Synthesis and Docking of Novel 3-Indolylpropyl Derivatives as New Polypharmacological Agents Displaying Affinity for 5-HT1AR/SERT

Article abstract of DOI:10.1002/ardp.201600271

A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT_1AR) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT_1AR (K_i = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (K_i = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug–target interactions, which allowed rationalizing the observed affinities.

Full text of DOI:10.1002/ardp.201600271

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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–15
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Full Paper
Synthesis and Docking of Novel 3-Indolylpropyl Derivatives as New
Polypharmacological Agents Displaying Affinity for 5-HT1AR/SERT
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Hernan Pessoa-Mahana ꢀ, Paul Silva-Matus , C. David Pessoa-Mahana , Hery Chung ,
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Patricio Iturriaga-Vasquez , Gabriel Quiroz , Patricia Moller-Acuna , Gerald Zapata-Torres ,
Claudio Saitz-Barrıa , Ramiro Araya-Maturana , and Miguel Reyes-Parada
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Departamento de Quımica Organica y Fisicoquımica, Facultad de Ciencias Quımicas y Farmaceuticas,
Universidad de Chile, Santiago, Chile
Departamento de Farmacia, Facultad de Quımica, Pontificia Universidad Catolica de Chile, Santiago, Chile
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DepartamentodeCienciasQuımicasyRecursosNaturales,FacultaddeIngenierıayCiencias,Universidadde
la Frontera, Temuco, Chile
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Programa de Doctorado en Farmacologıa, Universidad de Chile, Santiago, Chile
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CentrodeBioinformaticaySimulacionMolecular,FacultaddeIngenierıa,UniversidaddeTalca,Talca,Chile
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Departamento de Quımica Inorganica y Analıtica, Facultad de Ciencias Quımicas y Farmaceuticas,
Universidad de Chile, Santiago, Chile
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Instituto de Quımica de Recursos Naturales, Universidad de Talca, Talca, Chile
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Escuela de Medicina, Facultad de Ciencias Medicas, Universidad de Santiago de Chile, Santiago, Chile
Facultad de Ciencias de la Salud, Universidad Autonoma de Chile, Talca, Chile
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A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at
the serotonin-1A receptor subtype (5-HT1AR) and the 5-HT transporter (SERT). Compounds 11b and 14b
exhibited the highest affinities at the 5-HT1AR (Ki ¼ 43 and 56 nM), whereas compounds 11c and 14a were
the most potent analogs at the SERT (Ki ¼ 34 and 17 nM). On the other hand, compounds 14b and 11d
showed potent activity at both targets, displaying a profile that makes them promising leads for the search
for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds
unveiled relevant drug–target interactions, which allowed rationalizing the observed affinities.
Keywords: Docking / 5-Hydroxytryptamine 1A receptor / Indole / Piperazinylpropylindole derivatives /
Serotonin transporter
Received: September 21, 2016; Revised: November 21, 2016; Accepted: November 23, 2016
DOI 10.1002/ardp.201600271
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
be more efficacious and/or safer than selective compounds [1].
However, the rational design of polypharmacological agents
Introduction
Polypharmacology is a novel paradigm in drug discovery,
which is based on the concept that “promiscuous” drugs, that
is, targeting simultaneously multiple specific receptors, would
is a difficult task, particularly if the addressed targets exhibit
high structural or functional diversity.
The serotonin-1A receptor subtype (5-HT1AR) and the 5-HT
transporter (SERT) are the main molecular targets of
therapeutic agents currently used for the treatment of
anxiety and/or depression [2–4]. In addition, they represent
ꢀ
Correspondence: Dr. Hernan Pessoa-Mahana, Departamento de
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Quımica Organica y Fisicoquımica, Facultad de Ciencias Quımicas y
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Farmaceuticas, Universidad de Chile, Casilla 233, Santiago 1, Chile.
E-mail: hpessoa@ciq.uchile.cl
Fax: þ5629782868
ꢀAdditional correspondence: Dr. Miguel Reyes-Parada,
E-mail: miguel.reyes@usach.cl
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Figure 1. Chemical structure of 3-indolyl-
propyl derivatives and their affinity values
upon SERT and/or 5-HT1A receptor.
an attractive combination for the search of novel multitarget
drugs [5]. However, both types of proteins are highly
different. Thus, the 5-HT1AR is a G-protein-coupled receptor
(GPCR), containing seven transmembrane domains, whose
stimulation inhibits adenylyl cyclase-mediated responses [6].
On the other hand, SERT is a plasma membrane protein
containing 12 putative transmembrane domains, which
belongs to the neurotransmitter/sodium symporter (NSS)
family, and is in charge of terminating actions of 5-HT by
reuptake of the monoamine into the nerve terminals [7].
Despite these differences, both proteins recognize 5-HT as the
main ligand, suggesting that the indole moiety might act as a
common pharmacophore in both targets.
Compounds 11a–d were based on homodimers previously
reported by us [9], since preliminary docking studies indicated
that reducing the length of the aliphatic chain linker
(connecting indole moieties) to n ¼ 1 might increase both
SERT and 5-HT1A affinity. Finally, compounds 14a–d were
conceived taking into account the good 5-HT1A bioactivity
displayed by indolylpropylarylpiperazine derivatives [9], and
the notion that bis-indole ligands show also good SERT
affinity.
Results and discussion
Chemistry
Forseveral years, we have been interested indeveloping new
indolic compounds containing a C-5-substituted 3-indolyl-
propyl fragment as the pharmacophore, for drugs acting at
both the SERT and the 5-HT1AR. In the search of multitarget
bioactivity, this structural portion has been either connected to
different moieties such as arylpiperazine or utilized to develop
dimeric bis-piperazinyl indole derivatives [8–10]. Thus, some of
these compounds have shown affinity for the two aforemen-
tioned targets, a condition which has been proposed as a
mechanism to overcome the poor efficacy and slow clinical
action of current antidepressants [11]. An example of these
structures and their corresponding affinities is shown in Fig. 1.
Keeping in mind the concept of developing dual-acting
agents, we conducted a new exploratory study focused to the
synthesis, docking, and biological evaluation of a new set
of indolic derivatives. In order to evaluate the impact of novel
scaffolds on the binding properties, in this work, the
3-indolylpropyl moiety was connected to the following
frameworks: 5-methoxy-1-benzazepinone, 1-benzyl-3-indo-
lylmethylpiperazine, and 1-benzyl-3-indolylmethyl-4-amino-
phenylpiperazine. The selection of these scaffolds was made
considering the following general criteria: Compounds 4a–d
(benzazepinone series) were synthesized in order to evaluate
whether this moiety could be beneficial for activity consider-
ing that some 3-benzazepine derivatives have exhibited good
affinity for 5-HT1AR [12–14].
The synthesis of compounds 4a–d was carried out by the
Fischer reaction between commercially available C-4 substi-
tuted phenylhydrazines and 3,4-dihydro-2H-pyran under
reflux conditions in a three-step sequence as is outlined in
Scheme 1. The 3-(3-indolyl)-1-propanol analogs 2a–d were
obtained in good yield (65–80%) and subsequently reacted
with tosyl chloride to provide tosylates 3a–d (56–63% yield),
which finally reacted with 6-methoxy-1-benzazepin-2-one,
obtained by Schmidt reaction of 5-methoxy-1-tetralone with
sodium azide [15], to afford compounds 4a–d (36–61% yield).
On the other hand, compounds 11a–d were obtained in
moderateyield(35–46%)byanucleophilicsubstitutionreaction
between 3-(3-indolylpropyl)piperazines 5a–d (61–72% yield)
and 3-indolylmethyl methanesulfonate 10a, as shown in
Scheme 2.
The synthesis of the 3-indolylmethyl methanesulfonate 10a
was achieved by a four-step sequence as follows: Vilsmeier–
€
Haack reaction of 1H-indole 6a in a POCl3/DMF mixture to
provide 7a, N-benzylation to provide 8a followed by carbonyl
reduction to afford alcohol 9a, which was finally reacted with
Although the benzazepinone series lacks a basic amine, a
requirement apparently essential for the binding of com-
pounds to the 5-HT1AR, we decided to explore binding studies
on this family mainly based on a recent report showing that
cannabinoid D9-THCV (a compound which also lacks
a
protonable nitrogen, Fig. 2), exhibited affinity (2060 nM)
for the human 5-HT1AR expressed in CHO cells.
Figure 2. Cannabinoid D9-THCV and 4b derivative.
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Scheme 1. Synthesis of compounds 4a–d.
mesylchloride to give the expected O-mesylate derivative 10a
(Scheme 3), which was immediately utilized due its rapid
decomposition.
Finally, the mesylates 10a–c were immediately reacted with
4-amino-phenylpiperazinylpropylindole derivatives 13a–b, to
provide the bis-indoles 14a–d (38–44% yield; Scheme 6).
Finally, compounds 14a–d were obtained according to the
retrosynthetic strategy shown in Scheme 4.
Pharmacology and molecular docking
Thus, tosylates 3a–b were reacted with 4-nitrophenylpiper-
azine to achieve nitroindolylpiperazine derivatives 12a–b
(51–64% yield), which were further reduced with iron in
powder, to give 4-aminoarylpiperazinyl indol derivatives 13a–b
(42–53% yield; Scheme 5).
Table 1 summarizes the affinity measurements for all
compounds at the 5-HT1A receptor and the SERT.
1-[3-(1H-3-Indolyl)-propyl]-1,3,4,5-tetrahydrobenzo[b]-
azepin-2-one derivatives (4a–d)
The indolylmethyl-O-mesylates 10b–c (R ¼ F, Br) were
Regarding the effects of compounds 4a–d upon the 5-HT1A
receptor, the most striking observation was that only the
synthesized in a similar procedure as described for 10a.
Scheme 2. Synthesis of compounds 11a–d.
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Scheme 3. Synthetic sequence for the preparation of 10a.
Scheme 4. Retrosynthetic analysis of compounds 14a–d.
Scheme 5. Synthetic sequence for the preparation of compounds 13a–b.
