Synthesis and antioxidant properties of substituted 2-phenyl-1H-indoles

Article abstract of DOI:10.1016/j.bmcl.2013.02.090

In this study, we report the design, synthesis and antioxidant activity of a series of substituted 2-(4-aminophenyl)-1H-indoles and 2-(methoxyphenyl)-1H- indoles. The new compounds are structurally related to the known indole-based antioxidant lead compou

Full text of DOI:10.1016/j.bmcl.2013.02.090

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2671–2674
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antioxidant properties of substituted
2-phenyl-1H-indoles
b,
Cigdem Karaaslan a,b, Hachemi Kadri b, Tulay Coban c, Sibel Suzen a, , Andrew D. Westwell
⇑
⇑
a Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University, 06100 Tandogan, Ankara, Turkey
b School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB Wales, UK
c Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Ankara University, 06100 Tandogan, Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, we report the design, synthesis and antioxidant activity of a series of substituted 2-(4-ami-
nophenyl)-1H-indoles and 2-(methoxyphenyl)-1H-indoles. The new compounds are structurally related
to the known indole-based antioxidant lead compound melatonin (MLT), and the antitumour 2-(4-ami-
nophenyl)benzothiazole and 2-(3,4-dimethoxyphenyl)benzothiazole series. Efficient access to the target
2-phenylindoles was achieved via Fischer indole synthesis between substituted phenylhydrazines and
acetophenones. 2-(4-Aminophenyl)indoles (such as the 6-fluoro analogue 3b) in particular showed
potent antioxidant activity in the DPPH and superoxide radical scavenging assays (80% and 81% inhibition
at 1 mM concentration of 3b, respectively), at a level comparable with the reference standard MLT (98%
and 75% at 1 mM).
Received 18 December 2012
Revised 16 February 2013
Accepted 20 February 2013
Available online 1 March 2013
Keywords:
Antioxidant
Indoles
Melatonin
Ó 2013 Elsevier Ltd. All rights reserved.
The design of small molecule agents to combat cellular oxida-
tive stress has become an important therapeutic objective, given
the wide-ranging damage to cellular macromolecules caused by
reactive oxygen (and reactive nitrogen) radical species (ROS). Oxi-
dative stress that gives rise to generation of ROS and related radi-
cals has been associated with a wide range of diseases including
those of cardiovascular, inflammatory, neurodegenerative and
autoimmune origin.1 The naturally occurring hormone melatonin
(N-acetyl-5-methoxytryptamine, Fig. 1) has been known since
1993 as a potentially useful lead compound due to its wide-rang-
ing free radical scavenging and antioxidant properties,2,3 in addi-
tion to its common use for controlling circadian rhythms that
regulate the sleep-wake cycle.4
R1
R2
MeO
HN
O
N
H
N
H
Melatonin
Antioxidant 2-phenylindoles
(R1 = H, CHO; R2 = Cl, OH, NO2, NH2)
OMe
F
F
N
S
N
(CH2)4 NH2
NH
OMe
S
.2HCl
NH2
O
Phortress
PMX 610
Figure 1. Antioxidant and antitumour lead compounds relevant to this study.
Melatonin (MLT) represents one example amongst many indole-
based compounds with therapeutic activity; other indole deriva-
tives with notable biological activity include antitumour agents,
particularly modulators of tubulin dynamics.5 A number of studies
have been published on the discovery of melatonin analogues,
mainly designed to improve free radical scavenging antioxidant
properties,6–12 including 2-phenylindoles that have particular rele-
vance to the present study (Fig. 1).13 Previous studies have estab-
lished that both the methoxy and amide side chains of MLT
contributeto the antioxidantactivity of MLT in addition to the indole
reported to possess inhibitory activity against lipid peroxidation
(ex vivo) and DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical
scavenging ability,13 provided the starting point for this study.
Substituted 2-(4-aminophenyl)benzothiazoles were found to
possess potent and selective antitumour activity within certain
in vitro and in vivo cancer cell models containing inducible
cytochrome P450 1A1,14–18 culminating in the identification of
the 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole prodrug
Phortress (Fig. 1) as a clinical trial candidate.19,20 The related 2-
(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, Fig. 1)
was also found to possess potent and selective antitumour activ-
ity;21 extension of this work to related 2-phenyl-benzoxazoles22
and -benzimidazoles23 led to antitumour agents with lower
potency.
ring. 2-(4-Aminophenyl)-1H-indole,
a
compound previously
⇑
Corresponding authors. Tel.: +90 312 203 3074 (S.S.); tel.: +44 2920 875800
(A.D.W.).
