Design, synthesis, and molecular docking of new 5-HT reuptake inhibitors based on modified 1,2-dihydrocyclopenta[b]indol-3(4H)-one scaffold

Article abstract of DOI:10.1007/s12039-019-1621-x

Abstract: A new group of serotonin reuptake inhibitors containing 1,2-dihydrocyclopenta[b]indol-3(4H)-one scaffold was synthesized, starting from indole 5-((1H-indol-3-yl)(1,3-dioxane-4,6-diones as a key intermediates. Following three transformations including intramolecular cyclization and formation of imines, a series of new ligand for human serotonin transporter was obtained. The ability of these ligands to inhibit human TS3 serotonin transporter as well as selectivity toward human D3 dopamine receptor and dopamine transporter were tested in silico using docking software. Graphical Abstract: SYNOPSIS?A series of new serotonin reuptake inhibitors containing 1,2-dihydrocyclopenta[b]indol-3(4H)-one scaffold were designed and synthesized. Affinity to human TS3 transporter and D3 receptor were tested in silico.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-019-1621-x

J. Chem. Sci.
(2019) 131:45
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1621-x
REGULAR ARTICLE
Design, synthesis, and molecular docking of new 5-HT reuptake
inhibitors based on modified 1,2-dihydrocyclopenta[b]
indol-3(4H)-one scaffold
MILENA SZEWCZYK, PAWEŁ PUNDA, KAROLINA JANIKOWSKA and
SłAWOMIR MAKOWIEC∗
Department of Organic Chemistry, Faculty of Chemistry, Gdan´sk University of Technology, Narutowicza 11/12,
80-233 Gdan´sk, Poland
E-mail: mak@pg.edu.pl
MS received 17 September 2018; revised 22 November 2018; accepted 18 March 2019
Abstract. A new group of serotonin reuptake inhibitors containing 1,2-dihydrocyclopenta[b]indol-3(4H)-one
scaffold was synthesized, starting from indole 5-((1H-indol-3-yl)(1,3-dioxane-4,6-diones as a key intermediates.
Following three transformations including intramolecular cyclization and formation of imines, a series of new
ligand for human serotonin transporter was obtained. The ability of these ligands to inhibit human TS3 serotonin
transporter as well as selectivity toward human D3 dopamine receptor and dopamine transporter were tested in
silico using docking software.
Keywords. Meldrum’s acid; cyclization; 5-HT; SSRI.
1. Introduction
However, there still exists a large group of patients
with drug-resistant depression.20 Moreover, most of
the currently used antidepressants are not completely
devoid of side effects. Examples of less dangerous
side effects are sleep disorders, dermatological prob-
lems, and sexual function. The most disturbing is the
impact on the suicidal tendency during the initial stage
of therapy, especially in the under-25 age group.21,22
Therefore, the search for new substances that mod-
ulate serotonin levels in the central nervous system
(CNS), particularly targeted as (SSRIs) is still an on-
going topic of interest in research. Among the various
groups of chemical compounds exhibiting affinity for
serotonin receptors or transporters, our attention was
drawn to carbazole derivatives. This rigid molecule
contains an indole moiety and is conductive to derivati-
zation. SmithKline Beecham has obtained a series of
patents for the synthesis and application of tetrahy-
drocarbazoles23,24 as 5-HT agonists. They focused the
investigation on an indole moiety fused with a six-
membered saturated ring-functionalized with an amine
group in position 3. In contrast, in our work, we have
focused on derivatives with smaller rings. We planned
Moleculescontainingindolemotifareoftenbiologically
active species such as: anti-inflammatory agents,1–5
phytohormones,6,7 anticancer medication,8–10 or treat-
ment for human papillomavirus disease.11 One of the
most important neurotransmitters - serotonin is an
indole derivative.12,13 Probably the most well-known
uses of compounds containing the indole structure
is the modulation of serotonergic receptors or sero-
tonin transporters.14–16 Pharmacological treatment of
mental illnesses such as mood or anxiety disorders
is associated mainly with manipulating the serotonin
level in the central nervous system. Thus, design and
synthesis of molecules targeted at serotonin receptors
and/or serotonin transporters are still in the focus of
medicinal chemistry. The invention17 and introduction
of fluoxetine18 have revolutionized the treatment of
depressive disorders. This is one of the most popular
antidepressants; together with other selective serotonin
reuptake inhibitors (SSRIs) such as sertraline, parox-
etine, citalopram it is invaluable in the treatment of
mental disorders for the vast majority of patients.19
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1621-x) contains
supplementary material, which is available to authorized users.
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45 Page 2 of 13
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(2019) 131:45
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Scheme 1. Approach to preparation of target 1,2,3,4-tetrahydrocyclopenta[b]indole.
to use 2,2-dimethyl-5-(aryl(1H-indol-3-yl)methyl)-1,3- 1H NMR (CDCl3, 400 MHz): δ 8.18 (s, NH), 7.44–7.35 (m,
5 H, Ar-H); 7.30–7.17 (m, 4 H, Ar-H); 7.08–7.05 (m, 1 H,
Ar-H); 5.65 (d, 1 H, J = 2.0, H-6); 4.31 (d, 1 H, J = 2.4,
H-11); 1.71 (s, CH3); 1.42 (s, CH3). 13C NMR (CDCl3, 100
MHz): δ 165.8 (C-1); 164.9 (C-5); 140.0 (C-12); 136.0 (C-
20); 129.3 (C-14, C-18); 128.6 (C-16); 127.4 (C-15, C-17);
127.2(C-19);124.4(C-25);122.5(C-22);119.9(C-24);119.3
(C-23); 115.2 (C-13); 111.4 (C-26); 105.4 (C-3); 52.1 (C-6);
41.9 (C-11); 28.3 (C-9); 28.2 (C-10).
dioxane-4,6-diones (1) as a starting material; however,
due to a reactive and thermally labile dioxanedione
ring, it may be a source of ketenes. This multipurpose
reagent is conducive to preparing our target molecule
with 1,2,3,4-tetrahydrocyclopenta[b]indole (2) substi-
tuted in 1 and 3 positions (Scheme 1).
2. Experimental
2.2b 5-((1-Methyl-1H-indol-3-yl)(phenyl)methyl)-2,
2-dimethyl-1,3-dioxane-4,6-dione (6b)26: Yellow oil,
yield 50%, H NMR (CDCl3, 400 MHz): δ 7.49–7.43 (m,
2.1 Materials and reagents
1
3 H, Ar-H); 7.34–7.22 (m, 6 H, Ar-H); 7.10–7.07 (m, 1 H,
Ar-H); 5.67 (d, 1 H, J = 2.4, H-6); 4.31 (d, 1 H, J = 2.4, H-
11); 3.81 (s, NCH3); 1.74 (s, CH3); 1.45 (s, CH3). 13C NMR
(CDCl3, 100 MHz): δ = 165.5 (C-1); 164.7 (C-5); 140.09 (C-
20); 136.6 (C-12); 128.9 (C-14, C-18); 128.9 (C-22); 128.4
(C-15, C-17);127.5(C-19);127.1(C-16);121.8(C-25);119.2
(C-24); 119.0 (C-23); 113.3 (C-13); 109.2 (C-26); 105.1 (C-
3); 52.1 (C-6); 41.5 (C-11); 32,9 (C-27) 28.1 (C-9); 27.9
(C-10).