5-methoxy derivative 4b displayed affinity in the nanomolar
range. Moreover, no affinity was detected for any of these
compounds at the SERT. These results indicate that the
presence of a 1-benzazepinone nucleus connected to an
indolepropyl framework is detrimental for the affinity at both
targets, as compared with previously reported indolealkylar-
ylpiperazine derivatives [8, 9, 16, 17]. This is likely due to the
benzazepinone nucleus, which lacks a protonable nitrogen
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Scheme 6. Synthesis of compounds 14a–d.
and is not capable to establish critical coulombic interactions
with negatively charged residues at both receptors [18]. This
was confirmed by docking experiments of compounds 4a–d at
the 5-HT1A receptor, which revealed that although these
ligands locate at the same binding site described for
indolylalkylpiperazines, they do not establish an ionic
interaction with Asp116. Nevertheless, it is interesting to
see that interactions with residues such as Phe361, Phe362,
Ser199, and Ile113 were observed for compounds 4b and 4c,
which might explain the affinity exhibited by these com-
pounds. Notably, compound 4b showed an additional
interaction with Cys187, which has been shown to be critical
Table 1. Binding affinities of compounds 4a–d, 11a–d, and 14a–d at SERT and 5-HT1A receptor.
Compound
R
R0
5-HT1A Ki (nM) ꢁ SD
SERT Ki (nM) ꢁ SD
8-OH-DPATa)
–
–
–
–
4.7 ꢁ 0.6
ND
Fluoxetinea)
4a
ND
13.7 ꢁ 0.9
>10000
>10000
>10000
>10000
91 ꢁ 14
>10000
34 ꢁ 7
H
OMe
F
Br
H
OMe
F
Br
H
OMe
H
–
>10000
169 ꢁ 15
3226 ꢁ 37
>10000
994 ꢁ 46
43 ꢁ 3.9
908 ꢁ 15
292 ꢁ 10
168 ꢁ 28
56 ꢁ 5.3
>10000
>10000
4b
4c
4d
11a
11b
11c
11d
14a
14b
14c
–
–
–
–
–
–
–
99 ꢁ 8.6
17 ꢁ 0.8
365 ꢁ 24
57 ꢁ 5.1
>10000
H
F
F
14d
H
Br
ND: not determined.
a)The affinity values of fluoxetine and 8-OH-DPAT are included as reference compounds for SERT and 5-HT1A receptor,
respectively.
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for stabilizing other potent indolic 5-HT1A ligands [9, 19].
These results are illustrated in Fig. 3, which shows the most
stable docking poses for the most and least potent
compounds of this series (4b and 4d, respectively). As can
be seen, both compounds adopt clearly different orientations,
and in the case of 4b, the indole moiety (NH) establishes a
direct interaction with Cys187, in addition to an exclusive
hydrogen bond interaction between the 5-methoxy group of
Docking experiments showed that the two most potent
compounds of this series at the 5-HT1A receptor (11b and 11d)
exhibited a binding mode in which the main contact was the
well-described coulombic interaction between a protonated
nitrogen atom of the piperazine ring and Asp116 [8, 9, 20, 21].
Interestingly, in the case of compounds 11a and 11c, this
interaction was absent, which agrees with the lower affinity
exhibited by these derivatives (Fig. 4). In addition, drugs
docked into the 5-HT1A receptor model in such a way that
their aromatic rings appeared located in positions favorable
to interact with an “aromatic cage” formed by Trp358,
Phe361, Phe362, and Tyr195. An additional interaction with
Ile189 was observed in the case of the most potent compound.
As shown in Fig. 4, the receptor–ligand complexes with
the highest affinity (as inferred from docking energies; see
Supporting Information Figs. S1 and S2) showed that
interactions between the aromatic rings of compounds and
the aromatic cage at the receptor involved both the non-
benzylated and benzylated indole rings, requiring the
bending of the molecule around the piperazine ring. These
aromatic interactions were favored by the presence of a
methoxy group (11b), whereas in the case of the less potent
members of this series, the bended conformation weakened
the interaction with Asp116. This is illustrated in Fig. 4, which
shows the most favorable poses of 11a and 11b.
̊
the indolic ring with Ser199 at 3.7 A. On the other hand, the
benzazepinone ring appears located in a position favorable to
interact with Phe361 and Phe362.
With regard to compound 4c, which showed an interme-
diate affinity value, it docked into the 5-HT1A receptor
adopting a position between the most and least favorable
binding modes (not shown). Thus, our results revealed that
although the lack of a basic nitrogen reduces the affinity of
indolepropyl derivatives at the 5-HT1A receptor, its presence
is not essential for having compounds with nanomolar
affinity for this target.
1-Benzyl-3-{4-[3-(1H-3-indolyl)-propyl]-1-
piperazinylmethyl}-1H-indole derivatives (11a–d)
The analysis of the affinities showed again that the most
potent compound at the 5-HT1A receptor was the 5-methoxy
derivative 11b (Table 1). This is in agreement with previous
reports of indole-alkylpiperazine derivatives, which showed
that the introduction of a methoxyl substituent at C5 position
elicits an increase of affinity at this target [17]. Interestingly,
compound 11b displayed a marked selectivity for the 5-HT1A
receptor in comparison with its effect on the SERT, a condition
also observed for other methoxyindole derivatives in earlier
studies [16, 17].
In the case of the SERT, most of the compounds of this series
displayed nanomolar affinity, being the C5 fluorinated
derivative 11c the most active (Table 1). These results agree
with previous reports [9, 22] showing that the introduction of
a fluorine atom at position C5 of the indole moiety generates
Figure 3. Superimposed structures of compounds 4b (blue) and
4d (red) docked into the binding site of the 5-HT1A receptor.
Main binding site amino acid residues (cyan) are rendered as
stick models.
Figure 4. Superimposed structures of compounds 11a (blue)
and 11b (red) docked into the binding site of the 5-HT1A
receptor. Main binding site amino acid residues (cyan) are
rendered as stick models.
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an increase in affinity of indolylpropyl derivatives as
compared with the unsubstituted derivative. Docking experi-
ments revealed that the unsubstituted and halogenated
compounds (i.e., 11a, 11c, and 11d) exhibited similar binding
modes (Fig. 5). Here, an electrostatic interaction between
one of the protonated nitrogen atoms of the piperazine ring
and Glu493 (although in some cases this interaction might
also involve the adjacent Glu494) appears as the main
interaction.
These results are somewhat different from those previ-
ously observed by us when evaluating similar piperazinyl-
propylindole derivatives [9]. Thus, in that earlier study, we
reported that the main interaction underlying the affinity of
these compounds at the SERT was a coulombic interaction
established by a piperazine nitrogen with Asp400, a residue
located a few angstroms closer to the extracellular domain of
the SERT as compared with Glu493. Noteworthy, diverse
studies (see for example [23, 24]) have shown that both
Asp400 and/or Glu493 are critical for the binding of different
arylpiperazine derivatives. In our view, an alternating
interaction involving both residues might be the main
molecular determinant explaining the affinity of these
and other SERT ligands. Further experiments are necessary
to evaluate the role of these residues (either individually or
collectively) in the binding of piperazinylpropylindole
derivatives and other drugs containing substituted or
unsubstituted amino groups.
(11c and 11d). A distinctive p–p interaction between the
N-benzyl-indole moiety and Trp103 was also present only in
the case of the most potent compound 11c. Interestingly, the
presence of a methoxyl group at position C5 of the non-
benzylated indole moiety (compound 11b) forced this
derivative to adopt a binding mode that clearly differs from
those obtained for all the other members of this series (Fig. 5).
Therefore, many of the aforementioned interactions were not
preserved in this derivative, which could explain its lack of
affinity at the SERT.
(1-Benzyl-1H-3-indolylmethyl)-(4-{4-[3-(1H-3-indolyl)-
propyl]-1-piperazinyl}-aryl)amine derivatives (14a–d)
The introduction of an aniline moiety between the N-benzyl-
indole framework and the piperazine ring induced a 5–6-fold
increase in the affinity of the compound for both the 5-HT1A
receptor and the SERT (compare 14a with 11a). Thus,
considering the three series evaluated, 14a was one of the
most potent compounds at both targets, although it retained
the relative selectivity of the unsubstituted derivative (one
order of magnitude approximately) for the SERT over the
5-HT1A receptor (Table 1). As could be predicted from the
results obtained with the two other series, the introduction of
a methoxyl group at the C5 position elicited an increase in the
affinity for the 5-HT1A receptor (14b). Interestingly, this was
not accompanied by a total lack of effect at the SERT (as
observed in the two other methoxylated derivatives 4b and
11b). Accordingly, 14b and 11d are the most promising
compounds of the series evaluated, in terms of serving as
leads for the search of novel potent ligands with a dual action.
On the other hand, the introduction of a fluorine atom at the
Additional interactions of molecules of this series with
residues at the SERT included a p–cation interaction between
one of the indole moieties and Arg104 and van der Waals
interactions with Pro403 (compounds 11a, 11c, and 11d), and
a hydrogen bond between the other indole N-H with Asp400
C50 position of the N-benzyl-indole moiety induced
a
significant decrease of affinity at the 5-HT1A receptor without
affecting much the affinity for the SERT. Thus, compound 14c
was the most selective SERT ligand of the three series studied.
Notably, the introduction of a bromine atom at the same
position (14d) abolished the affinity of the compound at both
protein targets. Docking experiments revealed that com-
pounds of this series displayed interactions at both targets
that were similar to those described in the previous analyses.
Thus, the most potent compounds at the 5-HT1A receptor (14a
and 14b) adopted a bent conformation that allowed the
coulombic interaction with Asp116 and the interaction of the
ligand aromatic rings with aromatic residues such as Trp358,
Phe361, and Tyr195 (Fig. 6). Conversely, 14c and 14d (which
showed no activity at this receptor) docked at the binding site
in a more extended conformation, thus preventing the
establishment of the most critical interactions.
In the case of the SERT, all compounds but 14d exhibited a
similar binding mode, in which the main interaction was the
electrostatic contact established between one of the
protonated nitrogen atoms of the piperazine ring and
either Glu493 (14a) or Asp400 (14b and 14c), Fig. 7. Likewise,
the least potent compound (14d) showed a clearly different
binding mode, which would explain its lack of affinity for the
SERT.
Figure 5. Superimposed structures of compounds 11b (yellow)
and 11c (blue) docked into the binding site of the SERT. Main
binding site amino acid residues (cyan) are rendered as stick
models.
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acting at the 5-HT1A receptor. In addition, our results were
coherent with previous data regarding how substituents such
as methoxyl groups and/or halogen atoms modulate the
affinity of indolylpropyl derivatives at both the 5-HT1A
receptor and the SERT. Interestingly, some of the compounds
showed a high selectivity for one target, whereas others could
serve as leads for the development of ligands with dual
activity. Since these effects were obtained with a few and
relatively homogeneous series, it would be necessary to carry
out further studies for
a better understanding of the
molecular basis underlying the selectivity and non-selectivity
in this type of drugs.