E-mail addresses: sibel@pharmacy.ankara.edu.tr (S. Suzen), WestwellA@cf.ac.uk
(A.D. Westwell).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.090

2672
C. Karaaslan et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2671–2674
Given the previously reported moderate antioxidant properties
reference standard MLT. For example, compounds 3b–h showed
similar activity to MLT particularly at the 1 mM test concentration
(well in excess of 50% inhibition). In general the 2-(methoxy-
phenyl)indole derivatives (3i–p) and 2-(4-nitrophenyl)indole com-
pound (3q) showed lower antioxidant activity at the test
concentrations (1 mM and 0.1 mM) compared to MLT.
The results of the superoxide radical scavenging assay revealed
some potent novel compounds. In particular, compound 3b pre-
sented a higher level of radical scavenging (81% inhibition at
1 mM) compared to reference compound MLT (75% inhibition at
1 mM) at the two concentrations studied, while 3i was found to have
a similar activity and 3j–m showed moderate inhibitory activity.
Among the 2-(4-aminophenyl)indole derivatives, only the 6-fluoro
analogue 3b was very active, whilst among the (methoxy-
phenyl)indole derivatives, a number of compounds (3i–m) showed
moderate to high superoxide anion scavenging activity. There re-
mains the possibility that MLT or the active indole analogues inhibit
xanthine oxidase directly, in turn reducing superoxide radical for-
mation by an alternative mechanism; however further experimental
studies would be required to test this hypothesis.
In the lipid peroxidation assay, the newly synthesized 2-phen-
ylindole analogues showed rather weaker inhibitory effects on
MDA formation at the test concentrations. In general, the 2-(4-ami-
nophenyl)indole compounds 3b–h containing Cl, F and OCH3
groups on the indole ring showed moderate activity in the lipid
peroxidation assay. Activity of 2-(4-aminophenyl)indoles was
comparable with the previously reported inhibitory activity of
compound 3d (26% at 1 mM in this study), although activities were
lower than reference compound MLT. However compounds 3i–p
containing (methoxyphenyl) groups or 2-(4-nitrophenyl)indole
3q showed weak lipid peroxidation inhibitory activity.
Overall the most active compound across the three antioxidant
assays was found to be 2-(4-aminophenyl)-6-fluoro-1H-indole
(3b), with radical scavenging activities at a similar level to MLT,
as judged by the DPPH and superoxide radical scavenging assays.
In general, most of the substituted 2-(4-aminophenyl)-1H-indoles
(particularly 3b–h) displayed higher levels of antioxidant activity
compared to their 2-(methoxyphenyl)indole counterparts.
In our earlier studies various modifications were made on MLT
and many significant antioxidant results were obtained.8,9,12,13
However the effect of the methoxy group still remains unclear. In
this study replacement of the 5-methoxy group of MLT by F, Cl
or H did not increase the antioxidant activity significantly except
in the case of 3b. Similar to our earlier findings8,13 and those of
Poeggeler et al.,31 2-(4-aminophenyl)-5-methoxyindole (3h)
showed lower antioxidant activity overall activity compared to
MLT.
of 2-(4-aminophenyl)-1H-indole,13 and the exciting biological
properties associated with the structurally related 2-(4-aminophe-
nyl)- and 2-(3,4-dimethoxyphenyl)-benzothiazoles, we have
herein prepared and studied the antioxidant properties of a series
of 2-phenyl-1H-indole derivatives (eight of which are novel com-
pounds). Our chosen 2-phenylindole substitution patterns are here
based on the known antitumour fluorinated 2-(4-aminophe-
nyl)benzothiazole and 2-(3,4-dimethoxyphenyl)benzothiazole
series.
Substituted 2-phenyl-1H-indoles (3a–q) were prepared via the
acetic acid-promoted Fischer indole synthesis24 between substi-
tuted -phenylhydrazines (1a–g) and -acetophenones (2a–f) in
refluxing ethanol (Scheme 1), followed by heating with polyphos-
phoric acid (PPA).25 Purification by column chromatography gave
the required 2-phenylindoles26 in low to moderate yields
(10–74%). For the 4-substituted phenylhydrazine starting materi-
als (1a, d, f and g) the synthetic method resulted in a single regio-
isomer of 2-(4-aminophenyl)-1H-indole product (3a, 3e, 3h, 3j,
3m, 3n, 3o, 3p and 3q). However in the case of the 3-chlorophen-
ylhydrazine starting material 1e (but not 3-fluorophenylhydrazine
1b), cyclisation of the intermediate enamine to either of the two
positions ortho to nitrogen resulted in a regioisomeric mixture of
products (3f and 3g) that required careful separation by column
chromatography. For the reaction sequence starting with 2-fluor-
ophenylhydrazine (1c), cyclisation and subsequent aromatisation
resulted in the 7-fluoroindole product (3c) plus unsubstituted
2-(4-aminophenyl)-1H-indole (3d) via fluoride displacement, fol-
lowing chromatographic separation.