Commercially available reagents were purchased from
Sigma-Aldrich. Sodium triacetoxyborohydride was of 97%,
polyphosphoric acid was of reagent grade, indole was of 99%,
all other chemicals were of 98% and solvents were of analyti-
cal grade. Analytical TLC was performed on aluminum sheets
of silica gel UV-254 Merck and visualized with UV lamp at
254 nm. Flash chromatography was performed using 40–63
microns of Zeochem silica gel. The 1H, 13C were recorded on
Bruker Avance III HD 400 MHz, Varian Gemini 200 and Var-
ian Unity Plus 500, chemical shifts (δ) in ppm rel. to internal
Me4Si; coupling constants J in Hz. High-resolution (HRMS)
was recorded on Agilent 6540 Q-TOF.
2.2c 5-((1H-Indol-3-yl)(4-(trifluoromethyl)phenyl)
methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (6c): Yel-
low oil, yield 56%, 1H NMR (CDCl3, 400 MHz): δ 8.22 (s,
NH); 7.55 (s, 4 H, Ar-H); 7.44–7.39 (m, 3 H, Ar-H); 7.25–
7.121 (m, 1 H, Ar-H); 7.12–7.08 (m, 1 H, Ar-H); 5.73 (d,
1 H, J = 2.2, H-6); 4.33 (d, 1 H, J = 2.2, H-11); 1.78
(s, CH3); 1.57 (s, CH3). 13C NMR (CDCl3, 100 MHz): δ
165.1 (C-1); 164.3 (C-5); 144.0 (C-12); 135.8 (C-20); 129.4
(C-14, C-18); 129.2 (q, JC−F = 32.1, C-16); 126.8 (C-19);
125.1 (q, JC−F = 3.7, C-15,C-17); 124.1 (C-25); 124.1 (q,
JC−F = 270.3, C-27); 122.6 (C-22); 119.9 (C-24); 118.8
(C-23); 114.1 (C-13); 111.2 (C-26); 105.2 (C-3); 51.9 (C-
6); 40.5 (C-11); 28.1 (C-9); 27.6 (C-10). HRMS (ESI-):
m/z [M - H]− calcd for C22H17F3NO4: 416.1109; found:
416.1094
2.2 General procedure for preparation of 5-((1H-
indol-3-yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-
dione (6a–d)
According to original procedure.25 To a stirred mixture of
Meldrum’s acid 1.44 g (10 mmol), appropriate aryl aldehyde
(10 mmol) and indole 1.17 g (10 mmol) in acetonitrile 50
mL was added. L-proline 57 mg (0.5 mmol) was also added.
The mixture was stirred for 18 h at 30 ◦C. After completion
of the reaction, the solvent was removed under reduced pres-
sure and the residue was purified with flash chromatography,
(EtOAc/Hex, 1:2).
2.2d 5-((3-Chlorophenyl)(1H-indol-3-yl)methyl)-2,2-
2.2a 5-((1H-Indol-3-yl)(phenyl)methyl)-2,2-dimethyl- dimethyl-1,3-dioxane-4,6-dione(6d)27: Yellowoil, yield
1,3-dioxane-4,6-dione (6a)25: Yellow oil, yield 48%, 60%, 1H NMR (CDCl3, 400 MHz): δ 8.23 (s, NH); 7.47–7.44

J. Chem. Sci.
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45
(m, 2 H, Ar-H); 7.40–7.37 (m, 2 H, Ar-H); 7.33–7.29 (m, 1 H, H, Ar-H); 7.10–7.04 (m, 2 H, Ar-H); 4.87 (t, 3H, J = 7.6,
Ar-H); 7.24–7.19 (m, 3 H, Ar-H); 7.12–7.08 (m, 1 H, Ar-H); H-5); 3.23 (dd, 1 H, J2 = 15.8, J3 = 7.7, H-3); 3.08 (dd,
5.66 (d, 1 H, J = 2.3, H-6); 4.31 (d, 1 H, J = 2.3, H-11); 1 H, J2 = 15.8, J3 = 7.7, H-3). 13C NMR (CDCl3, 100
1.76 (s, CH3); 1.54 (s, CH3). 13C NMR (CDCl3, 100 MHz): MHz): δ 176.9 (C-1); 147.5 (C-6); 136.5 (C-14); 128.8 (q,
δ 165.2 (C-1); 164.4 (C-5); 142.1 (C-12); 135.7 (C-20); 134.2
JC−F = 32.1, C-10); 128.1 (C-8, C-12); 126.2 (C-13); 125.5
(C-17); 129.5 (C-18); 129.2 (C-14); 127.4 (C-15); 127.3 (C- (q, JC−F = 3.7, C-9, C-11); 124.2 (q, JC−F = 270.0, C-
16); 126.8 (C-19); 124.2 (C-25); 122.5 (C-22); 119.9 (C-24); 21); 122.5 (C-16); 121.2 (C-19); 119.7 (C-18); 119.1 (C-17);
118.8 (C-23); 114.2 (C-13); 111.2 (C-26); 105.2 (C-3); 51.9 117.6 (C-7); 111.3 (C-20); 40.6 (C-3); 38.7 (C-5). HRMS
(C-6); 40.6 (C-11); 28.2 (C-9); 27.7 (C-10).
(ESI+): m/z [M + H]+ calcd for C18H15F3NO2: 334.1055;
found: 334.1003.
2.3 General procedure for preparation of
3-(1H-indol-3-yl)-3-arylpropanoic acids (7a–d)
2.3d 3-(3-Chlorophenyl)-3-(1H-indol-3-yl)propanoic
acid (7d): Yield 58%, H NMR (acetone-d6, 400 MHz):
1
δ 10.21 (s, 1 H, OH); 8.01 (s, NH); 7.51–7.39 (m, 5 H, Ar-
H); 7.35–7.31 (m, 1 H, Ar-H); 7.31–7.27 (m, 1 H, Ar-H);
7.20–7.18 (m, 1 H, Ar-H); 7.10–7.06 (m, 1 H, Ar-H); 6.97-
6.93 (m, 1 H, Ar-H); 4.81 (t, 1 H, J = 7.8, H-5); 3.21 (dd,
1 H, J2 = 15.6, J3 = 7.3, H-3); 3.10 (dd, 1 H, J2 = 15.6,
J3 = 7.3, H-3). 13C NMR (acetone-d6, 100 MHz): δ 172.1
(C-1); 147.5 (C-6); 136.9 (C-14); 133.5 (C-11); 129.8 (C-
12); 127.8 (C-8); 126.6 (C-13); 126.4 (C-9); 126.2 (C-10);
121.6(C-16);121.5(C-19);118.8(C-18);118.7(C-17);117.3
(C-7); 111.3 (C-20); 40.3 (C-3); 38.8 (C-5). HRMS (ESI+):
m/z [M + H]+ calcd for C17H15ClNO2: 300.0790; found:
300.0746.
5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-
4,6-dione (6a–d) (1 mmol) was dissolved in mixture of DMF
(10 mL) and water (1mL). Resulted solution was stirred and
heated in oil bath at 100◦C for 4 h. After completion of the
reaction, solvent was removed under reduced pressure and
the residue was dissolved in ethyl ether and extracted with
NaHCO3 (2x10 mL, sat. aq). Water layer was acidified with
conc. aq. HCl. Resulted suspension was extracted with DCM
(4x10 mL). Organic extract was dried with MgSO4, filtered
and solvents was removed under reduced pressure to give acid
7a–d.
