Antibacterial activity of a novel series of 3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione derivatives - An extended structure-activity relationship study

Article abstract of DOI:10.1016/j.ejmech.2007.05.009

Compounds containing 3-bromo-2,5-dihydro-1H-2,5-pyrroledione and indole substructures were found to have antibacterial activity against resistant strains of Staphylococcus aureus and some other Gram positive bacteria. The investigated compounds exhibit mi

Full text of DOI:10.1016/j.ejmech.2007.05.009

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 633e656
http://www.elsevier.com/locate/ejmech
Original article
Antibacterial activity of a novel series
of 3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione
derivatives e An extended structureeactivity relationship study
a
a
Siavosh Mahboobi a, , Emerich Eichhorn , Matthias Winkler ,
*
Andreas Sellmer a, Ute Mollmann b
¨
a Department of Pharmaceutical Chemistry I, University of Regensburg,
D-93040 Regensburg, Germany
b Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute,
Department of Molecular and Applied Microbiology, 07745 Jena, Germany
Received 13 April 2007; received in revised form 14 May 2007; accepted 24 May 2007
Available online 3 June 2007
Dedicated to Professor Wolfgang Wiegrebe on the occasion of his 75th birthday.
Abstract
Compounds containing 3-bromo-2,5-dihydro-1H-2,5-pyrroledione and indole substructures were found to have antibacterial activity against
resistant strains of Staphylococcus aureus and some other Gram positive bacteria. The investigated compounds exhibit minimal inhibition con-
centrations (MICs) lower than those of common antibiotics like vancomycin or ciprofloxacin. Activity against multiresistant strains suggests
a mechanism of action different from common antibiotics. This might be important in circumventing existing resistance mechanisms. Here
we report about the antibacterial activity in an extended structureeactivity relationship study.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: SAR study; Antibacterial compounds; Indole derivatives; Resistance of Staphylococcus aureus
1. Introduction
diseases a global challenge. In many countries, an increasing
number of clinical isolates of multiresistant Staphylococcus
aureus strains have been observed and the pathogenetic poten-
tial in nosocomial and community acquired infections is well
known [2].
The incidence of infections caused by multidrug-resistant
Gram positive bacteria is increasing despite advances in anti-
bacterial therapy over the last decades. As the pathogens caus-
ing these infections are frequently resistant to most currently
available antibacterials, they are extremely difficult to treat.
Almost all bacteria treated with antibiotics have developed
at least some degree of resistance against these drugs [1].
The emergence of high levels of penicillin resistance followed
by the evolvement and spread of strains resistant to the semi-
synthetic penicillins (methicillin, nafcillin, and oxacillin),
macrolides, tetracyclines, aminoglycosides and glycopeptides
(e.g., vancomycin) has made therapy of staphylococcal
Indole-substituted pyrrolediones like, for example, arcyriar-
ubin A (see Fig. 1) and related compounds, in which one in-
dole substituent can be replaced by various heterocycles,
show high antimicrobial and antiviral activity and are potent
protein kinase C inhibitors [3,4]. Recently we reported on
the antimicrobial activity of indole-substituted 2,5-dihydro-
1H-2,5-pyrrolediones developed by our group [5]. These
compounds are derivatives of the lead structure 3-bromo-
4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione (Fig. 2)
with variable substituents in the indole-2-position. In the pres-
ent work we demonstrate the results of the biological activity
of more substances of this class of compounds with substitu-
tions in indole 2,5- and/or 2,7-position.
* Corresponding author. Tel.: þ49 941 9434824; fax: þ49 941 9431737.
E-mail address: siavosh.mahboobi@chemie.uni-regensburg.de (S. Mahboobi).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.05.009

634
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
H
N
1) 2 eq. BuLi, hexane,
O
CH3
NH2
O
2) THF, -78°C
N
H
O
OR1
OR1
N
H
O
N
1a-g
2a-g
H
Scheme 1. Formation of 2-alkyloxyphenyl indoles according to Smith et al.
[6,7].
Fig. 1. Arcyriarubin A.
2. Chemistry
available dicarboxylic acid monoesters or monoester halides
29aee and the respective anilines 30aed. These estereani-
lides (31aeh; 31f and 31g are commercially available [13])
had to be N-metallated with n-BuLi before being reacted
with Li2TMSOT. Otherwise, the amide H protonates the
Li2TMSOT, regenerating its methyl group and so preventing
the indole formation. Therefore, we added 1 eq of n-BuLi at
ꢀ78 ꢁC before we added the Li2TMSOT suspension. Using
this procedure, we got the desired indoles 32aeh.
To couple dibromomaleinimide with the respective indole,
we first protected the NH-group with TBS (tert-butyldimethyl-
silyl) by stirring a solution of dibromomaleinimide, TBSCl
and NEt3 in dichloromethane for 1 h at room temperature
[14]. To form the bond between the indole and the pyrroledione,
we lithiated the 3-position of the respective indole with lithium
hexamethyldisilazane (LiHMDS). The reaction of the lithiated
indole and TBSedibromomaleinimide led to silyl-protected
products, which we isolated as raw materials (mixture of pro-
tected and unprotected products and remaining indoles). After
removal of the silyl-protecting group by tetrabutylammonium
fluoride, we could easily isolate the final products (Scheme 5).
The preparation of the investigated compounds comprises
two main steps. In the first step we prepared a substituted in-
dole. The second step was the condensation of dibromomalei-
nimide with the respective indole.