Experimental
Chemistry
General
Melting points were determined on a hot-stage apparatus and
areuncorrected. TheIRspectrawererecordedinKBrdiscsonan
FT-IR Bruker IFS 55 spectrophotometer and wavenumbers are
reported in cmꢂ1. The 1H and 13C-NMR spectra were obtained
on a Bruker DRX-300 spectrometer (300 and 75 MHz, respec-
tively) in CDCl3 or DMSO-d6. Chemical shifts were recorded in
ppm (d) relative to TMS as an internal standard. J values are
given in Hz. Micro-analyses were carried out on a Fisons EA
1108 analyzer. High-resolution mass spectra were recorded
on a ThermoFinnigan MAT 95XP mass spectrometer and
DSA–TOF AxION 2 TOF MS (Perkin Elmer, Shelton, CT, USA),
positive mode. Silica gel Merck 60 (70–230 mesh) and alumi-
num sheets coated with silica gel 60 F254 were used for column
and TLC chromatography, respectively.
Figure 6. Superimposed structures of compounds 14b (blue)
and 14d (red) docked into the binding site of the 5-HT1A
receptor. Main binding site amino acid residues (cyan) are
rendered as stick models.
Conclusions
The purpose of this study was to examine the effect of
incorporating bioactive heterocyclic rings to the indolylpropyl
moiety in the search of novel ligands with a potential dual
mechanism. Our results showed that although the presence of
a basic nitrogen is important for the affinity of these drugs, it
is still possible to find potent 5-HT1A ligands in molecules
lacking this function. This might enhance the structural
variability that can be explored in the search of novel drugs
The InChI codes of the investigated compounds are
provided as Supporting Information.
General procedure for the synthesis of 1-[3-(1H-indol-3-yl)-
propyl]-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
derivatives 4a–d, with 1-[3-(1H-indol-3-yl)propyl]-6-
methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (4a)
as a model
To a stirred solution of (0.1 g, 0.52 mmol) of 6-methoxy-1-
benzazepin-2-one 15 [15] in dry THF (15 mL), sodium hydride
NaH (0.03 g, 1.25 mmol) was added. The mixture was stirred at
0°C for 10 min and then slowly added to 3-(3-indolyl)propyl-4-
methylbenzenesulfonate (0.17 g, 0.52 mmol) 3a in dry
THF (10 mL). After this time, the mixture was heated to
70°C during 40 h and quenched with water (50 mL). The
reaction mixture was extracted with AcOEt 50 mL (2 ꢃ 25 mL)
and the organic layers dried over anhydrous Na2SO4 and
concentrated in vacuo. The obtained crude as an oil was
purified by column chromatography on silica gel AcOEt/n-
hexane (3:1) to afford (0.11 g, 61%) of a white solid 4a. m.p.
104ꢂ106°C (recrystallized from AcOEt/n-hexane 1:0.5). IRvmax
(cmꢂ1): 3230 (N-H), 3030 (C-H Arom.), 2921 (C-H Aliph.),
1640 (C¼O). 1H-NMR (300 MHz, CDCl3) d: 1.79–1.83 (br s, 3H,
indole-CH2-CH2-CH2, and COCH2-CH-CH2 benzazepine ring),
Figure 7. Superimposed structures of compounds 14a (red) and
14d (blue) docked into the binding site of the SERT. Main
binding site amino acid residues (cyan) are rendered as stick
models.
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Archiv der Pharmazie
–
2.12–2.17 (br s, 3H, indole-CH2-CH2-CH2, and CH2-CH-CH2
benzazepine ring), 2.4 (t, 2H, CO-CH2-CH2-CH2 benzazepine
ring), 2.62 (t, 2H, CO-CH2-CH2 benzazepine ring, J ¼ 8 Hz), 3.12
(br s, 1H, indole-CH2-CH2-CH-N), 3.4 (br s, 1H, indole-CH2-CH2-
CH-N), 3.79 (s, 3H, OMe), 6.89–7.35 (m, 8H, Arom.), 10.78 (s,
1H, N-H). 13C-NMR (75 MHz, CDCl3): 20.9, 22.1, 27.5, 28.4, 32.9,
46.4, 55.6, 108.4, 111.2, 113.5, 115.1, 117.9, 118.1, 120.8, 121.9,
123.2, 126.8, 127.5, 135.9, 142.8, 156.3, 171.8. HRMS: (EI)
Calcd. for C22H24N2O2 (Mþ): 348.1838. Found: 348.1836.
Aliph.), 1636 (C O). 1H-NMR (300 MHz, CDCl3) d: 1.85–1.89
–
(br s, 3H, indole-CH2-CH2-CH2, and COCH2-CH-CH2 benzaze-
pine ring), 2.03–2.07 (br s, 3H, indole-CH2-CH2-CH2, and CH2-
CH-CH2 benzazepine ring), 2.5 (t, 2H, CO-CH2-CH2-CH2
benzazepine ring), 2.81 (br s, 2H, CO-CH2-CH2 benzazepine
ring), 3.33 (s, 2H, indole-CH2-CH2-CH2-N), 3.80 (s, 3H, OMe),
6.75–7.21 (m, 7H, Arom.), 10.80 (s, 1H, N-H). 13C-NMR (75 MHz,
CDCl3): 20.8, 21.7, 27.0, 27.6, 31.5, 45.8, 55.5, 107.0, 107.6,
110.0, (2x)111.6, 114.9, 122.0, 122.7, (2x)126.8, 132.7, 142.5,
152.1, 155.6, 170.5. HRMS: (EI) Calcd. for C22H23BrN2O2 (Mþ):
426.0835. Found: 426.0830.
6-Methoxy-1-[3-(5-methoxy-1H-indol-3-yl)propyl]-4,5-dihy-
dro-1H-benzo[b]azepin-2(3H)-one (4b): Prepared from 6-
methoxy-1-benzazepin-2-one 15 (0.05 g, 0.26 mmol), sodium
hydride (0.01 g, 0.42 mmol) and (0.1 g, 0.28 mmol) of tosylate
3b, to afford pure 4b (0.05 g, 51%) as an oil. IRvmax (cmꢂ1):
General procedure for the synthesis of 1H-indol-3-
carbaldehyde derivatives 7a–c, with 1H-indole-3-
carbaldehyde (7a) as a model
–
3250 (N-H), 3033 (C-H Arom.), 2925 (C-H Aliph.), 1638 (C O).
To a solution of indole 6a at 0°C, (500 mg, 4.27 mmol) in DMF
(2.5 mL), a solution of recently prepared (1 h) POCl3 (0.4 mL,
4.36 mmol) in DMF (2.5 mL) was added. The mixture was
stirred for 30 min, then poured onto a water-ice mixture and
turned basic by adding NaOH (0.5 M) to pH 12. The obtained
white-yellow precipitate was filtered and dried to yield pure
indole 7a (526 mg, 85%). m.p. 181ꢂ182°C (recrystallized
–
1H-NMR (300 MHz, CDCl3) d: 1.75–1.81 (br s, 3H, indole-CH2-
CH2-CH2, and COCH2-CH-CH2 benzazepine ring), 2.14–2.18
(br s, 3H, indole-CH2-CH2-CH2 and CH2-CH-CH2 benzazepine
ring), 2.58 (t, 2H, CO-CH2-CH2-CH2 benzazepine ring), 2.62 (t,
2H, CO-CH2-CH2 benzazepine ring, J ¼ 8.1 Hz), 3.33 (s, 2H,
indole-CH2-CH2-CH2-N), 3.71 (s, 3H, OMe), 3.79 (s, 3H, OMe),
6.81–7.25 (m, 7H, Arom.), 10.57 (s, 1H, N-H). 13C-NMR (75 MHz,
CDCl3): 20.6, 21.8, 27.0, 27.9, 32.7, 45.9, 54.7, 55.2, 99.3, 107.9,
110.4, 111.4, 112.9, 114.7, 122.3, 122.8, 126.7, 126.9, 130.9,
142.6, 152.3, 155.9, 170.9. HRMS: (EI) Calcd. for C23H26N2O3
(Mþ): 378.1901. Found: 378.1910.
from AcOEt). IRvmax (cmꢂ1): 3168 (N-H), 1634 (C O), 1576
–
–
(C C). 1H-NMR (300 MHz, DMSO-d6) d: 7.21 (m, 2H, 5-H, and
–
–
6-H), 7.49 (dd, 1H, 7-H, Jo ¼ 7.1 Hz, Jm ¼ 1.5 Hz), 8.1 (dd, 1H,
4-H, Jo ¼ 6.7 Hz, Jm ¼ 1.9 Hz), 8.26 (s, 1H, 2-H), 9.9 (s, 1H, CHO),
12.1 (s, 1H, NH). 13C-NMR (75 MHz, DMSO-d6): 112.4, 118.2,
121.1, 122.1, 123.4, 124.1, 137.0, 138.4, 184.9. HRMS (EI) Calcd.
for C9H7NO: 145.05276. Found (Mþ): 145.05253.
1-[3-(5-Fluoro-1H-indol-3-yl)propyl]-6-methoxy-4,5-dihydro-
1H-benzo[b]azepine-2(3H)-one (4c): Prepared from 6-
methoxy-1-benzazepine-2-one 15 (0.05 g, 0.26 mmol), sodium
hydride (0.011 g, 0.46 mmol) and tosylate 3c (0.091 g,
0.26 mmol) to afford pure 4c (0.053 g, 55.2%) as a white
solid. m.p. 107ꢂ108°C (recrystallized from AcOEt/n-hexane
1:0.5). IRvmax (cmꢂ1): 3233 (N-H), 3010 (C-H Arom.), 2920 (C-H
5-Fluoro-1H-indole-3-carbaldehyde (7b): To a solution of
indole 6b (500 mg, 3.6 mmol) in DMF (2.5 mL) was added
POCl3 (0.37 mL, 4.00 mmol) in DMF (2.5 mL) to give pure 7b
(600 mg) in quantitative yield. m.p. 156ꢂ157°C (recrystallized
from AcOEt). IRvmax (cmꢂ1): 3224 (N-H), 1655 (C O), 1590
–
–
Aliph.), 1642 (C O). 1H-NMR (300 MHz, CDCl3) d: 1.80–1.85
–
–
(C C). 1H-NMR (300 MHz, DMSO-d6) d: 7.15 (td, 1H, 6-H
–
–
(br s, 3H, indole-CH2-CH2-CH2, and COCH2-CH-CH2 benzaze-
pine ring), 2.02–2.07 (br s, 3H, indole-CH2-CH2-CH2, and CH2-
CH-CH2 benzazepine ring), 2.57 (t, 2H, CO-CH2-CH2-CH2
benzazepine ring), 2.62 (t, 2H, CO-CH2-CH2 benzazepine ring,
J ¼ 8 Hz), 3.35 (s, 2H, indole-CH2-CH2-CH2-N), 3.79 (s, 3H, OMe),
6.88–7.25 (m, 7H, Arom.), 10.88 (s, 1H, N-H). 13C-NMR (75 MHz,
Jo ¼ 9.0 Hz, Jm ¼ 3.0 Hz), 7.49 (m, 1H, 7-H), 7.79 (dd, 1H, 4-H,
Jo ¼ 9.0 Hz, Jm ¼ 3.0 Hz), 8.37 (s, 1H, 2-H), 9.95 (s, 1H, CHO), 12.0
(br s, 1H, NH). 13C-NMR (75 MHz, DMSO-d6): 106.1 (d,
20
2
30
J
C–F
¼ 22.5 Hz), 112.1 (d, JC–F ¼ 23.9 Hz), 114.2 (d,
J
C–F
¼ 9.1
3
Hz), 115.0, 118.6 (d,
4
JC–F ¼ 4.2 Hz), 125.1 (d, JC–F ¼ 9.9 Hz),
1
140.1, 159.2 (d, JC–F ¼ 220.0 Hz), 185.5. HRMS (EI) Calcd. for
CDCl3): 21.1, 22.1, 27.5, 28.3, 33.1, 46.4, 55.8, 102.7 (d,
0
C9H6FNO: 163.04334. Found: 163.04328.
