, 4H), 2.54 (t, J = 5.0 Hz, 4H), 2.31 (s, 3H), 2.29 (s, 3H).13C NMR
(chloroform-d6,100 MHz): δ 167.84 (1C, C=N-N), 144.90 (Ar-C=N), 139.64, 137.77, 135.20,
132.44, 131.91, 131.65, 131.14, 130.84, 129.53, 129.20, 129.04, 128.24, 127.71, 127.04,
125.68, 124.83, 123.31, 120.21, 115.98 (aromatic), 61.82, 54.59, 50.96 (N-C-C-N), 46.10 (N-
C), 14.30 (C-C). HR-MS Calcd for C27H29N4O2S (M+H)+: 473.2006 found: 473.2010.
5.3.20. (1-(4-methoxyphenylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine(24)

o
1
Dark brown solid (38%), mp 162–164 C: H NMR (chloroform-d6,400 MHz) δ 8.37 (d, J =
7.2 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.47-7.44 (m, 4H), 7.40-7.38 (m, 2H), 7.34-7.31 (m,
4H), 6.70 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H), 3.08 (t, J = 5.0 Hz, 4H), 2.54 (t, J = 5.0 Hz, 4H),
2.31 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 167.80, 139.69 (Ar-C=N), 138.81,
131.90, 131.76, 130.87, 129.79,129.26, 129.18, 128.93, 128.23, 127.71, 125.65, 124.78,
123.29, 120.12, 115.99, 114.08 (aromatic), 55.76, 54.56, 50.94 (N-C-C-N), 46.07 (N-C). HR-
MS Calcd for C27H29N4O3S (M+H)+: 489.1955 found: 489.1960.
5.3.21.
(1-(4-(trifluoromethoxy)phenylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-
methylpiperazin-1-yl)methanimine(25)
o
1
Brown solid (44%), mp 175–178 C: H NMR (chloroform-d6,400 MHz) δ 8.39 (s, 1H),
8.31(d, J = 8.0 Hz, 1H), 7.47-7.40 (m, 6H), 7.37-7.34 (m, 3H), 7.27 (d, J = 11.6 Hz, 1H), 7.06
(d, J = 6.8 Hz, 2H), 3.09 (t, J = 5.0 Hz, 4H), 2.54 (t, J = 5.0 Hz, 4H), 2.31 (s, 3H). 13C NMR
(chloroform-d6,100 MHz): δ 153.11, 143.30(Ar-C=N), 140.73, 137.53, 136.18, 135.50,
131.86, 129.88,129.79, 129.28, 128.07, 128.01, 127.62, 126.24, 125.25, 123.26, 121.53,
120.80, 120.63, 119.37, 115.81 (aromatic), 53.10, 48.38 ( N-C-C-N), 44.03 ( N-C). HR-EI
Calcd for C27H26N4O3SF3 (M+H +: 543.1672, found: 543.1670
5.3.22.
(1-(4-butylphenylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (26)
o
1
Brown solid (63%), mp 119–121 C: H NMR (chloroform-d6,400 MHz) δ 8.38 (d, J = 6.4
Hz, 1H), 8.34 (d, J = 7.2 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.47-7.28 (m, 9H), 7.04 (d, J = 6.8
Hz, 2H), 3.08 (t, J = 5.0 Hz, 4H), 2.56-2.52 (m, 7H), 2.32 (s, 3H), 1.66-1.62 (m, 2H), 1.52-
1.46 (m, 2H), 1.41-1.36 (m, 2H). 13C NMR (chloroform-d6,100 MHz): δ 149.90, 142,21 (Ar-
C=N), 140.42, 137.67, 135.46, 134.01, 131.92, 130.43, 129.38, 128.96, 128.50, 127.77,
127.03, 126.00, 125.80, 124.80, 123.12, 119.38, 115.86 (aromatic), 53.71, 49.60 (N-C-C-N),
44.95 (N-C), 35.67, 33.07, 22.40, 13.98 (C-C). HR-MS Calcd for C30H35N4O2S (M+H)+:
515.2475 found: 515.2481.
5.3.23. (1-(4-isopropylphenylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (27)
o
1
Brown solid (56%), mp 155–157 C: H NMR (chloroform-d6,400 MHz) δ 8.38 (d, J = 7.6
Hz, 1H), 8.34 (d, J = 8.4Hz, 1H), 7.47-7.35 (m, 8H), 7.31 (t, J = 7.0 Hz, 2H), 7.09 (d, J = 8.4
Hz, 2H), 3.07 (t, J = 5.0 Hz, 4H), 2.84 (m, 1H), 2.54 (t, J = 5.0 Hz, 4H), 2.31 (s,3H), 2.04 (s,