Indoles 2aeg (Scheme 1) and 32aeh (Scheme 5) were pre-
pared analogous to Smith et al. [6,7]. The 4-alkoxybenzoic
acid methylesters 1aeg used for the synthesis of 2aeg were
obtained following the literature methods [8]. Thus, in analogy
to the protocols of Smith et al. [6,7], N-trimethylsilyl-u-tolu-
idine (TMSOT) was lithiated with 2 eq of n-BuLi leading to
metallation at the NHeSie and the methyl group. Reaction
of the bis-lithiated Li2TMSOT at ꢀ78 ꢁC with the respective
carboxylic acid esters 1aeg gave the desired 2-substituted in-
doles 2aeg [6,7] (Table 1).
In order to produce the indoles 8aef, 9aee, 14aef, 15aef,
20aed and 21aee we followed Bowden et al. [9] Thus, we ob-
tained the suitable substituted u-bromoacetophenones (4aec)
by bromination of the respective acetophenones (3aec) with
Br2/HBr [10]. The anilines 5aef used were prepared accord-
ing to well known methods [11], or were commercially avail-
able (5ger) (Fig. 3). The indoles were obtained by stirring
a mixture of dimethylaniline, xylene, the respective u-bro-
moacetophenone and the respective aniline for 24 h at
150 ꢁC. To form the indoles 8aef, 14aef and 20aed, we
used u-bromoacetophenone (4a). Compounds 9aee, 15aef
and 21aee were prepared from u-bromo-4-methoxyacetophe-
none (4b) (Scheme 2) [9].
3. Pharmacology
3.1. General antimicrobial properties
The synthesized compounds were tested against the Gram
positive bacteria Bacillus subtilis (ATCC 6633), Mycobacte-
rium vaccae (IMET10670), Mycobacterium aurum (SB 66),
Mycobacterium fortuitum B, Mycobacterium smegmatis SG
987, S. aureus SG 511, the multiresistant epidemic strains S.
aureus 134/93 [15] and S. aureus 994/93 [16] and the vanco-
mycin resistant Enterococcus faecalis 1528 [17]. The com-
pounds had good activities against the S. aureus strains but
The formation of the indoles 26aeh was performed in anal-
ogy to the protocols of Bischler et al. by stirring a mixture of
u-bromo-3-methoxyacetophenone (4c) and the respective an-
ilines (5ael) in DMF for 2 h at 150 ꢁC (Scheme 3) [12].
We got another series of indoles (32aeh) by linking
a substituted anilide substructure to the indole-2-position by
an alkyl spacer (Scheme 4). We had to modify Smith’s method
to form the spacer linked indoleeanilides 32aeh [6,7]. Thus,
we prepared the anilides 31aeh from the commercially
Table 1
Substitution patterns of compounds 2aeg
N
H
H
N
O
O
R1
Nr.
R1
Nr.
R1
Br
2a
2b
2c
2d
OMe
OBu
2e
2f
ODec
OBenz
N
H
OPen
OOct
2g
O-CH2eNaph
Fig. 2. Lead structure for the synthesized compounds.

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
635
NH2
NH2
O
NH2
O
R1
Br
R1
NH2
R1
R1
O
4c
R1
N
H
5m: R1 = Me
5n: R1 = Et
5o: R1 = Prop
5p: R1 = Bu
5q: R1 = Pent
5r: R1 = Hex
5g: R1 = Me
5h: R1 = Et
5i: R1 = Prop
5j: R1 = Bu
5k: R1 = Pent
5l: R1 = Hex
DMF
5a: R1 = Me
5b: R1 = Et
5c: R1 = Prop
5d: R1 = Bu
5e: R1 = Pent
5f: R1 = Hex
O
5a-l
26a-h
Scheme 3. Formation of the substituted indoles according to Bischler et al.
[12].
Fig. 3. Anilines used for indole synthesis.
error, estimated from the dilution steps used in the antimicro-
bial tests (see Section 6), is
only moderate activities against the other Gram positive bac-
teria. The compounds had no activity against the Gram nega-
tive bacterium Escherichia coli and the fungus Candida
albicans (data not shown). As a reference antibiotic we used
ciprofloxacin.
DpMIC ¼ ꢂ0:3
ð4Þ
The Eqs. (2) and (3) allow the calculation of expected MIC
values for every substance under the presumption that the MIC
is influenced only by the activity of the structural elements in
the lead structure and the pharmacokinetical properties of the
material.
The factor D describes the deviation of an observed pMIC
(pMIC(obs)) to the value expected from the log(P) functions
(Eq. (2)) or (Eq. (3)) (pMIC(cal)), that is
3.2. Structureeactivity relationship for S. aureus 134/93
and M. smegmatis SG 987
In our earlier investigations [5] we showed that the com-
pounds with the 3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione lead structure (Fig. 2) clearly exhibit a
structureeactivity relationship between their hydrophobic
properties and their activity against S. aureus 134/93 and M.
smegmatis SG 987.
D ¼ pMICðobsÞ ꢀ pMICðcalÞ
ð5Þ
The MICs of the novel compounds investigated vs. S.
aureus 134/93 and their D value to calculated MICs are listed
in Table 2.