2JC–F ¼ 17 Hz), 108.8 (d, 2 JC–F ¼ 19 Hz), 112.2 (d, 2JC–F ¼ 4.1 Hz),
3
30
114.0 (d, JC–F ¼ 9.8 Hz) 122.8, (2x)123.9, 126.0 (d,
J
¼ 9.8
C–F
Hz), (2x)127.0, 132.8, 143.1, 154.9 (d,
1
JC–F ¼ 211 Hz), 156.5,
5-Bromo-1H-indole-3-carbaldehyde (7c): To a solution of
171.5. HRMS: (EI) Calcd. for C22H23FN2O2 (Mþ): 366.1641.
Found: 366.1645.
indole 6c (500 mg, 2.55 mmol) in DMF (5 mL) was added
POCl3 (0.26 mL, 2.85 mmol) in DMF (5 mL) to give pure 7c
(515 mg) in 90.1% yield. mp. 171ꢂ172°C (recrystallized
from AcOEt). IRnmax (cmꢂ1): 3210 (N-H), 1645 (CO), 1525
(CC). 1H-NMR (300 MHz, DMSO-d6) d: 7.41 (dd, 1H, 6-H,
Jo ¼ 9.0 Hz, Jm ¼ 3.0 Hz), 7.52 (d, 1H, 7-H, Jo ¼ 9.0 Hz), 8.24 (d,
1H, 4-H, Jm ¼ 3.0 Hz), 8.37 (s, 1H, 2-H), 9.95 (s, 1H, CHO), 11.9
(br s, 1H, NH). 13C-NMR (75 MHz, DMSO-d6): 114.1, 115.9,
117.1, 123.7, 126.7, 128.4, 136.2, 136.9, 185.4. HRMS (EI) Calcd.
for C9H6BrNO: 222.96328. Found: 222.96337.
1-[3-(5-Bromo-1H-indol-3-yl)propyl]-6-methoxy-4,5-dihydro-
1H-benzo[b]azepin-2(3H)-one
(4d): Prepared
from
6-
methoxy-1-benzazepine-2-one 15 (0.06 g, 0.26 mmol), sodium
hydride (0.011 g, 0.46 mmol) and tosylate 3d (0.13 g,
0.32 mmol) to afford pure 4d (0.049 g, 36.5%) as a white
solid. m.p. 110ꢂ112°C (recrystallized from AcOEt/n-hexane
1:0.5). IRvmax (cmꢂ1): 3231 (N-H), 3020 (C-H Arom.), 2925 (C-H
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2016, 349, 1–15
H. Pessoa-Mahana et al.
Archiv der Pharmazie
General procedure for the synthesis of 1-benzyl-1H-indole-
3-carbaldehyde derivatives 8a–c, with 1-benzyl-1H-indole-
3-carbaldehyde (8a) as a model
Et2O (3 ꢃ 25 mL). The combined organic layers were dried on
anhydrous Na2SO4 and concentrated in vacuo. The organic
residue was purified by column chromatography on silica gel
(AcOEt/n-hexane (1:1) to give pure 9a (330 mg. 65%). m.p.
68ꢂ70°C (recrystallized from AcOEt/n-hexane 1:1). IRvmax
To a solution of indole 7a (500 mg, 3.44 mmol) in dry DMF
(10 mL), NaH (123 mg, 5.16 mmol, 60% suspension in mineral
oil) was slowly added. The reaction mixture was stirred and
cooled to 5°C and benzyl bromide (816 mg, 4.8 mmol) was
added dropwise. After stirring for 30 min, the mixture was
poured onto a water-ice mixture affording a white-pink
precipitate, which was filtered and dried to yield pure indole
8a (607 mg, 75%). m.p. 94ꢂ95°C (recrystallized from AcOEt/n-
(cmꢂ1): 3386 (O-H), 3030 (C-H Arom.), 2924–2860 (C-H Aliph.),
1
–
–
–
1612 (C C), 1555 (C C), 1494 (C C). H-NMR (300 MHz, CDCl )
–
–
–
3
d: 4.65 (d, 2H, -CH2-OH, J ¼ 5.1 Hz), 4.83 (m, 1H, OH), 5.35 (s,
2H, Ar-CH2), 7.00 (t, 1H, J ¼ 7.4 Hz, 5-H or 6-H), 7.09 (t, 1H,
J ¼ 7.4 Hz, 6-H or 5-H), 7.18–7.32 (m, 5H,-C6H5), 7.38 (s, 1H,
2-H), 7.41 (d, 1H, 7-H, J ¼ 8.1 Hz), 7.62 (d, 1H, 4-H, J ¼ 7.9 Hz).
13C-NMR (75 MHz, CDCl3): 49.8, 54.0, 109.8, 118.7, 119.0,
120.8, 121.2, (2x)126.9, 127.2, 127.9, (2x)128.2, 130.4, 136.4,
139.0. Anal. Calcd. for C16H15NO: C, 80.98; H, 6.37; N, 5.90.
Experimental, C, 80.88; H, 6.38; N, 5.89.
hexane 1:1). IRvmax (cmꢂ1): 3108 (C-H Arom.), 2815 (C-H
1
–
–
Aliph.), 1661 (C O), 1536 (C C). H-NMR (300 MHz, DMSO-d )
–
–
6
d: 5.3 (s, 2H, Ar-CH2-), 7.14–7.35 (m, 8H, 5-H, 6-H, 7-H, and Ar-
CH2), 7.7 (s, 1H, 2-H), 8.3 (m, 1H, 4-H), 9.97 (s, 1H, CHO).
13C-NMR (75 MHz, DMSO-d6): 50.4, 109.9, 118.0, 121.7, 122.6,
123.7, 125.0, (2x)126.8, 127.8, (2x)128.7, 134.9, 137.0, 138.1,
184.2. HRMS (EI) Calcd. for C16H13NO (Mþ): 235.09971. Found:
235.09946.
(1-Benzyl-5-fluoro-1H-3-indolyl)methanol (9b): To a solution
of N-benzyl-3-formyl-1H-indole 8b (300 mg, 1.18 mmol) in
ethanol (25 mL), NaBH4 (300 mg, 7.92 mmol) was added to
give 9b (50 mg. 17%). m.p. 60 ꢂ 62°C (recrystallized from
AcOEt/n-hexane 1:1). IRvmax (cmꢂ1): 3406 (O-H), 3062 (C-H
1-Benzyl-5-fluoro-1H-indole-3-carbaldehyde (8b): To a solu-
tion of indole 7b (500 mg, 3.07 mmol) in dry DMF (10 mL), NaH
(184 mg, 7.67 mmol) and benzyl bromide (734 mg, 4.29 mmol)
were added to provide pure indole 8b in quantitative
yield. m.p. 137.2–138.9°C (recrystallized from AcOEt/n-hexane
Arom.), 2920 (C-H Aliph.), 1660 (C C), 1191 (C-O). 1H-NMR
–
–
(300 MHz, CDCl3) d: 4.05 (t, 1H, OH, J ¼ 6 Hz), 4.70 (d, 2H, –CH2-
OH, J ¼ 6 Hz), 5.20 (s, 2H, Ar-CH2), 7.0–7.3 (m, 8H, 2-H, 4-H, 6-H,
and Ar-CH2), 7.35 (dd, 1H, 7-H, Jo ¼ 6 Hz and Jm ¼ 3 Hz).
0
13C-NMR (75 MHz, CDCl3): 51.3, 53.8, 104.4 (d, 2 JC–F ¼ 23.4 Hz),
0
1:1). IRvmax (cmꢂ1): 3047 (C-H Arom.), 2920 (C-H Aliph.), 1663
1
(C O), 1623 and 1582 (C C). H-NMR (300 MHz, DMSO-d ) d:
110.1 (d, 2JC–F ¼ 26.4 Hz), 112.4 (d, 3 JC–F ¼ 8.3 Hz), 114.1, 114.3
–
–
–
–
6
4
3
5.57 (s, 2H, Ar-CH2-), 7.2–7.8 (m, 7H, 6-H, 7-H, and Ar-CH2), 7.82
(d, JC–F ¼ 4.5 Hz), 122.3 (d, JC–F ¼ 9.1 Hz), (2x)126.7, 126.9,
1
(d, 1H, 4-H, Jo ¼ 9 Hz), 8.56 (s, 1H, 2-H), 9.95 (s, 1H, CHO).
128.2, (2x)128.9, 135.6, 157.6 (d, JC–F ¼ 234 Hz). HRMS: (EI)
20
13C-NMR (75 MHz, DMSO-d6): 50.5, 106.5 (d,
J
¼ 25 Hz),
Calcd. for C16H14FNO (M þ 1)þ: 256.1137. Found: 256.1135.
C–F
0
112.2 (d, 2JC–F ¼ 25.7 Hz), 113.4 (d, 3 JC–F ¼ 9.8 Hz), 114.1, 117.8
4
3
(d, JC–F ¼ 4.5 Hz), 125.8 (d, JC–F ¼ 11.3 Hz), (2x)127.8, 128.4,
(2x)129.3, 136.2, 137.0, 159.5 (d, 1JC–F ¼ 235.5 Hz), 185.2. HRMS
(EI) Calcd. for C16H12FNO (Mþ): 253.09029. Found: 253.09022.