6H). 13C NMR (chloroform-d6,100 MHz): δ 155.52, 139.81, 137.68 (Ar-C=N), 135.64,
132.35, 131.94, 130.67, 129.24, 127.99, 127.70, 127.22, 127.08, 125.71, 124.77, 123.20,
119.82, 115.86 (aromatic), 34.51 (N–C), 54.34, 50.62 (N-C-C-N), 45.78 (N-C), 34.31 (C-C).
HR-MS Calcd for C29H33N4O2S (M+H)+: 501.2319 found: 501.2311.
5.3.24.
(1-(benzylsulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-
yl)methanimine (28)
Light brown solid (12%), mp 171–13 oC: 1H NMR (chloroform-d6,400 MHz) δ 8.52 -8.50 (m,
1H), 8.04-8.01 (m, 1H), 7.40-7.36 (m, 3H), 7.32-7.27 (m, 3H), 7.21 (s, 1H), 7.16 (t, J = 7.6
Hz, 2H), 6.94 (d, J = 7.2 Hz, 2H), 6.74 (d, J = 7.2 Hz, 2H), 4.29 (s, 2H), 3.08 (t, J = 5.0 Hz,
13
4H), 2.55 (t, J = 5.0 Hz, 4H, 2.32 (s, 3H). C NMR (chloroform-d6,100 MHz): δ 141.00,
137.26 (Ar-C=N), 132.48, 131.26, 130.99, 130.30 129.36, 129.09, 128.90, 127.51, 126.80,
125.79, 124.72, 123.77, 118.39, 114.59 (aromatic), 59.25, 54.26, 50.54 (N-C-C-N), 45.68 (N-
C). HR-MS Calcd for C27H29N4O2S (M+H)+: 477.1755 found: 477.1763.
5.3.25.
N-(4-methylpiperazin-1-yl)(1-(naphthalensulfonyl)-2-phenyl-1H-indol-3-
yl)methanimine (29)
o
1
Dark brown solid (18%), mp 148–152 C: H NMR (chloroform-d6,400 MHz) δ 8.43 (t, J =
7.6 Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75
(d, J = 11.6 Hz, 1H), 7.52-7.29 (m, 5H), 7.21 (t, J = 7.6 Hz, 2H), 7.17-7.10 (m, 2H), 6.99 (d, J
13
= 6.8 Hz, 2H), 3.10 (t, J = 5.0 Hz, 4H), 2.49 (t, J = 5.0 Hz, 4H), 2.28 (s, 3H). C NMR
(chloroform-d6,100 MHz): δ 139.12, 137.97, 135.01 (Ar-C=N), 134.59, 133.88, 132.06,
131.67, 131.31, 131.15, 130.17, 129.74,129.03, 128.93, 128.80, 128.20, 127.67, 127.14,
126.94, 125.71, 124.36, 123.89, 123.51, 118.82, 115.63 (aromatic), 54.54, 50.93 (N-C-C-N),
46.04 (N-C ). HR-MS Calcd for C30H29N4O2S (M+H)+: 509.2006 found: 509.2014.
5.3.26.
N-(4-methylpiperazin-1-yl)(1-(naphthalene-2-sulfonyl)-2-phenyl-1H-indol-3-
yl)methanimine (30)
Brown oil (46 %): 1H NMR (chloroform-d6,400 MHz) δ 8.42 (d, J = 6.8 Hz, 1H), 8.36 (d, J =
7.2 Hz, 1H),7.91 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4
Hz, 1H), 7.60-7.40 (m, 7H), 7.37-7.32 (m, 4H), 3.03 (t, J = 5.0 Hz, 4H), 2.50 (t, J = 5.0 Hz,
4H), 2.28 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 139.48, 137.85, 135.34 (Ar-C=N),