We defined
The results shown in Table 2 demonstrate that the com-
pounds 7aeg substituted in 2-position, except for 7d and 7e,
show antibacterial activities in a submicromolar range. The ac-
tivity decreases with increasing chain length of the alkyloxy
substituents, 7d and 7e have either weak or no activity against
S. aureus 134/93. The antibacterial activities of the com-
pounds 12aef are not uniform. The activities of 12a, 12c
and 12d are within experimental error consistent with ex-
pected values of the log(P) function (Eq. (2)). The compounds
pMIC ¼ ꢀlogðMIC=mol=lÞ
ð1Þ
and found a linear correlation between pMIC and log(P). P is
the partition coefficient of the compound in the n-octanol/
water system and describes the hydrophobic properties of a
compound. Linear regression led to the function
pMIC ¼ 0:79 logðPÞ þ 3:87
ð2Þ
for the activity of the compounds against S. aureus 134/93 and
NH2
pMIC ¼ 1:63 logðPÞ þ 0:57
ð3Þ
O
X
O
HN
C
C
R3
for the activity of the compounds against M. smegmatis SG
987 with a correlation coefficient of 94%. The experimental
R3
n
n
H2
H2
MeO
O
MeO
O
29a,b,d,e:
30a: R3 = H
31a-h
30b: R3 = 4-Me
30c: R3 = 3-Me
30d: R3 = 2-Me
n = 2,3,5,6; X = Cl
29c: n = 4; X = OH
O
Br
R2
4a,b
O
R1
N
H
R1
NH2
R3
N
H
N
H
Xylene, DMA
R2
n
8a-f, 9a-e, 14a-f, 15a-f,
20a-d, 21a-e
5a-r
32a-h
Scheme 4. Formation of the substituted indoles according to Smith et al. [6,7].
Scheme 2. Formation of the substituted indoles according to Bowden et al. [9].

636
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
H
N
t
TBS
N
O
ClSiMe2 Bu
O
O
O
5
DCM/ NEt3
Br
Br
Br
Br
TBS
N
TBS
N
TBS
N
O
O
O
O
O
O
Br
Br
Br
R1
N
N
N
H
H
H
R2
O
NH
R2
R3 = H:
10a-f, 11a-e, 16a-f, 17a-f
22a-d, 23a-e, 27a-h
R3
6a: R2 = OMe
6b: R2 = OBu
6c: R2 = OPen
6d: R2 = OOct
6e: R2 = ODec
6f: R2 = OBenz
6g: R2 = ONaph
33a: n = 2
33b: n = 3
33c: n = 4
33d: n = 5
33e: n = 6
33f: R3 = 4-Me, n = 3
33g: R3 = 3-Me, n = 3
TBAF,
THF
TBAF,
THF
TBAF,
THF
H
N
H
N
H
N
O
O
O
O
O
O
Br
Br
Br
R1
N
N
H
N
H
H
R2
O
NH
R2
7a: R2 = OMe
7b: R2 = OBu
7c: R2 = OPen
7d: R2 = OOct
7e: R2= ODec
7f: R2 = OBenz
7g: R2 = ONaph
12a-f, 13a-e, 18a-f, 19a-f
24a-d, 25a-e, 28a-h
R3
R3 = H:
34a: n = 2
34b: n = 3
34c: n = 4
34d: n = 5
34e: n = 6
34f: R3 = 4-Me, n = 3
34g: R3 = 3-Me, n = 3
Scheme 5. Reaction with dibromomaleinimide.
12b, 12e and 12f exhibit a significant weaker activity as ex-
pected. In the case of 12e and 12f the weak solubility of the
materials in the test medium might contribute to the low
activities. Compounds 13aee show increasing activities with
increasing length of the alkyloxy chain, except for 13d and
13e, which precipitated in the test medium due to low solubil-
ity. Compounds 18aee and 19aee having alkyl substituents
instead of alkyloxy substituents, demonstrate antibacterial
activity in a submicromolar range. Their activities decrease
with increasing substituents. Compounds with small substitu-
ents like 18a, 18b, and 19a show much stronger activities as
expected from Eq. (2). The compounds 24aed and 25aee
with various alkyl substituents in 7-position of the indole
show increasing activities against S. aureus with increasing
length of the alkyl substituents. These activities, however,
are much weaker than expected from Eq. (2). The activities

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
637
Table 2
Activity of compounds against Staphylococcus aureus 134/93
H
N
O
O
Br
R1
N
H
R2
Nr.
R1
R2
MIC mgꢀ1 mlꢀ1
MIC 10ꢀ6 M
pMIC
D
Log(P)
7a
7b
H
4-OMe
4-OBu
4-OPen
4-OOct
4-ODec
4-OBzl
4-ONaph
H
0.13
0.2
0.32
0.45
0.88
50
6.5
6.3
6.1
4.3
n.d.
6.7
5.8
6.0
5.4
6.0
6.9
4.6
n.d.
5.7
6.4
7.0
n.d.
n.d.
6.9
6.9
6.3
6.6
6.0
n.d.
6.9
6.6
6.3
6.4
6.1
n.d.
5.4
5.7
6.6
6.3
5.7
6.3
6.3
6.6
6.4
5.7
5.5
5.5
4.9
6.6
6.3
5.5
4.6
0.7
2.42
3.87
4.20
5.21
5.94
3.30
3.76
2.48
2.77
3.16
3.42
3.75
4.08
2.77
3.12
3.43
3.77
4.10
2.88
3.15
3.43
3.74
4.07
4.39
2.85
3.23
3.45
3.83
4.10
n.d.
H
ꢀ0.6
ꢀ1.1
ꢀ3.7
n.d.
7c
7d
H
0.4
H
25
7e
H
n.d.
0.1
n.d.
7f
7g
H
0.21
1.5
0.2
H
0.8
ꢀ1.0
0.2
12a
12b
12c
12d
12e
12f
13a
13b
13c
13d
13e
18a
18b
18c
18d
18e
18f
19a
19b
19c
19d
19e
19f
24a
24b
24c
24d
25a
25b
25c
25d
25e
28a
28b
28c
28d
28e
28f
28g
28h
5-OMe
5-OEt
5-OPr
5-OBu
5-OPen
5-OHex
5-OEt
5-OPr
5-OBu
5-OPen
5-OHex
5-Me
5-Et
0.40
1.56
0.4
1.00
3.80
0.95
0.11
27
H
ꢀ0.6
ꢀ0.3
0.4
H
H
0.05
12.5
n.d.