(1-Benzyl-5-bromo-1H-indol-3-yl)methanol (9c): A solution of
N-benzyl-3-formyl-1H-indole 8c (300 mg, 0.95 mmol) in etha-
nol (25 mL), NaBH4 (300 mg, 7.92 mmol) was added to give 9c
(42 mg. 14%). m.p. 66 ꢂ 68°C (recrystallized from AcOEt/n-
1-Benzyl-5-bromo-1H-indole-3-carbaldehyde (8c): To a solu-
tion of indole 7c (500 mg, 2.23 mmol) in dry DMF (10 mL), NaH
(134 mg, 5.58 mmol) and benzyl bromide (535 mg, 3.12 mmol)
were added to give indole 8c (560 mg, 80% yield). m.p. 113.1–
115.2°C (recrystallized from AcOEt/n-hexane 1:1). IRvmax
hexane 1:1). IRvmax (cmꢂ1): 3422 (O-H), 3029 (C-H Arom.), 2921
1
–
(C-H Aliph.), 1663 (C C), 1078 (C-O). H-NMR (300 MHz, CDCl )
–
3
d: 4.06 (t, 1H, OH, J ¼ 6 Hz), 4.84 (d, 2H, -CH2-OH), 5.34 (s, 2H,
Ar-CH2), 7.10–7.40 (m, 6H,-C6H5, and 2-H), 7.43 (dd, 1H, 6-H,
Jo ¼ 6 Hz, Jm ¼ 3.0 Hz), 7.61 (d, 1H, 7-H, J ¼ 9.0 Hz), 8.55
(s, 1H, 4-H). 13C-NMR (75 MHz, CDCl3): 51.2, 53.5, 111.9,
116.8, 117.9, 124.9, 127.0, (2x)127.1, 127.2, 128.6, (2x)129.3,
134.9, 136.1, 138.9. HRMS: (EI) Calcd. for C16H14BrNO (M þ 1)þ:
316.0337. Found: 316.0336.
(cmꢂ1): 3026 (C-H Arom.), 2921 (C-H Aliph.), 1663 (C O),
–
–
1
–
–
1604 and 1565 (C C). H-NMR (300 MHz, DMSO-d ) d: 5.56 (s,
6
2H, Ar-CH2-), 7.2–7.5 (m, 6H, 7-H, Jo ¼ 6 Hz, and Ar-CH2), 7.60
(d, 1H, 6-H, Jo ¼ 9 Hz), 8.26 (s, 1H, 2-H), 8.54 (s, 1H, 4-H), 9.95 (s,
1H, CHO). 13C-NMR (75 MHz, DMSO-d6): 50.4, 114.1, 115.9,
117.1, 123.7, 126.7, 127.0, (2x)127.8, 128.4, (2x)129.3, 136.2,
137.0, 142.2, 185.4. HRMS (EI) Calcd. for C16H12BrNO (Mþ):
313.01023. Found: 313.01022.
General procedure for the synthesis of (1-benzyl-1H-indol-
3-yl)methyl methanesulfonate derivatives 10a–c, with
(1-benzyl-1H-indol-3-yl)methyl methanesulfonate (10a)
as a model
General procedure for the synthesis of (1-benzyl-1H-indol-
3-yl)methanol derivatives 9a–c, with (1-benzyl-1H-3-
indolyl)methanol (9a) as a model
To a solution of (1-benzyl-1H-indol-3-yl)methanol 9a (500 mg,
2.1 mmol) in dichloromethane (20 mL), Et3N (0.32 mL,
2.31 mmol) and mesylchloride (0.18 mL, 2.31 mmol) were
added. The mixture was stirred for 1 h at 0°C. The mixture
was subsequently concentrated under vaccum to give a white
solid very unstable, being immediately utilized. In such sense, a
rapid high-resolution mass spectrum was run to confirm the
A
solution of N-benzyl-3-formyl-1H-indole 8a (500 mg,
2.12 mmol) in ethanol (30 mL), NaBH4 (500 mg, 13.22 mmol)
was added at 0°C and the mixture stirred for 45 min. The
mixture was diluted with water (30 mL) and extracted with
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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10

RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2016, 349, 1–15
Novel Indoles Endowed with Serotonergic Activity
Archiv der Pharmazie
identity. HRMS: (EI) Calcd. for C17H17NO3S (Mþ): 315.0929.
Found: 315.0922.
CH2-Pip), 2.58 (m, 4H, Pip), 2.7 (m, 6H, 4H-Pip, and Indole-CH2-
CH2-CH2), 3.80 (s, 3H, ꢂOCH3), 3.83 (s, 2H, Indole-CH2-Ph), 5.23
(s, 2H, Pip–CH2-Indole), 6.79 (dd, 1H, Indole 6-H, Jo ¼ 8.7 Hz,
Jm ¼ 2.4 Hz), 6.88 (s, 1H, Indole-Bn 2-H), 7.01–7.22 (m, 11H,
Indole 2-H, 4-H, 7-H, Indole-Bn 5-H, 6-H, 7-H, and Indole-Bn 2-
H, 3-H, 4-H, 5-H, 6-H), 7.65 (d, 1H, J ¼ 7.2 Hz, Indole-Bn 4-H),
8.45 (br s, 1H, N-H). 13C-NMR (75 MHz, CDCl3): 22.6, 26.9, 49.9,
51.1, 51.6, (2x)52.0, 52.2, 55.8, 57.4, 108.5, 109.8, 111.9, 114.9,
119.2, 119.4, 119.7, 121.9, 122.2, 122.4, (2x)127.7, 127.6, 127.8,
128.5, (3x)128.7, 129.0, 136.5, 137.1, 153.6. Anal. Calcd. for
(1-Benzyl-5-fluoro-1H-indol-3-yl)methyl
methanesulfonate
(10b): Prepared from (1-benzyl-5-fluoro-1H-indol-3-yl)meth-
anol 9b (500 mg, 1.96 mmol) in dichloromethane (20 mL),
Et3N (0.3 mL, 2.16 mmol) and mesylchloride(0.17 mL, 2.16 mmol).
HRMS: (EI) Calcd. for C17H16FNO3S (Mþ): 333.08349. Found:
333.08348.
(1-Benzyl-5-bromo-1H-indol-3-yl)methyl methanesulfonate
(10c): Prepared from (1-benzyl-5-bromo-1H-indol-3-yl)meth-
anol 9c (500 mg, 1.58 mmol) in dichloromethane (20 mL),
Et3N (0.24 mL, 1.74 mmol) and mesylchloride (0.14 mL,
1.74 mmol). HRMS: (EI) Calcd. for
393.0034. Found: 393.0035.
C32H36N4O: C, 78.01; H, 7.37; N, 11.37. Experimental: C, 77.98;
H, 7.36; N, 11.35.
1-Benzyl-3-{(4-[3-(5-fluoro-1H-indol-3-yl)-propyl]piperazin-1-
yl)methyl}-1H-indole (11c): Prepared from (1-benzyl-1H-
indol-3-yl)methyl methanesulfonate 10a (0.71 g, 2.37 mmol),
triethylamine (0.35 mL, 2.37 mmol) and 5-fluoro-3-(3-(piper-
azin-1-yl)propyl)-1H-indole 5c (0.61 g, 2.34 mmol) to provide
pure 11b (0.46 g, 40%, recrystallized from AcOEt/n-hexane
2:1). m.p. 106ꢂ108°C. IRvmax (cmꢂ1): 3414 (N-H), 3006 (C-H
C
17H16BrNO3S (Mþ):
General procedure for the synthesis of 3-{(4-[3-(1H-indol-
3-yl)propyl]piperazin-1-yl)methyl}-1-benzyl-1H-indole
derivatives 11a–d, with 1-benzyl-3-{(4-[3-(1H-indol-3-yl)-
propyl]piperazin-1-yl)methyl}-1H-indole (11a) as a model
To a solution of (1-benzyl-1H-indol-3-yl)methyl methansulfo-
nate 10a (0.65 g, 2.17mmol) in dry CH3CN (20 mL) was added 3-
(3-(piperazin-1-yl)propyl)-1H-indole 5a (0.51 g, 2.1 mmol) and
triethylamine (0.32 mL, 2.40mmol). The mixture was heated
under reflux conditions overnight. After this time, water
(50 mL) was added and the reaction mixture was extracted with
AcOEt (2 ꢃ 30 mL), dried over anhydrous Na2SO4, and the
solvent removed under reduced pressure to give a crude, which
was purified by column chromatography (AcOEt/n-hexane/
MeOH 2:0.5:0.3)toprovide pure11a(0.45 g, 46%, recrystallized
from AcOEt/n-hexane 2:1). m.p. 108ꢂ110°C. IRvmax (cmꢂ1): 3240
(N-H), 3030 (C-H Arom.), 2923 (C-H Aliph.). 1H-NMR (300 MHz,
CDCl3) d: 1.91 (q, 2H, J ¼ 7.6 Hz, CH2-CH2-CH2), 2.46 (t, 2H,
J ¼ 8.2 Hz, CH2-CH2-CH2-Pip), 2.55 (m, 4H, Pip), 2.62 (m, 4H, Pip),
2.75 (t, 2H, Indole-CH2-CH2-CH2, J ¼ 7.50 Hz), 3.76 (s, 2H, Indole-
CH2-Ph), 5.25 (s, 2H, Pip–CH2-Indole-Bn), 6.93 (s, 1H, 2-H, Indole-
Bn),7.05–7.18(m, 7H, Indole2-H,4-H,5-H,6-H, 7-H,and2-H, 6-H
Indole-Bn), 7.23–7.32 (m, 5H,5-H, 6-H Indole-Bn and 3-H, 4-H
and 5-H Indole-Bn), 7.57 (d, 1H, J ¼ 7.8 Hz, 7-H Indole-Bn), 7.71
(d, 1H, J ¼ 7.7 Hz, 4-H Indole-Bn), 8.22 (br s, 1H, N-H). 13C-NMR
(75 MHz, CDCl3): 22.0, 26.1, 49.1, (2x)51.7, (2x)52.0, 52.2, 57.3,
108.8, 109.8, 110.1, 115.1, 117.9, 118.1, 118.4, 118.6, 120.1,
120.9, (2x)125.9, 126.5, 126.6, 126.7, 127.3, (3x)127.8, 135.3,
135.7,136.5.Anal.Calcd.forC31H34N4:C,80.48;H,7.41;N,12.11.
Experimental: C, 80.46; H, 7.40; N, 12.09.