135.09, 132.09, 131.74, 131.46, 130.67, 129.57, 129.41, 128.94, 128.04, 127.75, 127.71,
125.79, 124.87, 123.39, 123.30, 121.62, 121.33, 120.20, 120.63, 115.94, 110.74 (aromatic),
54.54, 50.89 (N-C-C-N), 46.07 (N-C). HR-MS Calcd for C30H29N4O2S (M+H) +: 509.2006
found:509.2001.
5.3.27.
5-((3-((4-methylpiperazin-1-ylimino)methyl)-2-phenyl-1H-indol-1-yl)sulfonyl)-
N,N-dibutylnaphthalen-1-amine (31)
o
1
Brown solid (39%), mp 113–115 C: H NMR (chloroform-d6,400 MHz) δ 8.49 -8.42 (m,
3H), 7.79 (d, J = 8.4 Hz, 1H),7.54-7.52 (m, 1H), 7.46 (t, J = 7.2 Hz, 1H),7.39-7.36 (m, 2H),
7.33-7.29 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H),7.18-7.13 (m, 3H), 7.05 (t, J = 8.0 Hz, 1H), 6.94
(d, J = 6.8 Hz, 2H), 3.05-3.00 (m, 7H), 2.49 (t, J = 5.0 Hz, 4H), 2.28 (s, 3H), 1.40-1.35 (m,
5H), 1.27-1.21 (m, 5H), 0.82 (t, J = 7.2 Hz, 5H). 13C NMR (chloroform-d6,100 MHz): δ
167.85, 149.64, 139.15, 138.00 (Ar-C=N), 134.61, 132.45, 131.98, 131.40, 131.14, 130.18,
129.77, 129.60, 129.05, 128.94, 128.65, 127.59, 126.75, 125.64, 124.21, 123.38, 122.95,
119.68, 118.72, 118.50, 115.60 (aromatic), 61.82, 54.64, 54.58, 50.97 (N-C-C-N), 46.07 (N-
C), 29.36, 20.65, 14.31, 14.14 (C-C). HR-MS Calcd for C38H46N5O2S (M+H)+: 636.3367
found: 636.3362.
5.3.28. 5-((3-(4-methylpiperazin-1-ylimino)methyl)-2-phenyl-1H-indol-1-yl)sulfonyl)-
N,N-dimethylnaphthalen-1-amine (32)
Brown oil (11%): 1H NMR (chloroform-d6,400 MHz) δ 8.45-8.36 (m, 2H), 7.76-7.70 (m, 3H),
7.58-7.30 (m, 7H), 7.23-7.15 (m, 2H), 7.10-7.02 (m, 1H), 6.97 (d, J = 7.2 Hz, 1H), 3.03 (t, J
= 5.0 Hz, 4H), 2.81 (s, 6H), 2.54 (t, J = 5.0 Hz, 4H), 2.31 (s, 3H).13C NMR (chloroform-
d6,100 MHz): δ 167.79, 151.76, 139.21(Ar-C=N), 138.95, 137.94, 136.39, 134.69, 132.37,
131.96, 131.08, 130.09, 129.67, 129.06, 128.44, 128.23, 127.57, 125.59, 124.19, 123.37,
123.32, 123.09, 122.82, 121.17, 118.09, 115.54, 110.88 (aromatic), 61.76, 54.40, 54.36,
51.60, 50.73 (N-C-C-N), 45.81, 45,72, 45.45 (N-C). HR-MS Calcd for C32H34N5O2S (M+H)
+: 552.2428, found: 552.2431.
5.3.29.
(1-(1-methyl-1H-imidazol-4-sulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-
methylpiperazin-1-yl)methanimine (33)
o
1
Brown solid (10%), mp 183–185 C: H NMR (chloroform-d6,400 MHz) δ 8.46 (d, J = 5.6
Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H),7.72 (dd, J = 5.6 Hz, 3.6 Hz, 1H), 7.53 (dd, J = 9.6 Hz, 3.4