0.8
H
ꢀ2.3
n.d.
H
n.d.
2.0
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
ꢀ0.3
0.0
0.2
0.44
0.10
n.d.
0.05
n.d.
n.d.
0.05
0.05
0.2
0.4
n.d.
n.d.
n.d.
0.13
0.13
0.50
0.24
0.91
n.d.
0.7
0.5
H
5-Pr
H
ꢀ0.3
ꢀ0.2
ꢀ1.0
n.d.
5-Bu
5-Pen
5-Hex
5-Me
5-Et
H
0.1
0.4
H
H
n.d.
0.05
0.1
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
0.12
0.23
0.45
0.44
0.85
n.d.
0.8
0.2
5-Pr
0.2
0.2
ꢀ0.3
ꢀ0.5
ꢀ1.0
n.d.
5-Bu
5-Pen
5-Hex
7-Me
7-Et
0.4
n.d.
1.56
0.78
0.10
0.20
0.78
0.20
0.20
0.10
0.20
0.8
3.98
2.51
0.25
0.50
2.00
0.50
0.50
0.25
0.40
1.90
3.50
3.30
12.60
0.20
0.50
3.40
26.00
ꢀ1.0
ꢀ0.9
ꢀ0.3
ꢀ0.8
ꢀ0.6
ꢀ0.2
ꢀ0.4
ꢀ0.2
ꢀ0.9
ꢀ0.3
ꢀ0.8
ꢀ1.1
ꢀ2.1
0.3
3.19
3.42
3.88
4.11
3.12
3.35
3.58
3.81
4.27
2.79
2.97
3.46
3.92
3.12
3.35
3.81
4.26
H
7-Bu
7-Pen
7-Me
7-Et
H
H
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
7-Pr
7-Bu
7-Hex
5-OMe
5-OEt
5-OBu
5-OHex
5-Me
5-Et
1.56
1.56
6.25
0.1
0.2
1.56
12.5
ꢀ0.2
ꢀ1.4
ꢀ2.6
5-Bu
5-Hex
(continued on next page)

638
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
Table 2 (continued)
H
N
O
O
Br
N
H
O
NH
R3
Nr.
n
R3
MIC mgꢀ1 mlꢀ1
MIC 10ꢀ6 M
pMIC
D
Log(P)
34a
34b
2
3
4
5
6
3
3
3
H
0.08
0.8
0.18
1.7
6.7
5.8
5.8
7.0
7.0
5.8
6.1
6.5
4.4
0.9
2.42
2.56
2.56
2.68
2.85
2.56
2.56
2.56
2.56
H
ꢀ0.1
ꢀ0.1
1.0
34c
34d
H
0.8
1.7
H
0.05
0.05
0.6
0.10
0.10
1.58
0.79
0.32
38.1
34e
34f
H
0.9
4-Me
3-Me
2-Me
ꢀ0.4
0.0
34g
34h [5]
Ciprofloxacin
0.3
0.15
12.5
0.6
ꢀ
of compounds 21aee with the exception of 21d are nearly par-
allel to the values of Eq. (2) but on a lower level. Compounds
28aeh demonstrate decreasing activity with increasing length
of the respective substituents in 5-position of the indole.
Finally, the compounds 34aeh having a substituted anilide
substructure linked to the indole-2-position by an alkyl spacer
(n-pentyl and n-hexyl spacers), are the most active compounds
in these tests (34d and 34e). The effect of a methylated phenyl
group (34feh) induces highest activity on ortho-methylated
34h which has been described in our previous work [5].
The MIC values compiled in Table 3 demonstrate that most
of our compounds exhibit only moderate activities against M.
smegmatis SG 987, as already observed for analogous com-
pounds in our previous work. Compounds 18aef, 19aef and
28aeh show the best results compared with other related se-
ries. Their activities do not strongly depend on their substitu-
ents. In the homologous series 18aef and 19aef the D values
(Eq. (5)) are decreasing with increasing substituent lengths.
The activities of 28aeh are parallel to the values of Eq. (3)
but on a much lower level. Most of the compounds of series
13aee are inactive against M. smegmatis SG 987.
the improvement of activity caused by a hydrogen-bond ac-
ceptor in this position [5]. The effect of alkoxy substituents
in the indole-5-position is investigated in the series 12aef,
13aee and 28aed. The influence of this structural modifica-
tion is not uniform. In the case of large substituents the results
are influenced by the poor solubility of the compounds. The
influence of alkyl substituents in position 5 of the indole is
shown by the activities of 18aef, 19aef and 28eeh. Small
substituents’ activity is lost, however, with increasing length
of the substituents due to steric obstruction. Alkylation in po-
sition 7 of the indole weakens the activity as demonstrated by
compounds 24aed and 25aee. On an average the activities of
24aed are 10 times lower than that expected from the log(P)
function (Eq. (2)). The effect is not as obvious in compounds
25aee. The positive effect of the hydrogen-bond acceptor in
phenyl-4-position partly neutralizes the negative effect of the
indole-7-alkylation. In our previous work [5] we have investi-
gated a series of compounds having a o-toluide substructure
linked to the indole-2-position by an alkyl spacer. Here we
found that the activity strongly depends on the length of the
alkyl spacer. We observed the best D values with propyl
(34h) and butyl (34c) spacers (pMIC ¼ 6.5 and 6.6, respec-
tively). Other spacers led to activities close to the expected
values of Eq. (2). The activities of the compounds 31aeh
show the influence and importance of the methyl group in
the toluide substructure. Compounds 34aee are a subset of
anilide derivatives without any methyl group in the substruc-
ture. In the case of anilide compounds we find a similar impor-
tance of the spacer as we have observed with the toluide
derivatives. Our most active substances 34d and 34e, however,
have the large pentyl and hexyl group spacers. The activity of
34d and 34e, with pMIC ¼ 7.0 is about 3 times higher than the
most active toluide compound. Compounds 34f and 34g are
equipped with a propyl spacer but have different positions
4. Discussion
In our former work [5] we discussed that derivatives with
the 3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione
(Fig. 2) lead structure show increasing activities against S.
aureus 134/93 increasing with their properties.