Arom.), 2933 (C-H Aliph.), 1579 (C C). 1H-NMR (300 MHz,
–
–
CDCl3) d: 1.87 (q, 2H, J ¼ 7.6 Hz, CH2-CH2-CH2), 2.46 (t, 2H,
J ¼ 7.9 Hz,CH2-CH2-CH2-Pip), 2.58 (m, 4H, Pip), 2.67 (m, 6H, 4H-
Pip, and Indole-CH2-CH2-CH2), 3.80 (s, 2H, Indole-CH2-Ph), 5.24
(s, 2H, Pip–CH2-Indole), 6.87 (dd, 1H, Indole 6-H, Jo ¼ 9.0 Hz,
Jm ¼ 2.4 Hz), 6.93 (s, 1H, Indole-Bn 2-H), 7.08–7.29 (m, 11H,
Indole 2-H, 4-H, 7-H, Indole-Bn 5-H, 6-H, 7-H, and Indole-Bn 2-H,
3-H, 4-H, 5-H, 6-H), 7.68 (d, 1H, J ¼ 7.1 Hz, Indole-Bn 4-H), 8.55
(br s, 1H, N-H), 13C-NMR (75 MHz, CDCl3): 22.3, 25.7, 49.1, (2x)
51.1, (2x)51.5, 51.8, 56.9, 102.7 (d, 2JC–F ¼ 23.2 Hz), 108.9, 109.1
0
0
(d,2 JC–F ¼ 26.3 Hz), 109.2, 110.8 (d,3 JC–F ¼ 9.7 Hz), 115.0
4
(d, JC–F ¼ 4.8 Hz), 118.6, 121.0, 122.3, (2x)125.9, 126.7, 126.8,
0
126.9 (d,3 JC–F ¼ 9.6 Hz), 127.6, 127.7, (2x)127.8, 132.0, 135.7,
1
136.4, 156.6 (d, JC–F ¼ 234Hz). Anal. Calcd. for C31H33FN4: C,
77.47;H, 6.92;N, 11.66. Experimental: C, 77.51;H, 6.90; N, 11.63.
1-Benzyl-3-{(4-[3-(5-bromo-1H-indol-3-yl)-propyl]piperazin-1-
yl)methyl}-1H-indole (11d): Prepared from (1-benzyl-1H-
indol-3-yl)methyl methanesulfonate 10a (0.62 g, 2.07 mmol),
triethylamine (0.30 mL, 2.15 mmol) and 5-bromo-3-(3-(piper-
azin-1-yl)propyl)-1H-indole 5d (0.64 g, 1.99 mmol) to provide
pure 11d (0.393 g, 35%) as an oil. IRvmax (cmꢂ1): 3310 (N-H),
3011 (C-H Arom.), 2930 (C-H Aliph.), 1578 (C C). 1H-NMR
–
–
(300 MHz, CDCl3) d: 1.84 (q, 2H, J ¼ 7.6 Hz, CH2-CH2-CH2), 2.39
(t, 2H, J ¼ 7.9 Hz, CH2-CH2-CH2-Pip), 2.50 (m, 4H, Pip), 2.66 (m,
6H, 4H-Pip, and Indole-CH2-CH2-CH2), 3.74 (s, 2H, Indole-CH2-
Ph), 5.23 (s, 2H, Pip–CH2-Indole), 6.86 (s, 1H, Indole-Bn 2-H),
7.04–7.25 (m, 11H, Indole 2-H, 6-H, 7-H, Indole-Bn 2-H- 6-H and
Indole-Bn 2-H, 3-H, 4-H, 5-H, 6-H, 7-H), 7.69 (d, 1H, J ¼ 7.2 Hz,
Indole-Bn 4-H), 7.73 (d, 1H, Jm ¼ 2.4 Hz, Indole 4-H), 8.54 (br s,
1H, N-H). 13C-NMR (75 MHz, CDCl3): 22.7, 26.9, 49.9, 52.8, (2x)
53.0, 58.0, 109.7, 111.1, 112.2, 112.4, 115.8, 119.3, 119.6, 121.5,
121.7, 122.5, 124.4, (2x)126.7, (2x)127.5, 127.9, (3x)128.7, (2x)
1-Benzyl-3-{(4-[3-(5-methoxy-1H-indol-3-yl)-propyl]piperazin-
1-yl)methyl}-1H-indole (11b): Prepared from (1-benzyl-1H-
indol-3-yl)methyl methanesulfonate 10a (0.80 g, 2.67 mmol),
triethylamine (0.36 mL,2.45 mmol) and 5-methoxy-3-(3-(piper-
azin-1-yl)propyl)-1H-indole 5b (0.66 g, 2.42 mmol) to provide
pure 11b (0.513 g, 39%, recrystallized from AcOEt/n-hexane
2:1). mp. 107ꢂ109°C. IRnmax (cmꢂ1): 3230 (N-H), 3022 (C-H
Arom.), 2929 (C-H Aliph). 1H-NMR (300 MHz, CDCl3) d: 1.92 (q,
2H, J ¼ 7.6 Hz, CH2-CH2-CH2), 2.54 (t, 2H, J ¼ 7.9 Hz, CH2-CH2-
129.3, 134.8, 136.5, 137.4. Anal. Calcd. for
C31H33BrN4:
C, 68.76; H, 6.14; N, 10.35. Experimental: C, 68.75; H, 6.13;
N, 10.37.
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
11

RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2016, 349, 1–15
H. Pessoa-Mahana et al.
Archiv der Pharmazie
General procedure for the synthesis of 3-{3-[4-(4-
(4 ꢃ 50 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated to dryness in vacuo to
give a crude mixture which was finally purified by column
chromatography (AcOEt/n-hexane/MeOH) (2:0.5:0.3) to pro-
vide pure 13a (0.15 g, 71.1%) as a white solid (recrystallized
from EtOH/n-hexane 2:1). mp. 128–130°C. IRvmax (cmꢂ1): 3426
and 3328 (Ar-NH2), 3414 (N-H indole), 3047 (C-H arom.), 2935–
2840 (C-H aliph.). 1H-NMR (DMSO-d6): 2.26 (m, 2H, 20-H), 2.61
(t, 2H, 30-H, J ¼ 6.5 Hz), 2.80 (s, 4H, 200-H, 600-H), 3.21 (t, 2H, 10-H,
J ¼ 6.8 Hz), 3.46 (s, 4H, 300-H, 500-H), 4.53 (s, 2H, NH2), 6.56 (m,
2H, 2000-H, 6000-H, J ¼ 8.2 Hz), 6.77 (d, 2H, 3000-H, 5000-H, J ¼ 8.3 Hz),
7.05 (t, 1H, 5-H, J ¼ 7.1 Hz), 7.15 (m, 2H, 4-H and 6-H), 7.27 (s,
1H, 2-H), 8.01 (d, 1H, 7-H, J ¼ 7.5 Hz), 10.41 (bs., 1H, NH indole)
ppm. 13C-NMR (DMSO-d6): 22.4, 27.0, (2x)46.1, (2x)52.2, 57.4,
111.3, (2x)112.5, 114.2, 118.2, 118.4, 120.7, 122.1, (2x)125.5,
127.1, 136.4, 137.0, 142.7 ppm. Anal. Calcd. forC21H26N4: C,
75.41; H, 7.84; N, 16.75. Experimental: C, 75.40; H, 7.85; N,
16.72.
nitrophenyl)piperazin-1-yl]-propyl}-1H-indole derivatives
12a,b, with 3-{3-[4-(4-nitrophenyl)piperazin-1-yl]-propyl}-
1H-indole (12a) as a model
To a solution of 3-(indol-3-yl)propyl-4-methylbenzenesulfo-
nate 3a (0.73 g, 2.2 mmol) in dry CH3CN (50 mL), anhydrous
K2CO3 (0.33 g, 2.42 mmol) and 4-nitrophenylpiperazine
(0.46 g, 2.2 mmol) were added. The mixture was stirred under
reflux condition for 6 h. After this time, the mixture was
poured onto water (50 mL) and extracted with AcOEt
(2 ꢃ 30 mL), dried over anhydrous Na2SO4, and the solvent
removed under reduced pressure to give a crude, which was
purified by column chromatography (AcOEt) to provide pure
12a (0.42 g, 52%) as a yellow solid (recrystallized from AcOEt/
n-hexane 1:1). mp. 158–160°C. IRvmax (cmꢂ1): 3415 (N-H), 3049
(C-H arom), 2936–2843 (C-H aliph.), 1600 (NO2, asym.), 1331
(NO2, sym.). 1H-NMR (DMSO-d6): 1.86 (m, 2H, 20-H), 2.41 (t, 2H,
30-H, J ¼ 6.8 Hz), 2.50 (s, 4H, 200-H, 600-H), 2.75 (t, 2H, 10-H,
J ¼ 7.2 Hz), 3.44 (s, 4H, 300-H, 500-H), 6.71–6.76 (m, 3H, 6-H, 2000-H,
6000-H), 7.09 (t, 1H, 5-H, J ¼ 7.3 Hz), 7.17 (s, 1H, 2-H), 7.38 (d, 1H,
4-H, J ¼ 8.0 Hz), 7.56 (d, 1H, 7-H, J ¼ 7.8 Hz), 8.07 (d, 2H, 3000-H,
5000-H, J ¼ 9.3 Hz), 10.84 (bs., 1H, NH). 13C-NMR (DMSO-d6):
22.5, 27.0, (2x)46.2, (2x)52.3, 57.4, 111.4, (2x)112.5, 114.3,
118.1, 118.3, 120.8, 122.2, (2x)125.7, 127.2, 136.3, 136.8, 154.7.
Anal. Calcd. for C21H24N4O2: C, 69.21; H, 6.64; N, 15.37.
Experimental: C, 69.23; H, 6.65; N, 15.35.