Hz, 1H), 7.43-7.26 (m, 6H), 6.96 (s, 1H), 6.77 (s, 1H), 3.43 (s, 3H), 3.09 (t, J = 5.0 Hz, 4H),
2.54 (t, J = 5.0 Hz, 4H), 2.31 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 167.84, 141.17
(Ar-C=N), 139.8, 137.78, 132.43, 131.82,131.13, 129.77, 129.27, 129.03, 127.82, 125.87,
125.45, 124.83, 123.49, 120.01, 115.37 (aromatic), 61.81, 54.53, 50.93 (N-C-C-N), 46.07 (N-
C), 14.29 (N-C). HR-MS Calcd for C24H27N6O2S (M+H) +: 463.1911 found: 463.1919.
5.3.30.
(1-(3,4-dihydro-2,2,5,7,8-pentamethyl-2H-chromen-6-sulfonyl)-2-phenyl-1H-
indol-3-yl)-N-(4-methylpiperazin-1-yl)methanimine (34)
o
1
Brown solid (17%), mp 177–180 C: H NMR (chloroform-d6,400 MHz) δ 8.47 (d, J = 6.4
Hz, 1H), 8.32 (d, J = 7.6 Hz, 1H), 7.73-7.71 (m, 1H), 7.54-7.52 (m, 1H), 7.40 (t, J = 7.2 Hz,
1H), 7.32 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 6.8 Hz, 2H), 6.91 (d, J = 6.8
Hz, 2H), 3.03 (t, J = 4.8 Hz, 4H), 2.52 (t, J = 4.8 Hz, 4H), 2.36 (t, J = 6.8 Hz, 2H), 2.29 (s,
3H), 2.04 (s, 6H), 1.96 (s, 3H), 1.93 (s, 3H), 1.89 (s, 3H), 1.75 (t, J = 6.8 Hz, 2H). 13C NMR
(chloroform-d6,100 MHz): δ 167.84, 160.69 (Ar-O), 140.89 (Ar-C=N), 138.83, 138.39,
135.36, 132.45, 132.40, 131.46, 131.14, 129.59, 129.41, 128.20, 127.35, 125.54, 125.31,
124.92, 123.48, 123.16, 117.92, 117.50, 115.52 (aromatic), 87.27 (O-C), 61.82, 54.59, 51.06
(N-C-C-N), 46.05 (N-C ), 42.91, 28.81 (O-C), 18.63, 16.70, 14.30, 12.31 (C-C). HR-MS
Calcd for C34H41N4O3S (M+H)+: 585.2894 found: 585.2897.
5.3.31.
(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-sulfonyl)-2-phenyl-1H-indol-3-yl)-N-(4-
methylpiperazin-1-yl)methanimine (35)
o
1
Brown solid (38%), mp 196–198 C: H NMR (chloroform-d6,400 MHz) δ 8.37 (d, J = 6.4
Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H),7.47-7.38 (m, 6H), 7.33 (t, J = 7.0 Hz, 2H), 6.92 (d, J = 8.0
Hz, 2H), 6.68 (d, J = 7.6 Hz, 1H), 4.22-4.20 (m, 2H), 4.17-4.09 (m, 2H), 3.09(t, J = 5.0 Hz,
4H), 2.54(t, J = 5.0 Hz, 4H), 2.31 (s, 3H). 13C NMR (chloroform-d6,100 MHz): δ 148.47,
143.33 (Ar-C=N), 139.66, 137.69, 131.90, 131.77, 130.86, 130.37, 129.19, 128.20, 127.71,
125.71, 124.81, 123.23, 121.04, 120.12, 117.48, 116.74, 115.93 (aromatic), 64.63 (O-C),
54.60, 51.01 (N-C-C-N), 46.12 (N-C). HR-MS Calcd for C28H29N4O4S (M+H)+: 517.1904
found:517.1898.
5.3.32.
(1-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl)-2-phenyl-1H-
indol-3-yl)-N-(4-methylpiperazin-1-yl)methanimine (36)