The D values (Eq. (5)) show the difference between the ob-
served activity and the activities expected from the log(P)
function (Eqs. (2) or (3)) of the respective compound. The D
values (Eq. (5)) of the phenyl compounds 7aeg may be inter-
preted in a way that voluminous substituents in 4-position
cause a decrease in antibacterial activity which eliminates

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
639
Table 3
Activity of compounds against M. smegmatis SG 987
H
N
O
O
Br
R1
N
H
R2
Nr.
R1
R2
MIC mgꢀ1 mlꢀ1
MIC 10ꢀ6 M
pMIC
D
Log(P)
7a
7b
H
4-OMe
4-OBu
4-OPen
4-OOct
4-ODec
4-OBzl
4-ONaph
H
20
50.12
15.85
125.89
100.00
100.00
25.12
3.16
31.5
30.4
58.8
28.4
27.5
n.d.
4.3
4.8
3.9
4.0
4.0
4.6
5.5
4.5
4.5
4.2
4.5
4.6
n.d.
4.8
n.d.
n.d.
n.d.
n.d.
5.4
5.4
5.4
5.7
5.5
n.d.
5.1
5.4
5.7
5.5
5.5
n.d.
4.5
4.5
4.8
4.9
4.5
4.5
4.8
n.d.
n.d.
4.8
5.2
5.2
5.2
5.1
5.4
5.5
5.2
ꢀ0.2
ꢀ2.0
ꢀ3.5
ꢀ5.1
ꢀ6.2
ꢀ1.3
ꢀ1.2
ꢀ0.1
ꢀ0.6
ꢀ1.5
ꢀ1.6
ꢀ2.0
n.d.
2.42
3.87
4.20
5.21
5.94
3.30
3.76
2.48
2.77
3.16
3.42
3.75
4.08
2.77
3.12
3.43
3.77
4.10
2.88
3.15
3.43
3.74
4.07
4.39
2.85
3.23
3.45
3.83
4.10
n.d.
H
6.25
50
50
7c
7d
H
H
7e
H
50
7f
7g
H
12.5
1.56
12.5
12.5
25
H
12a
12b
12c
12d
12e
12f
13a
13b
13c
13d
13e
18a
18b
18c
18d
18e
18f
19a
19b
19c
19d
19e
19f
24a
24b
24c
24d
25a
25b
25c
25d
25e
28a
28b
28c
28d
28e
28f
28g
28h
5-OMe
5-OEt
5-OPr
5-OBu
5-OPen
5-OHex
5-OEt
5-OPr
5-OBu
5-OPen
5-OHex
5-Me
5-Et
H
H
H
12.5
12.5
n.d.
6.25
n.d.
n.d.
n.d.
n.d.
1.56
1.56
1.56
0.8
H
H
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
14.1
n.d.
n.d.
ꢀ0.2
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
4.1
4.0
0.1
H
ꢀ0.3
ꢀ0.7
ꢀ1.0
ꢀ1.8
n.d.
5-Pr
H
3.8
1.9
5-Bu
5-Pen
5-Hex
5-Me
5-Et
H
H
1.56
n.d.
3.1
3.6
H
n.d.
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
7.6
ꢀ0.1
ꢀ0.4
ꢀ0.4
ꢀ1.3
ꢀ1.7
n.d.
1.56
0.8
3.67
1.8
5-Pr
5-Bu
5-Pen
5-Hex
7-Me
7-Et
1.56
1.56
n.d.
12.5
12.5
6.25
6.25
12.5
12.5
6.25
n.d.
n.d.
6.25
4.69
3.12
3.12
3.12
2.34
2.34
3.12
3.4
3.3
n.d.
32.6
31.7
14.7
14.3
30.4
29.4
14.2
n.d.
ꢀ1.3
ꢀ1.7
ꢀ2.1
ꢀ2.4
ꢀ1.1
ꢀ1.5
ꢀ1.5
n.d.
3.19
3.42
3.88
4.11
3.12
3.35
3.58
n.d.
H
7-Bu
7-Pen
7-Me
7-Et
H
H
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
7-Pr
7-Bu
7-Hex
5-OMe
5-OEt
5-OBu
5-OHex
5-Me
5-Et
n.d.
n.d.
n.d.
15.85
6.31
6.31
6.31
7.94
3.98
3.16
6.31
ꢀ3.6
ꢀ3.8
ꢀ3.8
ꢀ3.8
ꢀ3.8
ꢀ4.0
ꢀ4.0
ꢀ3.8
2.79
2.97
3.46
3.92
3.12
3.35
3.81
4.26
5-Bu
5-Hex
(continued on next page)

640
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
Table 3 (continued)
H
N
O
O
Br
N
H
O
NH
R3
Nr.
n
R3
MIC mgꢀ1 mlꢀ1
MIC 10ꢀ6 M
pMIC
D
Log(P)
34a
34b
2
3
4
5
6
3
3
3
H
9.2
25
21
55
4.7
4.3
4.6
4.6
4.9
4.6
4.6
4.8
5.9
0.2
2.42
2.56
2.56
2.68
2.85
2.56
2.56
2.56
2.36
H
ꢀ0.4
ꢀ0.1
ꢀ0.3
ꢀ0.3
ꢀ0.6
ꢀ0.5
ꢀ0.1
ꢀ
34c
34d
H
12.5
12.5
6.25
12.5
12.5
8.0
26
26
H
34e
34f
H
12.6
27
4-Me
3-Me
2-Me
34g
34h [5]
Ciprofloxacin
27
17.1
1.2
0.4
for the methyl group in the toluide substructure. The test
shows that the o-position favours the activity whereas other
positons do not improve the activity against S. aureus 134/93.