2.3a 3-(1H-Indol-3-yl)-3-phenylpropanoicacid(7a)28:
1
2.4 General procedure for preparation of
1-aryl-1,2-dihydrocyclopenta[b]indol-3(4H)-ones
(5a–d)
Yield 45%, H NMR (acetone-d6, 400 MHz): δ 10.1 (s, 1
H, OH); 7.98 (s, NH); 7.44–7.33 (m, 5 H, Ar-H); 7.28–7.24
(m,2 H, Ar-H); 7.17–7.13 (m, 1 H, Ar-H); 7.08–7.04 (m, 1
H, Ar-H); 6.94–6.90 (m, 1 H, Ar-H); 4.80 (t, 1 H, J = 7.6,
H-5); 3.20 (dd, 1 H, J2 = 15.5, J3 = 7.6, H-3); 3.06 (dd, 1
H, J2 = 15.5, J3 = 7.6, H-3). 13C NMR (acetone-d6, 100
MHz): δ 172.7 (C-14); 145.1 (C-10); 137.3 (C-4); 128.4 (C-
16, C-20); 128.0 (C-17, C-19); 126.3 (C-18); 121.8 (C-5);
121.7 (C-3); 121.6 (C-8); 119.2 (C-2); 118.8 (C-1); 111.5 (C-
9); 111.4 (C-6); 40.9 (C-11); 39.4 (C-12). HRMS (ESI+):
m/z [M + H]+ calcd for C17H16NO2: 266.1180; found:
266.1139.
Solution of 3-(1H-indol-3-yl)-3-arylpropanoic acid (7a–d) (5
mmol) in toluene (125 mL) and polyphosphoric acid (7.5
g) was stirred and mixed at 60 ◦C for the time selected in
the Table 2. After completion of the reaction, solvent was
removed under reduced pressure and the residue was dis-
solved in water (150 mL) and extracted with DCM 3x50 mL
Organic layer was dried with MgSO4, filtered and solvents
was removed under reduced pressure. Residue was purified
with flash chromatography, (EtOAc/Hex, 1:3).
2.3b 3-(1-Methyl-1H-indol-3-yl)-3-phenylpropanoic
acid (7b): Yield 60%, 1H NMR (CDCl3, 400 MHz): δ 10.2
(s, 1 H, OH); 7.47–7.44 (m, 1 H, Ar-H); 7.38–7.34 (m, 2 H,
Ar-H); 7.33–7.28 (m, 3 H, Ar-H); 7.25–7.19 (m, 2 H, Ar-H);
7.08–7.03 (m, 1 H, Ar-H); 6.93–6.91 (m, 1 H, Ar-H); 4.83 (t,
1 H, J = 7.8, H-5); 3.77(s, CH3); 3.22 (dd, 1 H, J2 = 15.7,
J3 = 7.8, H-3); 3.09 (dd, 1 H, J2 = 15.7, J3 = 7.8, H-
3). 13C NMR (CDCl3, 100 MHz): δ 178.1(C-1); 143.6 (C-6);
137.3 (C-14); 128.5 (C-8, C-12); 127.7 (C-9-C-11); 126.9 (C-
13); 126.5 (C-14); 125.9 (C-10); 121.8 (C-19); 119.5 (C-18);
118.9 (C-17); 116.9 (C-7); 109.2 (C-20); 41.2 (C-3); 38.9
(C-5); 32.8 (C-21). HRMS (ESI+): m/z [M + H]+ calcd for
C18H18NO2: 280.1337; found: 280.1295.
2.4a 1-Phenyl-1,2-dihydrocyclopenta[b]indol-3(4H)-
one (5a)29: Yield 38%, H NMR (DMSO-d6, 400 MHz):
1
δ 11.83 (s, 1 H, Ar-H); 7.48–7.46 (m, 1 H, Ar-H); 7.34–7.20
(m, 7 H, Ar-H); 7.03–6.99 (m, 1 H, Ar-H); 4.72 (dd, 1 H,
J3 = 2.1, J3 = 6.6, H-12); 3.58 (dd, 1 H, J2 = 18.3,
J3 = 6.6, H-11); 2.95 (dd, 1 H, J2 = 18.3, J3 = 2.1, H-
11). 13C NMR (DMSO-d6, 100 MHz): δ = 193.1 (C-10);
147.3 (C-8); 144.3 (C-14); 143.6 (C-4); 139.2 (C-9); 129.1
(C-15, C-18); 127.5 (C-16, C-18); 127.1 (C-17); 127.0 (C-
5); 122.8 (C-2); 121.7 (C-1); 120.6 (C-6); 114.3 (C-3); 51.4
(C-12); 39.0 (C-11). HRMS (ESI+): m/z [M + H]+ calcd for
C17H14NO: 248.1074; found: 248.1065.
2.3c 3-(1H-Indol-3-yl)-3-(4-(trifluoromethyl)phenyl)
2.4b 4-methyl-1-phenyl-1,2-dihydrocyclopenta[b]
propanoic acid (7c): Yield 60%, H NMR (CDCl3, 400 indol-3(4H)-one (5b)29: Yield 33%, H NMR (CDCl3,
MHz): δ 8.07 (s, NH); 7.56–7.53 (m, 2 H, Ar-H); 7.47–7.44 400 MHz): δ 7.44–7.42 (m, 2 H, Ar-H); 7.41–7.38 (m, 1 H,
(m, 2 H, Ar-H); 7.39–7.36 (m, 2 H, Ar-H); 7.22–7.19 (m, 1 Ar-H); 7.36–7.31 (m, 2 H, Ar-H); 7.29–7.24 (m, 3 H, Ar-H);
1
1

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7.13–7.08 (m, 1 H, Ar-H); 4.67 (dd, 1 H, J3 = 6.8, J3 = 2.4, 1H NMR (CDCl3, 400 MHz): δ 9.78 (brs, NH); 7.45–7.43 (m,
H-12); 4.01 (s, 3 H, H-20); 3.54 (dd, 1 H, J2 = 18.4, 1 H, Ar-H); 7.37–7.22 (m, 1 H); 7.32–7.22 (m, 9 H, Ar-H);
J3 = 6.8, H-11); 2.92 (dd, 1 H, J2 = 18.4, J3 = 2.4, H- 7.06–7.02 (m, 1 H, Ar-H); 4.58 (dd, 1 H, J3 = 7.1, J3 = 2.4,
11). 13C NMR (CDCl3, 100 MHz): δ 193.8 (C-10); 146.4 H-12); 3.75 (td, 2 H, J3 = 7.4, J3 = 2.4, H-20); 3.50 (dd,
(C-14); 145.1 (C-4); 142.9 (C-8); 138.9 (C-9);128.8 (C-15, 1 H, J2 = 17.5, J3 = 7.1, H-11); 3.07 (t, 2 H, J= 7.4, H-
C-19); 127.2 (C-16, C-18); 126.8 (C-5, C-17); 122.7 (C-2); 21) 2.74 (dd, 1 H, J2 = 17.5, J3 = 2.4, H-11). 13C NMR
122.2 (C-6); 120.5 (C-1); 111.0 (C-3); 52.1(C-12); 39.0 (C- (CDCl3, 100 MHz): δ = 165.6 (C-10); 143.6 (C-14); 142.9
11); 30.2 (C-20). HRMS (ESI+): m/z [M + H]+ calcd for (C-22); 140.5 (C-4); 139.9 (C-8); 138.0 (C-5); 128.9 (C-24,
C18H16NO: 262.1232; found: 262.1248.
C-26); 128.7 (C-23, C-27); 128.4 (C-15, C-19); 127.2 (C-16,
C-18); 126.7 (C-17); 126.2 (C-25); 125.1 (C-2); 123.5 (C-9);
120.7 (C-1); 120.2 (C-6); 112.9 (C-3); 54.6 (C-20); 44.3 (C-
12); 41.2 (C-11); 37.2 (C-21). HRMS (ESI+): m/z [M + H]+
calcd for C25H23N2: 351.1860; found: 351.1873.