Three different in vitro assays, previously described and estab-
lished by Süzen and co-workers,6–13 were carried out to assess the
antioxidant capacity of the newly synthesised compounds, using
MLT as a positive control. The results of the antioxidant test assays
are shown in Table 1. Initially, the free radical scavenging activities
of indole derivatives were tested by their ability to bleach the sta-
ble radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) at 517 nm.27
Compounds were also tested spectrophotometrically for their abil-
ity to scavenge xanthine/xanthine oxidase generated superoxide
anion formation, as measured by the nitroblue tetrazolium (NBT)
reduction method.28,29 Assessment of hydroxyl radical formation
in vivo was carried out by measuring the ability of the indole ana-
logues to inhibit malondialdehyde (MDA) formation through lipid
peroxidation, as detected using thiobarbituric acid.30 Unsubstitut-
ed 2-phenyl-1H-indole (commercially available) was initially
tested as a reference compound but found to be completely inac-
tive in our test assays. All data were recorded as the average of
at least triplicate analyses, and full protocols for the antioxidant
assays can be found in the Supplementary data.
The mechanism by which the indole ring interacts with reactive
species is still not entirely understood. Although it is thought that
melatonin interacts with free radicals by donation of an electron to
form the melatoninyl cation radical through a radical addition at
Free radical scavenging abilities of the new 2-phenylindole
derivatives as determined by the DPPH assay revealed a number
of compounds with inhibitory activity approaching that of the
O
R
R'
3
a
R
R'
3
i
j
k
l
m
NHNH2
+
R'
(i), (ii)
4-NH2
4-NH2
4-NH2
4-NH2
4-NH2
4-NH2
4-NH2
4-NH2
5-F
6-F
7-F
H
5-F
H
H
5-F
3,4-diOMe
3,4-diOMe
4-OMe
3,4,5-triOMe
3,4,5-triOMe
4-OMe
H3C
R
R
R'
b
c
d
e
f
N
H
1a-g
2a-f
3a-q
H
5-Cl
1
R
2
a
b
c
d
R'
4-NH2
4-Cl
n 5-F,7-Cl
a
b
c
4-F
g
h
6-Cl
o 5-F,7-Cl 3,4-diOMe
3-F
3,4-diOMe
5-OMe
p
5-F
3,F,4-OMe
4-NO2
2-F
4-Cl
4-OMe
q 5-F,7-Cl
d
e
3,4,5-triOMe
3,F,4-OMe
4-NO2
3-Cl
e
f
Reagents: (i) AcOH (catalytic), EtOH, reflux; (ii) polyphosphoric acid,120oC
f
4-OMe
2-Cl,4-F
g
Scheme 1. Synthesis of substituted 2-phenyl-1H-indoles 3a–q. Reagents: (i) AcOH (catalytic), EtOH, reflux; (ii) polyphosphoric acid, 120 o
C

C. Karaaslan et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2671–2674
2673
Table 1
Antioxidant activity of synthesised 2-phenylindole derivatives, represented as % mean inhibition
Compounda
Melatonin
Concn. (mM)
DPPH assayb
Superoxide radical scavenging assayb
Lipid peroxidation assayb
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
0.1 mM
1 mM
98
81
28
18
80
65
77
43
74
43
70
23
69
44
77
50
85
69
2
3
2
3
2
2
3
2
2
2
4
1
2
3
5
3
2
2
75
19
35
20
81
35
23
4
3
2
1
2
2
3
85
45
19
17
35
22
30
26
26
13
31
30
30
30
35
35
42
33
3
3
2
2
3
3
3
3
4
3
2
3
2
2
2
3
3
3
3a
3b
3c
3d
3e
3f
15 0.5
30
16
22
NA
18
NA
20
17
35
2
2
3
2
3g
3h
3i
3
2
3
14 0.5
70 3.5
12 2.1
51 4.2
NA
43 2.8
12 1.4
42 3.5
q13 0.7
50 4.2
44 0.7
12 2.1
21 0.7
2.0 1.4
38 2.8
6.0 1.4
35 3.5
9.0 2.1
23 1.4
3.0 0.7
NA
NA
10 2.8
NA
NA
NA
27 4.2
13 1.4
24 0.7
10 1.4
24 2.1
14 3.5
28 2.8
33 2.8
19 3.5
10 2.1
33 1.4
6.0 1.4
24 2.8
13 0.7
13 2.1
7.0 1.4
20 3.5
5.0 1.4
3j
3k
3l
3m
3n
3o
3p
3q
9
0.7
32 2.1
NA
39 1.4
NA
NA
NA
0.1 mM
1 mM
0.1 mM
1 mM
5.0 0.7
NA
39 2.1
NA
0.1 mM
a
Compound was dissolved in DMSO (solvent expressed no antioxidant activity).