In our previous work [5] we have shown that the influence of
the hydrophobicity of the substances on the antibacterial activity
is about three times higher for M. smegmatis SG 987 than for
S. aureus 134/93. Unfortunately we did not find a structural
modification which additionally increases the activity against
M. smegmatis SG 987. Most of our structural modifications
weaken the activity in respect of the expected values according
to Eq. (3). The 5-alkoxy derivatives with a methoxy group in the
4-position of the phenyl ring (13aef) are in most cases even
inactive against M. smegmatis. We observed activities close to
the expected values of Eq. (3) in the case of methyl and ethyl
substitution in indole-5-position. Larger alkyl groups weaken
the activity. We have also observed hydrophobic control of the
activities at the spacer linked anilide derivatives 34aee. It
should be noted that the same structural modification which
improves the activity against S. aureus 134/93, in the case of
M. smegmatis SG 987 led to activities close to the expected
values of the hydrophobic function (Eq. (3)). As observed ear-
lier, both microorganisms show similar effects in our struc-
ture–activity relationship study.
the toluide substructure along with the elongation of the alkyl
spacer led to three-fold increase of the activity. With those
modifications we could produce compounds with MIC values
of 10ꢀ7 mol/L against S. aureus. Alkylation in position 7 of
the indole and oxyalkylation in position 4 of the phenyl group
in general weakens the activity. In the case of M. smegmatis
SG 987, we found no structural modifications which generally
improved the antibacterial activity. The same modifications
which improve the activity against S. aureus 134/93, as shown
above, led to hydrophobically controlled activities against M.
smegmatis SG 987. As observed in our previous work [5],
the structureeactivity relationship (SAR) was similar for
both microorganisms.
6. Experimental
6.1. Biological testing procedure
Antibacterial activity of the compounds was studied by
determination of minimal inhibitory concentrations (MICs)
according to the NCCLS guidelines [18] using the broth micro-
dilution method [19]. The bacteria were grown overnight at
37 ꢁC in MuellereHinton broth (MHB) (Difco). Fifty microli-
ters of a 2 mM compound solution were serially diluted by fac-
tor 2 with MHB. Then the wells were inoculated with 50 ml of
the test organisms to give a final concentration of 5 ꢃ 105 CFU/ml.
After incubation of the microtiter plates at 37 ꢁC for 24 h, the
MIC values were read with a Nepheloscan Ascent 1.4 auto-
matic plate reader (Labsystems, Vantaa, Finland) as the lowest
dilution of antibiotic allowing no visible growth.
5. Conclusion
In our present work we extended our structureeactivity re-
lationship (SAR) study on substituted indolylemaleinimide
derivatives in order to find structural modifications which in
addition to the hydrophobic property can be used to improve
the antibacterial activity of our compounds against S. aureus
134/93 and M. smegmatis SG 987. For S. aureus 134/93 we
found that alkylation with methyl and ethyl groups in position
5 of the indole generally improved the activity. In the case of
spacer linked indolyl-amides, removal of the methyl group in
6.2. Chemistry
General. NMR spectra were recorded with a Bruker Avance
300 MHz spectrometer at 300 K, using TMS as an internal

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
641
standard, IR spectra (KBr or pure solid) were measured with
a Bruker Tensor 27 spectrometer. Melting points were deter-
mined with a Buchi B-545. MS spectra were measured with
¨
7.35 (d, 1H, J ¼ 7.9 Hz), 7.47 (d, 1H, J ¼ 7.5 Hz), 7.75
(d, 2H, J ¼ 8.7 Hz), 11.38 (s, 1H). EI-MS (70 eV) m/z (%):
ꢄ
265 (88) [Mþ ], 209 (100) [M ꢀ C4ꢄ H8]þ. Anal. (C18H19NO)
a Finnigan MAT 95 (EI, 70 eV), or with a Finnigan Thermo
Quest TSQ 7000 (ES) (DCM/MeOH þ 10 mmol/l NH4Ac).
All reactions were carried out under nitrogen atmosphere. Ele-
mental analyses were performed by the Analytical Lab. of the
University of Regensburg with an average deviation of
ꢂ0.4%. Thin layer chromatography (TLC) was carried out on
Al-sheets coated with 60 F245 silica. Column chromatography
(CC) was performed using Merck 60 (70e230 mesh ASTM) sil-
ica. Solvents and commercially available reagents were dried
and purified before use according to standard procedures.
log(P) valuesweredeterminedusingHPLCretention data. All
compounds were dissolved in methanol and subjected to HPLC.
Column: LiChrospher 100 RP-18 (5 mm) 250 ꢃ 4 mm, Merck
Art. 50983; eluent: methanol/water/acetic acid (80:20:0.1), ad-
justed with ammonia to pH 5.5; flow: 1.00 ml minꢀ1; detection:
254 nm; temperature: 25 ꢁC. From the retention data, the capacity
factor k0 is calculated according to Eq. (6):
C, H, N.