2.4c 1-(4-(trifluoromethyl)phenyl)-1,2-
dihydrocyclopenta[b]indol-3(4H)-one(5c): Yield25%,
1H NMR (acetone-d6, 400 MHz): δ 10.93 (s, NH); 7.71–7.68
(m, 2 H, Ar-H); 7.63–7.59 (m, 1 H, Ar-H); 7.55–7.53 (m, 2
H, Ar-H); 7.42–7.31 (m, 2 H, Ar-H); 7.13–7.05 (m, 1 H, Ar-
H); 4.91 (dd, 1 H, J3 = 7.2, J3 = 2.4, H-12); 3.55 (dd, 1
H, J2 = 18.4, J3 = 7.2, H-11); 2.79 (dd, 1 H, J2 = 18.4,
J3 = 2.4, H-11). 13C NMR (acetone-d6, 100 MHz): δ 191.4
(C-10); 148.3 (C-8); 145.9 (C-14); 144.1(C-4); 139.3 (C-5);
128.3 (q, JC−F = 31.8, C-17); 127.9 (C-15, C-19); 126.7
(C-2); 125.6 (q, JC−F = 3.8, C-16, C-18); 124.5 (q, JC−F
= 269.4, C-20); 122.9 (C-9); 121.2 (C-1); 120.5 (C-6); 113.7
(C-3); 50.8 (C-12); 38.8 (C-11). HRMS (ESI+): m/z [M +
H]+ calcd for C18H13F3NO: 316.0948; found: 316.0951.
2.5b N-(1-phenyl-1,2-dihydrocyclopenta[b]indol-3
(4H)-ylidene)cyclohexanamine (4aab): Yield 65%,
1
H NMR (CDCl3, 400 MHz): δ 12.07 (brs, NH); 7.58–7.53
(m, 1 H, Ar-H); 7.37–7.27 (m, 5 H, Ar-H); 7.19–7.16 (m, 2
H, Ar-H); 7.09–7.05 (m, 1 H, Ar-H); 4.83 (dd, 1 H, J3 = 6.0,
J3 = 1.4, H-12); 4.02 (dd, 1 H, J2 = 18.8, J3 = 6.0, H-
11); 3.57–3.48 (m, 1 H, C-20); 3.24 (dd, 1 H, J2 = 18.8,
J3 = 1.4, H-11); 2.10–2.00 (m, 2 H, H-25); 1.98–1.82 (m,
4 H, H-24); 1.71–1.65 (m, 1 H, H-23); 1.38–1.23 (m, 3 H,
H-23, H-25); 13C NMR (CDCl3, 100 MHz): δ 167.8 (C-10);
149.3 (C-8); 146.5 (C-14); 140.2 (C-4); 133.4 (C-5); 129.7
(C-17); 129.2 (C-15, C-19); 127.8 (C-2); 127.0 (C-16, C-18);
122.2 (C-9); 122.1 (C-1); 121.5 (C-6); 114.6 (C-3); 58.8 (C-
20); 45.2 (C-12); 41.7 (C-11); 32.0 (C-21); 31.9 (C-25); 24.5
(C-22); 24.5 (C-24); 24.4 (C-23). HRMS (ESI+): m/z [M +
H]+ calcd for C23H25N2: 329.2018; found: 329.2191.
2.4d 1-(3-chlorophenyl)-1,2-dihydrocyclopenta[b]
1
indol-3(4H)-one (5d): Yield 15%, H NMR (DMSO-d6,
400 MHz): δ 11.87 (s, NH); 7.52–7.46 (m, 1 H, Ar-H); 7.37–
7.25 (m, 5 H, Ar-H); 7.22–7.18 (m, 1 H, Ar-H); 7.07–7.02
(m, 1 H, Ar-H); 4.76 (dd, 1 H, J3 = 6.8, J3 = 2.4, H-
12); 3.48 (dd, 1 H, J2 = 18.3, J3 = 6.8, H-11); 2.74 (dd, 1
H, J2 = 18.3, J3 = 2.4, H-11). 13C NMR (DMSO-d6, 100
MHz): δ 192.7 (C-10); 146.4 (C-14); 146.3 (C-8); 144.3 (C-
4); 139.4 (C-18); 133.7 (C-16); 131.0 (C-19); 127.4 (C-15);
127.1 (C-17); 127.0 (C-9) 126.3 (C-2); 122.7 (C-5); 121.6 (C-
1); 120.8 (C-6); 114.4 (C-3); 51.1 (C-12); 38.6 (C-11). HRMS
(ESI+): m/z [M + H]+ calcd for C17H13ClNO: 282.0686;
found: 282.0679.
2.5c N-(4-methyl-1-phenyl-1,2-dihydrocyclopenta
[b] indol-3(4H)-ylidene)-2-phenylethanamine (4baa):
Yield 85%, 1H NMR (CDCl3, 400 MHz): δ 7.43–7.39 (m, 1
H, Ar-H); 7.36–7.28 (m, 8 H, Ar-H); 7.27–7.17 (m, 4 H, Ar-
H); 7.09–7.03 (m, 1 H, Ar-H); 4.54 (dd, 1 H, J3 = 7.3,
J3 = 2.8, H-12); 4.13 (s, CH3); 3.76–3.67 (t, 2 H,J3 = 7.1,
H-20); 3.49 (dd, 1 H, J2 = 17.3, J3 = 7.3, H-11); 3.09 (t,
2 H, J3 = 7.1, H-21); 2.75 (dd, 1 H, J2 = 17.3, J3 = 2.8,
H-11). 13C NMR (CDCl3, 100 MHz): δ 165.3 (C-10); 144.3
(C-8); 144.2 (C-14); 140.7 (C-4); 129.0 (C-24, C-26); 128.8
(C-22); 128.6 (C-23, C-27); 128.3 (C-15, C-19); 127.2 (C-16,
C-18); 126.8 (C-5); 126.5 (C-17); 126.0 (C-25); 124.1 (C-9);
123.2 (C-2); 120.7 (C-6); 119.7 (C-1); 110.3 (3); 55.4 (C-20);
44.5 (C-12); 40.7 (C-11); 37.7 (C-21); 30.5 (C-28). HRMS
(ESI+): m/z [M + H]+ calcd for C26H25N2: 365.2018; found:
365.2021.
2.5 General procedure for preparation N-(1-aryl-1,2-
dihydrocyclopenta[b]indol-3(4H)-ylidene)amines
(4aaa–acb)
Toacooledsolutionof1-aryl-1,2-dihydrocyclopenta[b]indol-
3(4H)-ones (5a–d) (0.5 mmol) in DCM (2 mL) 2-
phenylethylamine or cyclohexylamine (2.5 mmol) was added.
Followed by dropwise addition of TiCl4 solution in DCM
(0.33 mmol, 1M) through 30’. Resulted mixture was allowed
to warm to ambient temperature and stirred for 12 h. Reac-
tion was quenched with aqueous NaOH solution (10 mL, 0.5
M) and extracted with DCM (2x20 mL). Organic layer was
dried with MgSO4, filtered and solvents was removed under
reduced pressure. Residue was purified with flash chromatog-
raphy, (DCM/MeOH, 60:1).