o
1
Brown solid (22%), mp 143–146 C: H NMR (chloroform-d6,400 MHz) δ 8.47 (d, J = 8.0
Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H),7.73 -7.70 (m, 2H), 7.55-7.51 (m, 3H), 7.40 (t, J = 7.8 Hz,
1H),7.32 (t, J = 7.4 Hz, 1H), 7.14 (t, J = 7.6 Hz, 3H), 6.99-6.95 (m, 1H), 3.04 (t, J = 5.0 Hz,
4H), 2.52 (t, J = 5.0 Hz, 4H), 2.30 (s, 3H), 1.92 (d, J = 4.8 Hz, 6H), 1.87 (s, 3H), 1.39 (s, 6H).
13C NMR (chloroform-d6,100 MHz): δ 167.85, 155.67 (Ar-C=N), 139.03, 138.36, 137.77,
137.60, 132.79, 129.72, 129.39, 129.04, 128.12, 127.17, 125.44, 125.29, 124.58 123.42,
123.12, 118.15, 117.18, 117.18, 115.41 (aromatic), 74.36 (O-C), 61.81, 54.49, 50.92 (N-C-C-
N), 45.91 (N-C), 32.78, 26.88, 21.27, 17.41, 16.42, 14.29, 11.97 (C-C). HR-MS Calcd for
C33H39N4O3S (M+H)+: 571.2737 found: 571.2732.
5.4 Biological evaluation
5.4.1. cAMP accumulation assay for 5-HT6, 5-HT4 and 5-HT7 receptors
To analyze cAMP levels, cAMP dynamic 2 HTRF kits (Cisbio, France) which
provide homogeneous high-throughput assay were used. Cells incubated at 37℃ in 5% CO2
and 95% air atmosphere were suspended in PBS containing 2 mM IBMX (3-isobutyl-1-
methylxanthine) and stimulated by 5-HT for 30 min and with or without pretreatment with
compounds for 10 min. After 30 min, cAMP labeled with the dye d2 and anti-cAMP
antibodies labeled with cryptate were added into the cell plates. The plates were incubated at
room temperature for 1 hour. The fluorescence intensity of accumulated cAMP level was
measured at 314 nm excitation, and 668 and 620 nm emission using Flexstation3 microplate
reader (Molecular Devices, Downingtown, PA). The results were estimated as the percentage
inhibition compared with the untreated controls.
5.5 3D QSAR pharmacophore generation and mapping
HypoGen algorithm (catHypo/Discovery Studio (DS) 3.5/Accelrys (San Diego, USA),
running on an Intel(R) Core ™ computer with Linux Red Hat Enterprise WS release 4 OS)
was employed for the generation of predictive models. The 45 antagonists that were used for
the previous study by Lopez-Rodriguez et al. (2005) constituted the training set. The two-
dimensional (2D) structures of the compounds were drawn in ChemDraw Ultra 11.0.
Applying Poling algorithm, maximum 255 conformers were generated using the ‘Best’ option
with an energy cutoff of 20 kcal/mol. Other parameters were also set as follows: min points

(6), min subset points (6), inter-feature distance (2.97 Å), weight variation (0.3), tolerance
variation (1.0) and activity uncertainty (3). The following chemical features were selected:
hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), hydrophobic (HYD), positive
ionizable (PI) and ring aromatic (AR). The mapping studies were performed with ‘Ligand
Pharmacophore Mapping’ module of DS using the ‘Best/Flexible’ option.
Acknowledgment
This research was supported by Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and
Technology (2010-0004-883), and Korea Institute of Science and Technology.
.
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NH2
S
N
N
N
N
N
O
NH
SO2
SO2
N
Cl
NH
NH
S
Cl
N
E-6801
WAY-181187
EMDT
N
N
CF2
CF3
O
NH
F
O
N
N
H
N
SO2
N
Latrepirdine
Lu AE 58054
MS-245
Fig 1. 5-HT6 agonists and antagonists with indole core
Fig 2. Best hypothesis Hypo1. The features are color-coded as follows: hydrogen bond acceptor (HBA, green),
positive ionizable (PI, red), ring aromatic (AR, orange) and hydrophobic (HYD, blue).
A
B
C

D
E
Fig 3. Mapping of compounds 32 (A), 18 (B), 6 (C), 10 (D) and (E) 34.

Table 1. Percent Inhibition and IC50 values of the 2-methylindole derivatives against 5-HT6
receptor.
CH3
N
N
N
CH3
N
O
S
O
Ar
Compound
Ar
% Inhibition
88.6 6.5
71.7 9.1
13.5 12.6
52.4 7.1
49.1 3.7
15.1 5.7
0.1 4.7
IC50 (µM)
2.40 0.40
4.74 2.81
5
5-chloro-2-methoxy-4-methylphenyl
4-Fluorophenyl
6
7
4-Iodophenyl
8
4- Nitrophenyl
9
4-Methylphenyl
10
11
12
13
14
15
16
17
Biphenyl
4-Chlorobiphenyl
2-Naphtyl
78.9 8.6
9.5 0.1
2.04 1.31
5-(Dimethylamino)napthyl
5-(Dibutylamino)napthyl
2-(1-Naphthyl)-ethane
4- (Dimethylamino) azobenzene
4-Chloro-2,1,3-benzoxadiazole
44.6 8.0
12.2 4.9
16.1 7.1
27.2 2.7