6.2.1.3. 2-(4-Pentyloxyphenyl)-1H-indole (2c). Yield: 0.83 g
(3.0 mmol) from 3.2 g (14.9 mmol) of 1c [21] (21%), brown
crystals, m.p. 200 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3431, 2930,
1609, 1547. 1H NMR (DMSO-d6): d (ppm) ¼ 0.89 (t, 3H,
J ¼ 6.9 Hz), 1.36e1.42 (m, 4H), 1.69e1.75 (m, 2H), 3.99 (t,
2H, J ¼ 6.3 Hz), 6.73 (d, 1H, J ¼ 1.6 Hz), 6.93e7.07 (m,
4H), 7.35 (d, 1H, J ¼ 7.5 Hz), 7.47 (d, 1H, J ¼ 7.1 Hz), 7.75
(d, 2H, J ¼ 8.7 Hz), 11.38 (s, 1H). EI-MS (70 eV) m/z (%):
ꢄ
279 (100) [Mþ ]. Anal. (C19H21NO) C, H, N.
6.2.1.4. 2-(4-Octyloxyphenyl)-1H-indole (2d). Yield: 0.75 g
(2.3 mmol) from 3.8 g (14.4 mmol) of 1d [8] (16%), brown
crystals, m.p. 208 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3438, 2921,
2855, 1547. 1H NMR (DMSO-d6): d (ppm) ¼ 0.86 (t, 3H,
J ¼ 6.7 Hz), 1.20e1.50 (m, 10H), 1.65e1.80 (m, 2H), 3.99
(t, 2H, J ¼ 6.7 Hz), 6.73 (d, 1H, J ¼ 1.6 Hz), 6.93e7.07 (m,
4H), 7.35 (d, 1H, J ¼ 7.1 Hz), 7.47 (d, 1H, J ¼ 7.5 Hz), 7.76
(d, 2H, J ¼ 8.7 Hz), 11.38 (s, 1H). EI-MS (70 eV) m/z (%):
k0 ¼ logððtR=t0Þ ꢀ 1Þ
ð6Þ
ꢄ
321 (100) [Mþ ], 209 (80) [M ꢀ Cꢄ8H16]þ. Anal. (C22H27NO)
where tR ¼ retention time of the compound and t0 ¼ retention
time of methanol. From k0 we have determined log(P) using
a linear function which was calibrated with the following
reference substances: 4-nitrophenol (log(P) ¼ 1.91), 4-chloro-
phenol (log(P) ¼ 2.39), benzophenone (log(P) ¼ 3.18), naph-
thalene (log(P) ¼ 3.44) and anthracene (log(P) ¼ 4.49). We
have carried out two series of determinations, using two differ-
ent specimen of columns and separately mixed eluents. Every
log(P) value, given in tables, is an average value of two esti-
mations. The average deviation was ꢂ0.03 and in no case
larger than ꢂ0.1 log(P) units.
C, H, N.
6.2.1.5. 2-(4-Decyloxyphenyl)-1H-indole (2e). Yield: 0.35 g
(1.0 mmol) from 3.90 g (14.6 mmol) of 1e [8] (7%), brown
crystals, m.p. 212 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3438, 2923,
1
2853, 1609, 1547. H NMR (DMSO-d6): d (ppm) ¼ 0.84 (t,
3H, J ¼ 6.7 Hz), 1.20e1.50 (m, 12H), 1.65e1.80 (m, 2H),
3.99 (t, 2H, J ¼ 6.5 Hz), 6.73 (d, 1H, J ¼ 1.6 Hz), 6.93e7.07
(m, 4H), 7.35 (d, 1H, J ¼ 7.5 Hz), 7.47 (d, 1H, J ¼ 7.5 Hz),
7.76 (d, 2H, J ¼ 9.1 Hz), 11.38 (s, 1H). EI-MS (70 eV) m/z
ꢄ
(%): 349 (100) [Mþ ], 209 (88) [M ꢀ Cꢄ10H20]þ. Anal.
6.2.1. Synthesis of the substituted indoles 2aeg
(C24H31NO) C, H, N.
N-Trimethylsilyl-2-toluidine (TMSOT) was dissolved in
hexane and n-BuLi (2 eq) was added dropwise at ꢀ78 ꢁC. The
solution was stirred to reflux overnight, then the respective
carboxylic acid esters (1aeg) were added dropwise. After stir-
ring to reflux for 7 h, the mixture was cooled with ice water
and the crude product extracted with EE. The extracts were
washed with 0.5 N HCl, dried with Na2SO4 and recrystallized
from DCM.
6.2.1.6. 2-(4-Benzyloxyphenyl)-1H-indole (2f). Yield: 0.36 g
(1.2 mmol) from 3.5 g (15.1 mmol) of 1f [22] (9%), brown
1
crystals, m.p. 220 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3440, 1501. H
NMR (DMSO-d6): d (ppm) ¼ 5.15 (s, 2H), 6.75 (d, 1H,
J ¼ 1.6 Hz), 6.93e7.05 (m, 4H), 7.09 (d, 2H, J ¼ 9.1 Hz),
7.29e7.49 (m, 7H), 7.78 (d, 2H, J ¼ 8.7 Hz), 11.39 (s, 1H).
ꢄ
EI-MS (70 eV) m/z (%): 299 (56) [Mþ ], 208 (100)
[M ꢀ Cꢄ7H7]þ. Anal. (C21H17NO) C, H, N.
6.2.1.1. 2-(4-Methoxyphenyl)-1H-indole [9] (2a). Yield:
11.6 g (52 mmol) from 16.6 g (100 mmol) of 1a [20] (52%),
6.2.1.7. 2-[4-(Naphthalen-1-ylmethoxy)-phenyl]-1H-indole (2g).