4-{4-[3-(5-Methoxy-1H-indol-3-yl)propyl]piperazin-1-yl}ani-
line (13b): Prepared from 5-methoxy-3-{3-[4-(4-nitrophenyl)-
piperazin-1-yl]-propyl}-1H-indole 12b (0.8 g, 2.0 mmol),
a
mixture of H2O/EtOH/AcOH (1:1:1) and powder iron (1.13 g,
20.3 mmol) to provide pure 13b (0.68 g, 92%, recrystallized
from EtOH/n-hexane 2:1). m.p. 133–134°C. IRvmax (cmꢂ1): 3424
and 3330 (Ar-NH2), 3395 (N-H indole), 3037 (C-H arom.), 2925–
2842 (C-H aliph.). 1H-NMR (DMSO-d6): 2.03 (m, 2H, 20-H), 2.65
(t, 2H, 30-H, J ¼ 7.01 Hz), 2.75 (s, 4H, 200-H, 500-H, piperazine),
2.86 (t, 2H, 10-H, J ¼ 7.0 Hz), 3.50 (s, 4H, 300-H, 400-H, piperazine),
3.73 (s, 2H, NH2), 3.88 (s, 3H, OCH3), 6.58 (d, 2H, 2000-H, 6000-H,
J ¼ 9.0 Hz), 6.73 (d, 2H, 3000-H, 5000-H, J ¼ 8.9 Hz), 6.90 (dd, 1H, 6-
H, Jo ¼ 8.76 Hz and Jm ¼ 2.42 Hz), 7.08 (d, 1H, 4-H, J ¼ 2.31 Hz),
7.12 (s, 1H, 2-H), 7.29 (d, 1H, 7-H, J ¼ 8.72 Hz), 9.08 (bs., 1H, NH
indole) ppm. 13C-NMR (DMSO-d6): 22.7, 26.6, (2x)46.7, (2x)
52.3, 55.9, 58.0, 100.9, 111.6, 111.9, (2x)112.7, 115.4, 121.9,
(2x)125.9, 127.7, 131.2, 138.2, 143.2, 154.7 ppm. Anal. Calcd.
for C22H28N4O: C, 72.50; H, 7.74; N, 15.37. Experimental: C,
72.52; H, 7.75; N, 15.40.
5-Methoxy-3-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}-1H-
indole (12b): Prepared from 3-(5-methoxy-1H-indol-3-yl)pro-
pyl-4-methylbenzenesulfonate 3b (1.4 g, 3.9 mmol), anhy-
drous K2CO3 (0.65 g, 4.7 mmol) and 4-nitrophenylpiperazine
(0.81 g, 3.9 mmol) to provide pure 12b (0.97 g, 63%, recrystal-
lized from AcOEt/n-hexane 1:1). m.p. 166–167.1°C. IRvmax
(cmꢂ1): 3390 (N-H), 3030 (C-H arom), 2925–2850 (C-H aliph.),
1
1590 (NO2 asym.), 1320 (NO2 sym.). H-NMR (DMSO-d6): 2.05
(m, 2H, 20-H), 2.63 (t, 2H, 30-H, J ¼ 6.9 Hz), 2.70 (s, 4H, 200-H, 500-
H, piperazine), 2.80 (t, 2H, 10-H, J ¼ 7.0 Hz), 3.48 (s, 4H, 300-H, 400-
H, piperazine), 3.89 (s, 3H, OCH3), 6.82 (d, 2H, 2000-H, 6000-H,
J ¼ 9.42 Hz), 6.88 (dd, 1H, 6-H, Jo ¼ 8.78 Hz and Jm ¼ 2.4 Hz), 7.0
(s, 1H, 2-H), 7.05 (d, 1H, 4-H, J ¼ 2.26 Hz), 7.27 (d, 1H, 7-H,
J ¼ 8.72 Hz), 8.02 (bs., 1H, NH), 8.13 (d, 2H, 3000-H, 5000-H,
J ¼ 9.37 Hz). 13C-NMR (DMSO-d6): 22.8, 26.6, (2x)46.6, (2x)52.4,
55.9, 57.9, 100.8, 111.7, 111.9, (2x)112.6, 115.5, 121.9, (2x)
125.9, 127.7, 131.3, 138.4, 153.7, 154.7 ppm. Anal. calcd. for
General procedure for the synthesis of 4-{4-[3-(1H-indol-3-
yl)propyl]piperazin-1-yl}-N-((1-benzyl-1H-indol-3-yl)-
methyl)aniline derivatives 14a–d, with 4-{4-[3-(1H-indol-3-
yl)propyl]piperazin-1-yl}-N-((1-benzyl-1H-indol-3-yl)-
methyl)aniline (14a) as a model
C
22H26N4O3: C, 69.91; H, 6.64; N, 14.20. Experimental: C, 69.90;
A mixture of (1-benzyl-1H-indol-3-yl)methyl methanesulfo-
nate 10a (0.41 g, 1.37 mmol) in CH3CN (20 mL), triethylamine
(0.2 mL, 1.35 mmol), and 4-{4-[3-(1H-indol-3-yl)propyl]piper-
azin-1-yl}aniline 13a (0.45 g, 1.35 mmol) was stirred under
reflux for 24 h. After this time, water was added (20 mL) and
the mixture extracted with AcOEt (3 ꢃ 30 mL). The combined
organic layers were washed and dried over anhydrous
Na2SO4. The organic portions were filtered and concentrated
under vaccum to obtain a crude residue. The crude was
purified by column chromatography on silica gel (AcOEt/n-
hexane/MeOH) (2:0.5:0.3) to afford pure 14a as an oil (0.33 g,
44.3%). IRvmax (cmꢂ1): 3239 (N-H), 3030 (C-H Arom.), 2921 (C-H
H, 6.66; N, 14.19.
General procedure for the synthesis of 4-{4-[3-(1H-indol-3-
yl)propyl]piperazin-1-yl}aniline derivatives 13a,b, with 4-
{4-[3-(1H-indol-3-yl)propyl]piperazin-1-yl}aniline (13a) as a
model
To a solution of 3-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}-
1H-indole 12a (0.23 g, 0.63 mmol) in a mixture of H2O/EtOH/
AcOH (1:1:1), powder iron (0.21 g, 3.79 mmol) was added and
stirred at 55ꢂ60°C for 40 min. Then water (100 mL) was added
neutralized with NaHCO3 and extracted with AcOEt
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
12

RCHH HARM
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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–15
Novel Indoles Endowed with Serotonergic Activity
Archiv der Pharmazie
Aliph.), 1570 (C C). 1H-NMR (300 MHz, CDCl3) d: 1.83 (q, 2H,
indole). 13C-NMR (75 MHz, CDCl3): 22.0, 26.7, 48.4, (2x)49.8,
–
–
2
J ¼ 7.6 Hz, CH2-CH2-CH2), 2.38 (t, 2H, J ¼ 7.9 Hz, CH2-CH2-CH2-
Pip), 2.72 (t, 2H, J ¼ 7.9 Hz, Indole-CH2-CH2-CH2), 2.92 (m, 4H,
Pip), 3.44 (br s, 5H, N-H, and 4H Pip), 4.33 (s, 2H, Indole-CH2-
Phe), 5.36 (s, 2H, NH–CH2-Indole), 6.62 (d, 2H, J ¼ 7.1 Hz, Pip-
Ar), 6.73 (d, 2H, J ¼ 7.1 Hz, Pip-Ar), 6.95–7.43 (m, 13H, Indole 2-
H, 5-H, 6-H, 7-H, Indole-CH2-Ph 2-H,3-H, 4-H, 5-H, and 6-H,
Indole-CH2-Ph 2-H, 5-H, 6-H, and 7-H), 7.53 (d, 1H, J ¼ 7.1 Hz,
Indole 4-H), 7.65 (d, 1H, J ¼ 7.1 Hz, Indole-CH2-Ph 4-H), 10.77
(br s, 1H, N-H indole). 13C-NMR (75 MHz, CDCl3): 22.0, 26.7,
48.4, 49.8, (2x)52.6, (2x)57.2, 59.2, 109.6, 109.8, 110.8, 112.5,
112.7, 113.9, 117.2, 117.6, 117.8, 118.2, 118.7, 120.3, 120.8,
121.7, (2x)126.5, 126.7, (2x)126.8, (2x)126.9, (2x)127.9, 135.7,
135.8, 137.8, 141.9, 142.6. Anal. Calcd. for C37H39N5: C, 80.25;
H, 7.10; N, 12.65. Experimental: C, 80.21; H, 7.11; N, 12.68.
(2x)52.1, 52.6, 57.2, 102.9, 103.7, 108.9 (d, JC–F ¼ 31.4 Hz),
0
110.7 (d, 2 JC–F ¼ 25.6 Hz), 112.8 (d, 3JC–F ¼ 7.54 Hz), 113.9, 115.2
4
(d, JC–F ¼ 4.7 Hz), 117.2, 117.6, 117.8, 118.2, (2x)120.3, (2x)
30
121.7, (2x)126.5, 126.8 (d,
J
C–F
¼ 7.24 Hz), (2x)128.0, 128.9,
1
132.4, 135.8, 137.5, 137.7, 141.9, 142.4, 156.7 (d, JC–F ¼ 233
Hz). Anal. Calcd. for C H38FN5: C, 77.73; H, 6.70; N, 12.25.
37
Experimental: C, 77.75; H, 6.72; N, 12.24.
4-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-N-((1-benzyl-5-
bromo-1H-indol-3-yl)methyl)aniline (14d): Prepared from (1-
benzyl-5-bromo-1H-indol-3-yl)methyl methanesulfonate 10c
(0.40 g, 1.06 mmol), 4-{4-[3-(1H-indol-3-yl)propyl]piperazin-1-
yl}aniline 13a (0.37 g, 1.11 mmol) and triethylamine (0.16 mL,
1.14 mmol), to give pure 14d (0.241 g, 36%) as an oil residue.