Values are means standard deviation (n P3). NA = No Activity.
b
_
C3, other possibilities include hydrogen donation from the nitro-
gen atom or substitution at position C2, C4 and C7 on the indole
ring.3,32 It is possible that the 4-aminophenyl side chain may help
the formation of an indolyl cation radical during scavenging free
radicals in the in vitro assays. Results showed that for antioxidant
activity of melatonin analogue indole derivatives, both the indole
ring and side chain are important. These results suggest a new ap-
proach for the in vitro antioxidant activity properties and structure
activity relationships of substituted indole rings.
Scientific and Technological Research Council of Turkey (TÜBITAK),
Research and Development Grant 109S099.
Supplementary data
Supplementary data (compound characterization data (3a–q);
detailed protocols for antioxidant test assays) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.bmcl.2013.02.090.
Oxidative stress may initiate molecular events in the cancer for-
mation, and reduction of oxidative stress may protect against car-
cinogenesis.1 The new compounds synthesized herein are
structurally related to the known indole-based antioxidant lead
compound melatonin (MLT) and the antitumour 2-(4-aminophe-
nyl)benzothiazole and 2-(3,4-dimethoxyphenyl)benzothiazole ser-
ies. The lead compounds emerging with the most potent
antioxidant activity in this study (such as 3b, 3h and 3i) will be fur-
ther structurally modified towards the discovery of a compound
with optimal combined antioxidant and anticancer activities.
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appropriate substituted phenylhydrazine (1a–g, 1.0 mmol) and substituted
acetophenone (2a–f, 1.0 mmol) were mixed in ethanol (20 mL) and a few drops
of glacial AcOH were added. The solution was heated under reflux at 80 °C for
1–2 h. The solvents were evaporated in vacuo to give a solid that was added to
polyphosphoric acid (PPA) (30 mL), and the mixture slowly heated to 120 °C
and kept at this temperature for a few hours until the reaction was complete
(TLC monitoring). The mixture was allowed to cool and then poured into cold
water (50 mL). The acidic solution was neutralised by the slow addition of 1 M
NaOH (aq) and the solid precipitate of crude product was collected. Purification
26. Representative characterization data: (a) 2-(4-Aminophenyl)-5-fluoro-1H-indole
(3a).13 (74% yield). Mp 196–199 °C; 1H NMR (500 MHz, DMSO-d6) d 11.27 (1H,
s, indole-NH), 7.52 (2H, d, J = 8.5 Hz, H-20, H-60), 7.29 (1H, dd, J = 8.6, 4.7 Hz, H-
7), 7.17 (1H, dd, J = 10.1, 2.5 Hz, H-4), 6.82 (1H, dt, J = 9.2, 2.6 Hz, H-6), 6.64
(2H, d, J = 8.5 Hz, H-30, H-50), 6.57 (1H, s, H-3), 5.32 (2H, s, NH2); 13C NMR
(125 MHz, DMSO-d6) d 157.11 (d, J = 230.1 Hz, C-5-indole), 148.70, 141.18,
133.29, 129.32 (d, J = 10.5 Hz), 126.18, 119.47, 113.93, 111.40 (d, J = 9.7 Hz, C-
7-indole), 107.98 (d, J = 25.8 Hz), 103.66 (d, J = 23.5 Hz), 95.69 (d, J = 4.5 Hz, C-
3-indole); MS (EI+), m/z (%) 226.09 (100) (M+), 198.07 (18). (b) 2-(3,4-
Dimethoxyphenyl)-5-fluoro-1H-indole (3j). Yellow solid, 55% yield. 1H NMR
(500 MHz, DMSO-d6) d 11.51 (1H, s, indole-NH), 7.45 (1H, d, J = 2.0 Hz, H-20),
7.38 (1H, dd, J = 8.5, 2.0 Hz, H-60), 7.36 (1H, dd, J = 9.0, 5.0 Hz, H-7), 7.25 (1H,
dd, J 10.0, 2.5 Hz, H-4), 7.04 (1H, d, J = 8.5 Hz, H-50), 6.90 (1H, dt, J 9.0, 2.5 Hz, H-
6), 6.81 (1H, s, H-3), 3.87 (3H, s, OCH3), 3.80 (3H, s, OCH3); MS (ESI+), m/z 272.1
(M++1). Anal. calcd. for C16H14FNO2; C, 70.84; H, 5.20; N, 5.16; found C, 70.82;
H, 5.10; N, 5.17.
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