2.5d N-(4-methyl-1-phenyl-1,2-dihydrocyclopenta[b]
indol-3(4H)-ylidene)cyclohexanamine (4bab): Yield
1
90%, H NMR (CDCl3, 400 MHz): δ 7.42–7.36 (m, 1 H,
Ar-H); 7.35–7.21 (m, 7 H, Ar-H); 7.09–7.01 (m, 1 H, Ar-
H); 4.67–4.57 (m, 1 H, H-12); 4.11 (s, 3 H, H-20); 3.66 (dd,
1 H, J2 = 16.4, J3 = 6.4, H-11); 3.36–3.22 (m, 1 H, H-
21); 2.91–2.85 (m, 1 H, H-11); 1.94–1.64 (m, 5 H, H-22,
2.5a 2-phenyl-N-(1-phenyl-1,2-dihydrocyclopenta[b] H-23, H-25, H-26); 1.62–1.48 (m, 2 H, H-23, H-25); 1.45–
indol-3(4H)-ylidene)ethanamine (4aaa): Yield 29%, 1.28 (m, 3 H, H-24, H-25). 13C NMR (CDCl3, 100 MHz): δ

J. Chem. Sci.
(2019) 131:45
Page 5 of 13
45
161.7 (C-10); 144.8 (C-8); 143.9 (C-14); 142.0 (C-4) 133.6, (C-14); 143.5 (C-23); 139.7 (C-4); 139.5 (C-8); 138.6 (C-18);
(C-5); 128.6 (C-15, C-19); 127.2 (C-16, C-18); 126.4 (C-17); 134.6 (C-5); 130.0 (C-16); 129.0 (C-25, C-27); 128.5 (C-
123.6 (C-9); 123.2 (C-2); 120.5 (C-6); 119.5 (C-1); 110.2 (C- 24, C-28); 127.3 (C-19); 127.1 (C-15); 126.4 (C-26); 125.8
3); 61.8 (C-21); 43.8 (C-12); 40.7 (C-11); 34.0 (C-20); 33.9 (C-9); 125.4 (C-17); 123.2 (C-2); 120.7 (C-1); 120.5 (C-6);
(C-22, C-26); 30.3 (C-23); 25.9 (C-25); 24.8 (C-24). HRMS 113.3 (C-3); 54.2 (21); 44.3 (C-12); 40.9 (C-11); 36.9 (C-
(ESI+): m/z [M + H]+ calcd for C24H27N2: 343.2173; found: 22). HRMS (ESI+): m/z [M + H]+ calcd for C25H22ClN2:
343.2247.
385.1470; found: 385.1551.
2.5e 2-phenyl-N-(1-(4-(trifluoromethyl)phenyl)-1,2-
dihydrocyclopenta[b]indol-3(4H)-ylidene)ethanamine
(4aba): Yield 73%, 1H NMR (CDCl3, 400 MHz): δ 10.41
(1H, brs, NH); 7.58–7.53 (m, 2 H, Ar-H); 7.48–7.44 (m, 1 H,
Ar-H); 7.36–7.30 (m, 8 H, Ar-H); 7.26–7.22 (m, 7 H, Ar-H);
7.20–7.14 (m, 1 H, Ar-H); 7.09–7.05 (m, 1 H, Ar-H); 4.63
(dd, 1 H, J3 = 7.1, J3 = 2.4, H-12); 3.88–3.73 (m, 2 H, H-
20); 3.51 (dd, 1 H, J2 = 17.7, J3 = 7.0, H-11); 3.09 (t, 2 H,
J = 7.2, H-21) 2.62 (dd, 1 H, J2 = 17.7, J3 = 2.4, H-11).
13C NMR (CDCl3, 100 MHz): δ 165.7 (C-10); 147.3 (C-14);
143.5 (C-22); 139.7 (C-4); 139.5 (C-5); 138.4 (C-8); 129.2
(q, JC−F = 32.2, C-17); 129.0 (C-15, C-19); 128.5 (C-24,
C-26); 127.5 (C-23, C-27); 126.4 (C-25); 125.9 (C-9); 125.7
(q, JC−F = 3.7, C-16, C-18); 124.1 (q, JC−F = 270.2,
C-28); 123.1 (C-2); 120.7 (C-1); 120.6 (C-6); 113.3 (C-3);
54.2 (C-20); 44.1 (C-12); 40.9 (C-11); 36.8 (C-21). HRMS
(ESI+): m/z [M + H]+ calcd for C26H22F3N2: 419.1734;
found: 419.1878.
2.5h N-(1-(3-chlorophenyl)-1,2-dihydrocyclopenta[b]
indol-3(4H)-ylidene)cyclohexanamine (4acb): Yield
58%, H NMR (CDCl3, 400 MHz): δ 7.45–7.40 (m, 1 H,
1
Ar-H); 7.31–7.26 (m, 2 H, Ar-H); 7.25–7.22 (m, 3 H, Ar-
H); 7.14–7.10 (m, 1 H, Ar-H); 7.09–7.04 (m, 1 H, Ar-H);
4.64 (dd, 1 H, J3 = 7.2, J3 = 2.6, H-12); 3.71 (dd, 1 H,
J2 = 17.5, J3 = 7.2, H-11); 3.33–3.25 (m, 1 H, H-21);
2.92 (dd, 1 H, J2 = 17.5, J3 = 2.6, H-11); 1.90–1.76 (m,
4 H, H-22, H-26); 1.72–1.65 (m, 1 H, H-24); 1.60–1.50 (m,
2 H, H-23, H-25); 1.40–1.22 (m, 3 H, H-23, H-24, H-25);
13C NMR (CDCl3, 100 MHz): δ 162.1 (C-10); 145.9 (C-
14); 142.7 (C-4); 140.6 (C-8); 136.6 (C-18); 134.6 (C-16);
130.1 (C-19); 127.4 (C-15); 127.0 (C-17); 125.3 (C-2); 125.2
(C-5); 123.2 (C-9); 120.5 (C-1); 120.4 (C-6); 113.0 (C-3);
61.5 (C-21); 43.7 (C-12); 40.9 (C-11); 33.7 (C-22); 33.6 (C-
26); 25.5 (C-24); 24.9 (C-25); 24.8 (C-23). HRMS (ESI+):
m/z [M + H]+ calcd for C23H24ClN2: 363.1627; found:
363.1660.
2.5f N-(1-(4-(trifluoromethyl)phenyl)-1,2-
dihydrocyclopenta[b]indol-3(4H)-ylidene)
2.6 N-benzyl-1-(3-chlorophenyl)-1,2,3,4-tetrahydro-
cyclopenta[b]indol-3-amine (3cc)
cyclohexanamine (4abb): Yield 77%, 1H NMR (CDCl3,
400 MHz): δ 9.42 (1H, brs, NH); 7.60–7.55 (m, 2 H, Ar-
H); 7.44–7.40 (m, 1 H, Ar-H); 7.39–7.34 (m, 2 H, Ar-H);
7.31–7.25 (m, 2 H, Ar-H); 7.09–7.03 (m, 1 H, Ar-H); 4.72
(dd, 1 H, J3 = 7.3, J3 = 2.6, H-12); 3.73 (dd, J2 = 17.4,
J3 = 7.3, H-11); 3.34–3.22 (m, 1 H, H-20); 2.90 (dd, 1
H, J2 = 17.4, J3 = 2.6, H-11); 1.85–1.62 (m, 4H, H-21,
H-25); 1.59–1.47 (m, 2 H, H-22, H-24); 1.43–1.2 (m, 4H,
H-22, H-23, H-24). 13C NMR (CDCl3, 100 MHz): δ 161.7
(C-10); 148.1 (C-14); 142.6 (C-4); 141.1 (C-8); 135.8, (C-5)
129.1 (q, JC−F = 32.2, C-17); 127.5 (C-9, C-15, C-19);
125.7 (q, JC−F = 3.7, C-16, C-18); 125.0 (C-2); 124.2
(q, JC−F = 270.2, C-26); 123.3 (C-1); 120.4 (C-6); 113.0
(C-3); 61.6 (C-20); 43.5 (C-12); 41.0 (C-11); 33.8 (C-25);
33.7 (C-21); 25.5 (C-23); 24.9 (C-24); 24.8 (C-22). HRMS
(ESI+): m/z [M + H]+ calcd for C24H24F3N2: 397.1891;
found: 397.2385.