IRvmax (cmꢂ1): 3239 (N-H), 3032 (C-H Arom.), 2920 (C-H Aliph.),
1
–
N-((1-Benzyl-5-fluoro-1H-indol-3-yl)methyl)-4-{4-[3-(5-
methoxy-1H-indol-3-yl)propyl]piperazin-1-yl}aniline
1572 (C C). H-NMR (300 MHz, CDCl ) d: 1.79 (q, 2H, J ¼ 7.6 Hz,
–
3
CH2-CH2-CH2), 2.36 (t, 2H, J ¼ 7.8 Hz, CH2-CH2-CH2-Pip), 2.69 (t,
2H, J ¼ 7.9 Hz, Indole-CH2-CH2-CH2), 2.93 (m, 4H, Pip), 3.40
(br s, 5H, N-H, and Pip), 4.31 (s, 2H, Indole-CH2-Ph), 5.36 (s, 2H,
NH-CH2-Indole), 6.62 (d, 2H, J ¼ 7.1 Hz, Pip-Ar), 6.71 (d, 2H,
J ¼ 7.1 Hz, Pip-Ar), 6.89–7.45 (m, 12H, Indole 2-H, 5-H, 6-H,
7-H, Indole-CH2-Ph, 2-H, 3-H, 4-H, 5-H 6-H, Indole-CH2-Ph
2-H, 6-H, 7-H), 7.49 (s, 1H, Indole 4-H), 7.52 (s, 1H, Indole-CH2-
Ph 4-H), 10.70 (br s, 1H, N-H indole). 13C-NMR (75 MHz, CDCl3):
22.1, 25.6, 48.1, 49.8, (2x)52.6, (2x)57.3, 59.1, 103.2, 108.5,
111.3, 112.4, 112.7, 113.8, 117.1, 117.4, 117.7, 118.1, 119.3,
120.1, 120.9, 121.5, 122.6, (2x)125.9, 126.4, (2x)126.8, 127.1,
(2x)127.8, 135.7, 135.8, 138.1, 140.6, 143.2. Anal. Calcd. for
(14b): Prepared from (1-benzyl-5-fluoro-1H-indol-3-yl)methyl
methanesulfonate 10b (0.52 g, 1.64 mmol), 4-{4-[3-(5-
methoxy-1H-indol-3-yl)propyl]piperazin-1-yl}aniline 13b (0.6 g,
1.65 mmol), and triethylamine (0.24 mL, 1.65 mmol) to afford
pure 14b (0.379 g, 38.4%) as an oil. IRvmax (cmꢂ1): 3240 (N-H),
3035 (C-H Arom.), 2930 (C-H Aliph.), 1565 (C C). 1H-NMR
–
–
(300 MHz, CDCl3) d: 1.81 (q, 2H, J ¼ 7.6 Hz, CH2-CH2-CH2), 2.38
(t, 2H, J ¼ 7.9 Hz, CH2-CH2-CH2-Pip), 2.67 (t, 2H, J ¼ 7.9 Hz,
Indole-CH2-CH2-CH2), 2.92 (m, 4H, Pip), 3.42 (br s, 5H, N-H,
and Pip), 3.75 (s, 3H, OCH3), 4.29 (s, 2H, Indole-CH2-Ph), 5.36
(s, 2H, NH–CH2-Indole), 6.60 (d, 2H, J ¼ 7.1 Hz, Pip-Ar), 6.72 (d,
2H, J ¼ 7.1 Hz, Pip-Ar), 6.89–7.44 (m, 12H, Indole 2-H, 6-H, 7-
H, Indole-CH2-Ph, 2-H, 3-H, 4-H, 5-H, 6-H, Indole-CH2-Ph
2-H, 4-H, 6-H, 7-H), 7.52 (s, 1H, Indole 4-H), 10.60 (br s, 1H,
C
37H38BrN5: C, 70.25; H, 6.05; N, 11.07. Experimental: C, 70.23;
H, 6.06; N, 11.07.
N-H indole). 13C-NMR(75 MHz, CDCl3):22.5, 26.7, 49.2, (2x)50.1,
Pharmacological evaluation
Binding assays
0
(2x)52.9, 55.2, 55.9, 57.7, 100.1, 103.9, 109.4 (d, 2 JC–F ¼ 26.4 Hz),
2
3
111.2 (d, JC–F ¼ 20.4 Hz), 112.6 (d, JC–F ¼ 7.5 Hz), 113.1 (d,
The affinity of compounds for the SERT was determined via a
competitive binding assay, using [3H]paroxetine as radioli-
gand (Kd ¼ 0.07 nM [25]) and membranes from human
embryonic kidney (HEK-293) cells expressing the human
SERT (RBHSTM400UA; PerkinElmer Life and Analytical
Sciences, Waltham, MA, USA). The SERT membranes were
thawed and diluted in assay buffer (50 mM Tris-HCl pH 7.4,
120 mM NaCl, 5 mM KCl) to a concentration of 10 mg/100 mL.
Membranes (100 mL) were incubated for 30 min at 27°C with
50 mL 2 nM (final concentration) [3H]paroxetine and 50 mL of
the competing drugs at different concentrations (10ꢂ9 to
10ꢂ4 M) in a final volume of 500 mL. Incubations were
terminated by filtration through Whatman GF/C filters that
were previously soaked in 0.5% polyethyleneimine, using a
cell harvester (Brandel Instruments, Gaithersburg, MD, USA).
Radioactivity was counted in a Packard 1300 liquid scintilla-
tion counter with an efficiency of approximately 50%.
Nonspecific binding was determined in the presence of
10 mM fluoxetine.
4JC–F ¼ 4.7 Hz), 114.2, 117.6, 117.8, 117.9, (2x)122.8, (2x)126.9,
0
127.2(d,3 JC–F ¼ 7.8 Hz),(2x)127.5,127.6,(2x)128.6,129.5,131.3,
132.9, 138.0, 142.3, 142.8, 152.8, 156.6 (d, 1JC–F ¼ 231Hz). Anal.
Calcd. for C38H40FN5O: C, 75.85; H, 6.70; N, 11.64. Experimental:
C, 75.88; H, 6.72; N, 11.67.
4-{4-[3-(1H-Indol-3-yl)propyl]piperazin-1-yl}-N-((1-benzyl-5-
fluoro-1H-indol-3-yl)methyl)aniline (14c): Prepared from (1-
benzyl-5-fluoro-1H-indol-3-yl)methyl methanesulfonate 10b
(0.60 g, 1.89 mmol), 4-{4-[3-(1H-indol-3-yl)-propyl]piperazin-
1-yl}aniline 13a (0.60 g, 1.80 mmol) and triethylamine
(0.26 mL, 1.80 mmol) to give pure 14c (0.40, 39.2%) as an
oil. IRvmax (cmꢂ1): 3240 (N-H), 3028 (C-H Arom.), 2925 (C-H
Aliph.), 1570 (C C). 1H-NMR (CDCl3): 1.80 (q, 2H, J ¼ 7.6 Hz,
–
–
CH2-CH2-CH2), 2.35 (t, 2H, J ¼ 7.9 Hz, CH2-CH2-CH2-Pip), 2.7
(t, 2H, J ¼ 7.9 Hz, Indole-CH2-CH2-CH2), 2.9 (m, 4H, Pip), 3.37
(br s, 5H, N-H, and Pip), 4.27 (s, 2H, Indole-CH2-Ph), 5.34 (s,
2H, NH–CH2–Indole), 6.58 (d, 2H, J ¼ 7.1 Hz, Pip-Ar), 6.69 (d,
2H, J ¼ 7.1 Hz, Pip-Ar), 6.87–7.42 (m, 13H, Indole 2-H, 5-H, 6-H,
7-H, Indole–CH2–Ph, 2-H, 3-H, 4-H, 5-H, 6-H, Indole-CH2-Ph 2-
H, 4-H, 6-H, 7-H), 7.48 (s, 1H, Indole 4-H), 10.74 (br s, 1H, N-H
The affinity of the compounds toward the 5-HT1A receptor
was determined using [3H]8-OH-DPAT as radioligand
(Kd ¼ 0.87 nM [26]) and membranes from HEK-293 cells
ß 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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RCHH HARM
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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–15
H. Pessoa-Mahana et al.
Archiv der Pharmazie
expressing the human 5-HT1A receptor (RBHS1AM400UA;
PerkinElmer Life and Analytical Sciences), as previously
described [8].
[4] D.A.Morrissette,S.M.Stahl,CNSSpectr.2014,19(Suppl1),
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Inhibition curves were fitted using the sigmoidal dose–
response curve (variable slope) equation built into GraphPad
PRISM 5.01 (GraphPad Software, Inc., San Diego, CA, USA).
The IC50 values were determined from four to five indepen-
dent experiments, each in triplicate. Ki were determined
from the IC50 values using the Cheng-Prusoff equation:
Ki ¼ IC50/(1 þ [S]/Km) [27].
ꢀ~
[8] H. Pessoa-Mahana, C. U. Ugarte-Nunez, R. Araya-
Maturana,
C.
Saitz-Barria,
G.
Zapata-Torres,
Molecular simulation
The crystal structure of the human 5-HT2B receptor (Protein
Data Bank, PDB, code 4IB4, 2.7 A resolution; [28]) was used as
C. D. Pessoa-Mahana, P. Iturriaga-Vasquez, J. Mella-
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̊
ꢀ
template to build the 5-HT1A receptor model. Models were
prepared using MODELLER v9.9 [29] and the best model was
stereochemically and energetically evaluated by the ANOLEA
web service [30] and with PROCHECK [31]. In addition, the
recently reported crystal structure of the human SERT (PDB,
[9] H. Pessoa-Mahana, C. Gonzalez-Lira, A. Fierro,
G. Zapata-Torres, C. D. Pessoa-Mahana, J. Ortiz-Severin,
P. Iturriaga-Vasquez, M. Reyes-Parada, P. Silva-Matus,
C. Saitz-Barrıa, R. Araya-Maturana, Bioorg. Med. Chem.
ꢀ
2013, 21, 7604–7611.
̊
ꢀ
code 5I6X, 3.1 A resolution; [32]) was used to perform
[10] C. Ojeda-Gomez, H. Pessoa-Mahana, P. Iturriaga-
ꢀ
Vasquez, C. D. Pessoa-Mahana, G. Recabarren-Gajardo,
docking calculations. Both protein structures were then
embedded in a hydrated palmitoyl-oleyl-phosphatidyl-cho-
line (POPC) bilayer membrane, solvated in a water box (SCP
water model), and ions were added creating an overall
neutral system in approximately 0.02 M NaCl. The final
systems were subjected to a molecular dynamics simulation
for 5 ns using Desmond software from Schrodinger Mae-
stro [33]. The isobaric-isothermal ensemble (NPT, tempera-
ture of 310 K and 1 atm) was used to perform MD
calculations. The equations of motion were integrated using
a time step of 2 fs. The simulation time was sufficient to
obtain an equilibrated system (root mean square deviation-
ꢀ
C. Mendez-Rojas, Arch. Pharm. (Weinheim) 2014, 347,
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€
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̊
RMSD- values <2 A). All other conditions were as previously
€
described [9, 34]. Docking of compounds, both in the SERT
structure and the 5-HT1A model, were performed with the
AutoDock 4.2 suite [35], following protocols previously
described elsewhere [34, 36]. The models used in this study
were built and validated according to our previous pub-
lications [8, 9].
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This work was partially funded by FONDECYT Grants 1130347
to H.P.-M., 1130185 to M.R.-P., and 1150615 to P.I.-V. P.S.-M.,
G.Q., and P.M.-A. were the recipients of CONICYT (Chile)
doctoral fellowships.
Chem. 2013, 13, 1516–1539.
ꢀ
ꢀ
[19] M. Z. Wrobel, A. Chodkowski, F. Herold, A. Gomołka,
ꢀ
J. Kleps, A. P. Mazurek, F. Plucinski, A. Mazurek,
G. Nowak, A. Siwek, K. Stachowicz, A. Sławinska,
ꢀ
M. Wolak, B. Szewczyk, G. Satała, A. J. Bojarski, J. Turło.
Eur. J. Med. Chem. 2013, 63, 484–500.
The authors have declared no conflict of interest.
[20] M. Nowak, M. Kołaczkowski, M. Pawłowski,
A. J. Bojarski, J. Med. Chem. 2006, 49, 205–214.
ꢀ
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