Table 2. Percent Inhibition and IC50 values of the 2-phenylindole derivatives against 5-HT6
receptor.
CH3
N
N
N
N
O
S
O
Ar
Compound
18
Ar
% Inhibition
83.5 5.4
55.3 4.2
74.2 4.2
30.5 8.7
24.3 6.9
33.2 8.7
31.2 11.1
38.7 7.9
14.3 15.9
35.4 4.5
36.5 16.6
54.0 5.3
39.6 1.2
21.8 8.1
85.3 8.3
67.4 6.4
20.6 7.5
67.3 3.4
22.4 10.6
IC50 (µM)
1.8 0.5
7.4 1.2
2.9 0.2
Phenyl
19
5-Chloro-2-methoxy-4-methyl phenyl
4-Fluorophenyl
20
21
4-Chlorophenyl
22
4-Iodophenyl
23
4-Methylphenyl
24
4-Methoxyphenyl
25
4-Trifluoro methoxy phenyl
n-Butylphenyl
26
27
4-Isopropyl phenyl
28
1-Benzylphenyl
29
1-Napthyl
6.6 2.5
30
2-Naphthyl
31
5-(Dibutylamino)napthyl
5-(Dimethylamino)napthyl
1-Methylimidazole
32
1.4 0.5
3.6 1.3
33
34
2,2,5,7,8-Pentamethyl chromane
2,3 –Dihydro-1,4-benzodioxan
2,2,4,6,7-Pentamethyl dihyro benzofuran
35
3.8 1.4
36

Table 3. Percent inhibition of selected compounds against 5-HT receptors.
Compound
% Inhibition(10µM) (n=3)
5-HT6 receptor
88.6 ± 6.5
5-HT4 receptor
17.9 ± 7.2
83.0 ± 5.4
92.2 ± 6.5
79.9 ± 10.0
13.0 ± 11.9
37.3 ± 10.1
9.4 ±1 0.8
65.0 ± 5.3
31.1 ± 12.0
28.9 ± 9.0
5.8 ± 3.8
5-HT7 receptor
18.4 ± 5.0
12.3 ± 6.9
17.1 ± 8.1
34.6 ± 3.2
72.8 ± 3.9
28.5 ± 7.6
5.0 ± 5.4
5
6
71.7 ± 9.1
12
78.9 ± 8.6
18
83.5 ± 5.4
19
55.3 ± 4.2
20
74.2 ± 4.2
29
54.0 ± 5.3
32
85.3 ± 8.3
42.2 ± 5.2
46.4 ± 5.6
45.2 ± 3.9
5.0 ± 13.6
104 ± 8.5
33
67.4 ± 6.4
35
67.3 ± 3.4
SB258585
97.7 ± 1.7
SB269970
-
SB258585 : 5-HT6 antagonist
SB269970 : 5-HT7 antagonist

Graphical Abstract
Design and synthesis of novel series of 5-HT6 receptor ligands having indole,
a central aromatic core and 1-amino-4methyl piperazine as a positive
ionizable group
Faisal Hayat a, Sungjin Cho b, Hyewhon Rhim b, Ambily Nath I.Vc,d, Ae Nim Paec,d, Jae Yeol
Leee, Dong Joon Choo e, Hea-Young Park Choo a
a College of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans
University, Seoul 120-750, Republic of Korea
b Center for Neuroscience, Korea Institute of Science & Technology, Seoul, 136-791, Korea
c Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul, 136-791,
Korea
d Department of Medicinal & Pharmaceutical Chemistry, School of Science, University of
Science and Technology, 52 Eoeun dong, Yuseong-gu, Daejeon 305-333, Republic of Korea
e
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences,
Kyung Hee University, Seoul 130-701, Korea
CH3
N
CH3
N
N
O
S
N
O
N
H2N
N
N CH3
N
Ar
Cl
O
R
R
R
N
N
S
N
H
H
O
O
Ar

CH3
N
CH3
N
N
O
S
N
O
Ar
Cl
N
DMF/Reflux
152-154 oC
O
R
R
N
H2N
N
N CH3
+
N
N
H
THF, KH, room temp.
over night
O
S
O
R
Ar
N
H
2
1
5-17: R =CH3,
18-36: R = Phenyl
3, 4
Scheme 1: General Method for the Synthesis of (2-methyl-1-(Ar-sulfonyl)-1H-indol-3-
yl)-N-(4-methylpiperazin-1-yl)methanimine (5-17) and N-(4-methylpiperazin-1-yl)(2-
phenyl-1-( Ar-sulfonyl)-1H-indol-3-yl)methanimine (18-36)