Toasolutionof1-(3-chlorophenyl)-1,2-dihydrocyclopenta[b]
indol-3(4H)-one (5d) 147 mg (0.52 mmol) in DCM (5 mL);
NaBH(OAc)3 170 mg (0.80 mmol) was added followed by
acetic acid 46 μL (0.80 mmol) and benzylamine 0.087 μL
(0.80 mmol). Mixture was stirred at room temperature trough
24 h. Saturated aqueous NaHCO3 (5 mL) and EtOAc (5 mL)
was added and stirred for 30 min. Layers were separated,
water phase was washed with EtOAc (2 x 5 mL). Organic
solution was dried with anh. MgSO4, filtered and solvents
were removed under reduced pressure. The residue was puri-
fied with flash column chromatography on silica gel, using
(EtOAc/Hex, 1:2, NEt3 0.5%) to obtain amine 3 as a yellow
oil, 128 mg, yield 64%. 1H NMR (CDCl3, 400 MHz): δ 8.22
(1H, brs, NH); 7.40–7.29 (m, 7 H, Ar-H); 7.26–7.14 (m, 5
H, Ar-H); 7.05–7.01 (m, 1 H, Ar-H); 4.48 (1H, dt, J = 1.1,
J = 6.2, H-12); 4.35 (t, 1 H, J = 6.8, H-10); 3.99 (d, 1 H,
J = 13.0, H-21); 3.86 (d, 1 H, J = 13. 0, H-21); 3.42 (ddd,
1 H, J = 6.8, J = 6.2, J = 13, H-11); 2.18 (1H, brs, NH);
2.5g N-(1-(3-chlorophenyl)-1,2-dihydrocyclopenta
[b]indol-3(4H)-ylidene)-2-phenylethanamine (4aca):
1
Yield 55%, H NMR (CDCl3, 400 MHz): δ 10.39 (1H, brs, 2.13–2.07 (m, 1 H, H-11); 13C NMR (CDCl3, 100 MHz): δ
Ar-H); 7.49–7.44 (m, 1 H, Ar-H); 7.37–7.31 (m, 1 H, Ar- 147.5 (C-8); 144.3 (C-14); 141.1 (C-22); 139.3 (C-4); 134.4
H); 7.30–7.29 (m, 1 H, Ar-H); 7.27–7.22 (m, 6 H, Ar-H); (C-18); 129.8 (C-16); 128.7 (C-24, C-26); 128.5 (C-23, C-
7.20–7.13 (m, 2 H, Ar-H); 7.10–7.04 (m, 2 H, Ar-H); 4.54 27); 127.6 (C-19); 127.5 (C-15); 126.5 (C-25); 125.6 (C-17);
(dd, 1 H, J3 = 7.8, J3 = 2.4, H-12); 3.87–3.71 (m, 2 H, 123.7 (C-5); 121.7 (C-2); 121.2 (C-1); 119.8 (C-6); 119.2 (C-
H-21); 3.47 (dd, 1 H, J2 = 17.6, J3 = 7.8, H-11); 3.09 (t, 9); 111.9 (C-3); 57.0 (C-10); 51.3 (C-21); 48.4 (C-12); 42.5
2 H,J3 = 7.2, H-22); 2.62 (dd, 1 H, J2 = 17.6, J3 = 2.4, (C-11). HRMS (ESI-): m/z [M - H]− calcd for C24H20ClN2:
H-11). 13C NMR (CDCl3, 100 MHz): δ 165.9 (C-10); 145.3 371.1315; found: 371.1256.

45 Page 6 of 13
J. Chem. Sci.
3. Results and Discussion
3.1 Synthesis
(2019) 131:45
2.7 Molecular docking
Molecular docking for designed molecules was performed
with AutoDock Tools software package.30 Structures of
receptors were obtained from the PDB database. We used
crystallographic structures of human serotonin TS3 trans-
porter,31 human dopamine D3 receptor,32 and Drosophila
dopamine transporter.33 In case of crystallographic struc-
tures, including complexed ligand, atoms of ligand were
selectively removed from the crystallographic structures of
the proteins if necessary. The energy of ligand molecules
was minimized using an MM2 force field. During dock-
ing, the ligands had torsion allowed for all rotating dihedral
angles.
Inthepresentstudy, wehavefocusedourresearchefforts
on formation ligands for human serotonin transporter
based on rigid tricyclic scaffold containing an amine
3 or imine 4 side chain together with an aryl moiety
placed on the first asymmetry centre, as presented in
Figure 1.
The first step in designing a new bioactive molecule
is the synthetic pathway, which allows easy and efficient
preparation of the compound. The scaffold contain-
ing the indole moiety fused with an alicyclic ring
might be formed in a few different ways, includ-
ing Fisher indolization,34 oxidative cyclizations of
arylenaminones,35 Heck-type cyclizations,36 reductive
cyclizations,37 or Friedel-Crafts acylation.38 Retrosyn-
thetic analysis (Scheme 2) led us to assume that the
desired key intermediate 1-aryl-1,2-dihydrocyclopenta
[b]indol-3(4H)-one (5) might be easily formed through
intramolecular Friedel-Crafts acylation.
Ar
r
A
R1
R1
N
N
H
N
N
H
R2
3
4
However, for such a route of synthesis, a source
of 3-(1H-indol-3-yl)-3-arylpropanoic acids is required.
Figure 1. Ligands for the human serotonin transporter.
Scheme 2. Retrosynthetic analysis for the preparation of serotonin transporter ligands.
Scheme 3. Possible routes for the preparation of 3-(1H-indol-3-yl)-3-arylpropanoic acids (7).

J. Chem. Sci.
(2019) 131:45
Page 7 of 13
45
Table 1. Synthesis of 5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-diones 6a–d.
Entry
R1
R2
6
Yield [%]
1
2
3
4
H
CH3
H
H
H
4-CF3
3-Cl
a
b
c
48
50
56
60
H
d
Table 2. Hydrolysis of 5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-diones 6a–d and cyclization to 1-aryl-
1,2-dihydrocyclopenta[b]indol-3(4H)-ones (5).
Entry R1
R2
5, 6, 7
Hydrolysis Conditions
Yield of 7 [%] Cyclization time [h] Yield of 5 [%]
Solvent Time [h] Temp. [◦C]
1
H
H
a
DMF
Acetone
DMF
DMF
DMF
THF
Acetone
4
24
4
4
4
23
24
100
56
100
100
100
66
45
31
60
60
58
58
23
5
38
2
3
4
CH3
H
H
H
4-CF3
3-Cl
b
c
d
120
213
25
33
25
15
56
Scheme 4. Reductive amination of 1-(3-chlorophenyl)-1,2-dihydrocyclopenta[b]indol-3(4H)-one.
Simultaneously solving two synthetic problems, means achieved via the application of 5-((1H-indol-3-yl)(aryl)
the formation of 3-aryl propionic acid with an methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (6). Based
additional indole moiety on 3 positions, would be on analogous processes described in the literature,39

45 Page 8 of 13
J. Chem. Sci.
(2019) 131:45
Table 3. Synthesis of N-(1-aryl-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)alkylamines 4aaa–acb.
Entry
R1
R2
R3
4
Yield [%]
1
H
H
CH3
CH3
H
H
H
H
H
H
PhCH2CH2
c-Hex
PhCH2CH2
c-Hex
PhCH2CH2
c-Hex
PhCH2CH2
c-Hex
aaa
aab
baa
bab
aba
abb
aca
acb
29
65
85
90
73
77
55
58
2
3
4
5
6
7
8
H
4-CF3
4-CF3
3-Cl
3-Cl
H
Figure 2. Binding modes on TS3 transporter active site a) amine 3cc (1R, 3R), b) imine 4aba
(R), c) imine 4acb (R) d) binding comparison of 4acb (R) (green), paroxetine (red) and serotonin
(yellow).
(6) the compound can be easily transformed to 3-(1 three-component reaction composed of indole, aromatic
H-indol-3-yl)-3-arylpropanoic acid (7) through aldehyde, and Meldrum’s acid in the process origi-
hydrolysis in DMF/water solution. On the other hand, nally proposed by Oikawa,25 or through Friedel-Crafts
(6) can be prepared in two ways, either through a alkylation of indole with arylidene Meldrum’s acid

J. Chem. Sci.
(2019) 131:45
Page 9 of 13
45
Table 4. Binding energy of amines 3aa–ed to human serotonin transporter TS3.
Entry
R2
R3
3
Binding energy [kcal/mol]
(1R, 3R)
(1R, 3S)
(1S, 3R)
(1S, 3S)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
PhCH2CH2NH
c-HexNH
PhCH2NH
(Et)2NH
PhCH2CH2NH
c-HexNH
PhCH2NH
(Et)2NH
PhCH2CH2NH
c-HexNH
PhCH2NH
(Et)2NH
PhCH2CH2NH
c-HexNH
PhCH2NH
(Et)2NH
aa
ab
ac
ad
ba
bb
bc
bd
ca
cb
cc
cd
da
db
dc
dd
ea
eb
ec
−10.4
−11.6
−11.9
−9.2
−10.1
−11.8
−11.9
−9.3
−11.2
−10.5
−11.1
−9.8
−10.8
−11.0
−10.5
−9.3
Ph
4-CF3(C6H4)
4-CF3(C6H4)
4-CF3(C6H4)
4-CF3(C6H4)
3-Cl(C H4)
3-Cl(C6H4)
3-Cl(C6H4)
3-Cl(C6H4)
4-F(C66H4)
4-F(C6H4)
4-F(C6H4)
4-F(C6H4)
t-Bu
−12.1
−11.3
−11.9
−10.4
−10.5
−11.9
−12.3
−9.6
−11.3
−11.5
−11.9
−9.9
−11.3
−11.7
−11.9
−10.7
−11.5
−11.0
−11.7
−9.9
−10.4
−11.4
−10.9
−10.2
−11.0
−11.1
−10.2
−9.2
9
−10.6
−12.2
−12.2
−9.5
10
11
12
13
14
15
16
17
18
19
20
−10.2
−11.6
−11.4
−9.5
−10.4
−11.5
−12.0
−9.4
−11.5
−10.8
−11.4
−10.1
−10.6
−10.5
−10.5
−8.5
−10.9
−10.8
−10.7
−9.5
PhCH2CH2NH
c-HexNH
PhCH2NH
(Et)2NH
−10.6
−9.9
−10.3
−10.6
−10.1
−8.4
−10.0
−9.1
t-Bu
t-Bu
t-Bu
−10.2
−8.4
−9.9
ed
−8.3
(8)40 (Scheme 3). Due to the use of simple indole Thus, we anticipated that our model with highly
π
models, it was possible to apply a three-component
-excess indole system would be superior for such an
reaction for the preparation of 6. Thus, we prepared a approach and it will be possible to transform 6 to 5
series of 5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl- in one step. We performed experiments where 6d was
1,3-dioxane-4,6-diones (6a–d) in the reaction of indole refluxed in nitromethane in the presence of scandium
or N-methyl indole, Meldrum’s acid, and an appropriate (III) triflate or without Lewis acid; we also treated
derivative of benzaldehyde in acetonitrile in the pres- of 6d with polyphosphoric acid in toluene at 50 ◦C.
ence of L-proline.
However, regardless of the applied method, we were
Yields and constitution of prepared 6a–d are pre- unable to isolate any pure product, but we observed
sented in Table 1. At this point, compound 6 pos- complicated reaction mixtures in all cases. Therefore,
sesses a chiral center; however, as the application of we had to abandon this one-step cyclization idea and
L-proline does not affect enantiomeric excess, the pre- tried the two-step approach. Compounds 6a–d were
pared 5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl-1, hydrolysed to propionic acids 7a–d and after purifica-
3-dioxane-4,6-dioneswereracemic. Nevertheless, stere- tion, acids were treated with PPA in toluene to form
oselective synthesis of 5-((1H-indol-3-yl)(aryl)methyl)- 1-aryl-1,2-dihydrocyclopenta[b]indol-3(4H)-ones (5a–
2,2-dimethyl-1,3-dioxane-4,6-diones is possible with d).44 The yields for each step are presented in Table 2.
the application of thiourea organocatalysts.41
The most optimal condition for hydrolysis required
In the next synthetic step compound, 6 should be con- application of 10% solution of water in DMF. In this
verted into the desired 1-aryl-1,2-dihydrocyclopenta[b] situation, hydrolysis is quick with moderate yield; how-
indol-3(4H)-one (5). We should take into considera- ever, isolation of propionic acid from DMF solution
tion the work of Fillion42,43 describing intramolecular is tedious. We attempted to perform a second-step
Friedel-Crafts acylation with Meldrum’s acid deriva- intramolecular cyclization in a few different ways. First,
tives catalysed by metal trifluoromethanesulphonates, we tested the application of hydrochloric acid for the
where the aryl ring was activated with acyloxy groups. catalysis of Friedel-Crafts acylation of 7 to 5.45 We

45 Page 10 of 13
J. Chem. Sci.
(2019) 131:45
Table 5. Binding energy of imines 4aaa–bcc to human serotonin transporter TS3.
Entry
R1
R2
R3
4
Binding energy [kcal/mol]
(R)
(S)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
Ph
Ph
PhCH2CH2
c-Hex
PhCH2
PhCH2CH2
c-Hex
PhCH2
PhCH2CH2
c-Hex
PhCH2
PhCH2CH2
c-Hex
PhCH2
PhCH2CH2
c-Hex
PhCH2
PhCH2CH2
c-Hex
PhCH2
aaa
aab
aac
aba
abb
abc
aca
acb
acc
baa
bab
bac
bba
bbb
bbc
bca
bcb
bcc
−11.6
−11.7
−11.7
−11.7
−11.3
−11.8
−11.3
−12.4
−11.9
−11.2
−11.3
−11.2
−11.2
−11.9
−11.4
−10.1
−11.6
−11.4
−11.8
−10.8
−11.2
−11.4
−11.2
−12.0
−11.6
−10.8
−11.5
−10.9
−10.7
−11.1
−11.8
−11.6
−11.7
−11.0
−11.0
−11.4
4-CF3(C6H4)
4-CF3(C6H4)
4-CF3(C6H4)
3-Cl(C6H4)
3-Cl(C6H4)
3-Cl(C6H4)
Ph
9
10
11
12
13
14
15
16
17
18
Ph
Ph
4-CF3(C6H4)
4-CF3(C6H4)
4-CF3(C6H4)
3-Cl(C6H4)
3-Cl(C6H4)
3-Cl(C6H4)
also tried the formation of acid chloride with sub- acetic acid,48 sodium acetate in methanol with amine
sequent ring closure with use of thionyl chloride.46 hydrochloride and NaBH3CN,49 and we also tested
Both these attempts were not successful; therefore we the two-step approach with the preparation of imine
applied a third method with PPA as a cyclization agent.47 in azeotropic condition, followed by reduction with
Application of PPA, however successful, has some NaBH3CN.50 Finally, we tried the formation of imine
disadvantages, especially in the case of hydrophobic in the presence of TiCl4,51 two models were obtained:
carboxylic acid undergoing cyclization. The problem 4aca (with 2-phenylethylamine) and 4acb (with
is connected with phase transfer of reagents and effi-
cient stirring of the reaction mixture. On the micro
scale, the effect is negligible, but on the macro scale,
we observed a significant drop in yield (the results
presented in Table 2 correspond to the gram scale of
reaction).
The final step of synthesis leading to amines seems to
be a trivial procedure. We expected to run reductive ami-
nation in a typical one-pot procedure with in situ prepa-
ration of imine and subsequent reduction with borohy-
dride. However, we were able to obtain amine with this
procedure only in case of N-benzyl-1-(3-chlorophenyl)-
1,2,3,4-tetrahydrocyclopenta[b]indol-3-amine
(Scheme 4).
(3cc)
Application of the above procedure for other 1-
aryl-1,2-dihydrocyclopenta[b]indol-3(4H)-ones (5) in
combination with amines regardless of the used
conditions led to unreacted substrates. We tried to
apply cyanoborohydride in THF in the presence of
Figure 3. Unsuccessful fitting of 4aba (S) in the
active site of Dopamine D3 receptor.

J. Chem. Sci.
(2019) 131:45
Page 11 of 13
45
cyclohexylamine). However, the attempts to reduce side chain of ligand, instead of indole or benzodioxole
them with LiBH4, NaBH4, NaBH(OAc)3 or even with ring as in case of serotonin or paroxetine, respectively
LiAlH4 yielded no results. Prepared imines revealed (Figure 2a).
enormous stability and low electrophilicity, which can
In the case of 3aa–ed ligands, the indole moiety was
be explained with their electronic properties, imine placed in the middle of the pocket. The value of free
π
group conjugated with a -electronic system of indole. energy binding for four stereoisomers of amine types
On the other hand, docking experiments revealed high ligands are presented in Table 4.
affinity of imines to a used model of serotonin trans-
Next, we tested the binding mode for the series of
porter, evenhigherthanexpectedamines. Thesefactsled imines 4aaa–bcc. Again we observed that alkyliminum
us to change the intended objective; we decided to obtain side chain is placed near TYR176 and ILE 172 and the
a series of imines 4aaa–acb. Having a proven method in indole moiety is in the central place and interact with
hand, we have prepared imines in the reaction of 5a–d PHE 341 for 4aba (R) (Figure 2b), or TYR 95 for 4acb
and amines in the presence of TiCl4; the results are col- (R) (Figure 2c). In the case of imines, the affinity was
lected in Table 3. Prepared imines were stable enough to even better than for amines in many cases (Table 5).
allow purification with flash chromatography on silica This might be justified with the better fitting of pla-
gel.
nar imine side chain than alkylamino group located on
chiral sp3 carbon. In the last figure, the binding mode
of paroxetine, serotonin and 4acb (R) were compared
(Figure 2d). Summarizing, for proper binding mode of
our designed ligand 3aa–ed and 4aaa–bcc, the crucial
components are: primary or secondary alkyl amino side
chain with aromatic or cycloaliphatic ring, introducing a
secondary noncyclic amine moiety significantly decrees
the affinity of molecule (Entry: 4, 8, 12, 16, 20; Table 4).
The second side chain should be aromatic, but the type
of substitution is not a critical factor as it interacts with
PHE 335. Introducing the tert-butyl alkyl group disturbs
the interaction of the ligand with transporter (Entry: 17–
20; Table 4).
Additionally, we tried docking our imine ligands into
human dopamine D3 receptor46 and Drosophila dopa-
mine transporter.47 In the case of D3 dopamine receptor,
we did not observe good binding modes of our ligands.
Some docking results suggest steric hindrance caused
by TYR365, which blocks entering of ligand inside of
receptor pocket (Figure 3). Alkylamino side chain R3
tried to penetrate the binding site of the receptor, but the
aryl side chain was hindered with a tyrosine ring.
3.2 Docking study
Preselection of molecules to synthesis as well as obser-
vation of binding to serotonin transporter was performed
using the AutoDock Tools software package.30 Since
the structures of the human serotonin TS3 transporter,31
we used contain paroxetine complexed in the central
site, we verified if, in our docking procedure, parox-
etine will dock in the same place as was observed in
the crystallographic structure. The test was positive,
docked paroxetine overlapped the molecule present in
the crystallographic structure. Moreover, docking of
serotonin was also similar, with indole ring near TYR
176 and ILE 172 and with amine residue oriented to
the side chain COOH of ASP98. Thus, we could start a
docking study with our designed ligands. In the first
set, we docked a series of amines 3aa–ed to a TS3
transporter; surprisingly, we observed a different way
of docking in the central site of the transporter. In the
case of our amine ligands 3cc (1R, 3R), the region of
TYR176 and ILE 172 was occupied with an alkylamino
Figure 4. Binding modes on Dopamine Transporter active site (a) 4acb (S) (b) binding com-
parison of 4aba (S) (yellow) and dopamine (blue).

45 Page 12 of 13
J. Chem. Sci.
(2019) 131:45
For dopamine transporter binding, the modes of our lig-
ands were not perfect as they were for TS-3 transporter.
However, the analysis of affinity energy exhibited a bet-
ter interaction with enantiomeric forms. We observed
moderately good interaction of 4acb (S) (Figure 4a) and
4aba (S) (Figure 4b). The side chain of the aromatic ring
of our ligand fit at an angle to a place normally occupied
by the aromatic ring of dopamine or RTI-55.
of 4,6-diethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-4-
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4. Conclusions
The series of 1,2-dihydrocyclopenta[b]indol-3(4H)-
ones were synthesized based on a three-step procedure
including the formation of Meldrum’s acid adduct; a
transformation to 3-substituted propionic acid followed
with intramolecular cyclization. These tricyclic scaf-
folds were converted to a series of imines and amines as
designed ligands for the human serotonin transporter.
The binding energies of these ligands to human TS3
serotonintransporteraswellasselectivitytowardhuman
D3 dopamine receptor and dopamine transporter were
tested in silico using docking software. During docking,
the prepared ligands exhibited high affinity to sero-
tonin transporter together with very similar placement
on active site compared to serotonin and paroxetine.
Supplementary Information (SI)
1H NMR, 13C NMR, and mass characterization data are sub-
mitted as Supplementary Information. Supplementary Infor-
mation is available on www.ias.ac.in/chemsci.
Acknowledgements
The project was carried-out within the PARENT-BRIDGE
programme of the Foundation for Polish Science (POMOST/
2013-8/6), co-financed from the European Union under the
European Regional Development Fund. We warmly thank
undergraduate and graduate students Mateusz Les´niewski and
Marek Cichon for their contribution to the project.
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