Yield: 0.69 g (2.0 mmol) from 4.2 g (14.4 mmol) of 1g [23]
(14%), brown crystals, m.p. 167 ꢁC. IR (KBr): n (cmꢀ1) ¼
3436, 1609, 1501, 1285. 1H NMR (DMSO-d6):
d (ppm) ¼ 5.60 (s, 2H), 6.76 (d, 1H, J ¼ 1.2 Hz), 6.96 (t, 1H,
J ¼ 7.5 Hz), 7.06 (t, 1H, J ¼ 7.5 Hz), 7.19 (d, 2H,
J ¼ 9.1 Hz), 7.37 (d, 1H, J ¼ 7.9 Hz), 7.47e7.62 (m, 3H),
7.70 (d, 1H, J ¼ 7.1 Hz), 7.81 (d, 2H, J ¼ 9.1 Hz), 7.92e8.00
(m, 2H), 8.10e8.14 (m, 1H), 11.42 (s, 1H). EI-MS (70 eV)
1
yellow crystals, m.p. 237 ꢁC. H NMR (CDCl3): d (ppm) ¼
3.80 (s, 3H), 6.72 (s, 1H), 6.98e7.08 (m, 4H), 7.37e7.56
(m, 2H), 7.80 (d, 2H, J ¼ 9 Hz), 11.36 (s, 1H).
6.2.1.2. 2-(4-Butoxyphenyl)-1H-indole (2b). Yield: 0.72 g
(2.7 mmol) from 3.0 g (16.7 mmol) of 1b [21] (16%), brown
crystals, m.p. 211 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3440, 2956, 1609,
1547. 1H NMR (DMSO-d6):
J ¼ 7.3 Hz), 1.37e1.51 (m, 2H), 1.65e1.76 (m, 2H), 3.99 (t,
2H, J ¼ 6.3 Hz), 6.73 (d, 1H, J ¼ 2.0 Hz), 6.93e7.07 (m, 4H),
d
(ppm) ¼ 0.93 (t, 3H,
ꢄ
m/z (%): 349 (36) [Mþ ], 209 (36) [M ꢀ C1ꢄ 1H9]þ, 141 (100)
[Cꢄ11H9]þ. Anal. (C25H19NO) C, H, N.

642
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
6.2.2. Condensation of TBSedibromomaleinimide with
indole derivatives (6aeg, Scheme 5)
6.2.3.4. 3-Bromo-4-[2-(4-octyloxyphenyl)-1H-indole-3-yl]pyr-
role-2,5-dione (7d). Yield: 0.15 g (0.3 mmol) from 0.65 g
(2.0 mmol) of 2d (15%), red crystals, m.p. 185 ꢁC. IR
The respective indoles (2aeg) were dissolved in dry THF
and cooled under argon to ꢀ20 ꢁC. Then LiHMDS (2 eq,
1 M in THF) was slowly added. After stirring for 45 min,
TBSedibromomaleinimide (1 eq) in THF was added within
3 h. The solution was stirred for 15 min, poured into sat. aq.
NH4Cl, extracted with ethyl acetate, dried over Na2SO4 and
concentrated in vacuo. The crude products were processed to
7aeg without further purification.
1
(KBr): n (cmꢀ1) ¼ 3376, 2927, 1719, 1607, 1497. H NMR
(DMSO-d6): d (ppm) ¼ 0.85 (t, 3H, J ¼ 6.7 Hz), 1.2e1.5 (m,
10H), 1.65e1.76 (m, 2H), 3.98 (t, 2H, J ¼ 6.3 Hz), 7.01 (d,
2H, J ¼ 8.7 Hz), 7.08 (t, 1H, J ¼ 7.9 Hz), 7.18 (1H,
J ¼ 7.3 Hz), 7.42 (d, 1H, J ¼ 7.1 Hz), 7.45 (d, 1H,
J ¼ 6.7 Hz), 7.47 (d, 2H, J ¼ 8.7 Hz), 11.31 (s, 1H), 12.01
ꢄ
(s, 1H). EI-MS (70 eV) m/z (%): 494 (100) [Mþ ], 260
(100), Anal. (C26H27BrN2O3) C, H, N.
6.2.3. Removal of the sylil-protecting group to give 7aeg
(Scheme 5)
6.2.3.5. 3-Bromo-4-[2-(4-decyloxyphenyl)-1H-indole-3-yl]pyr-
role-2,5-dione (7e). Yield: 0.115 g (0.22 mmol) from 0.70 g
(2.0 mmol) of 2e (11%), red crystals, m.p. 190 ꢁC. IR (KBr):
The raw silyl-protected indoleemaleinimides (6aeg) were
dissolved in THF under N2 and tetrabutylammonium fluoride
trihydrate (1.3 eq) was added. The mixture was stirred for
2 h, poured into ice, mixed with saturated NH4Cl solution
and extracted with ethyl acetate. The extract was dried
over Na2SO4, the solvent was removed in vacuo and the
remaining oil was purified by CC (DCM) and crystallized
from pentane.
n
(cmꢀ1) ¼ 3378, 2925, 1709, 1609, 1497. 1H NMR
(DMSO-d6): d (ppm) ¼ 0.85 (t, 3H, J ¼ 6.5 Hz), 1.2e1.5 (m,
12H), 1.65e1.76 (m, 2H), 3.98 (t, 2H, J ¼ 6.4 Hz), 7.01 (d,
2H, J ¼ 8.7 Hz), 7.08 (t, 1H, J ¼ 8.1 Hz), 7.18 (1H,
J ¼ 8.1 Hz), 7.43 (d, 1H, J ¼ 6.7 Hz), 7.45 (d, 1H,
J ¼ 6.7 Hz), 7.47 (d, 2H, J ¼ 9.1 Hz), 11.32 (s, 1H), 12.01
ꢄ
(s, 1H). EI-MS (70 eV) m/z (%): 522 (100) [Mþ ], 260 (92),
Anal. (C28H31BrN2O3) C, H, N.
6.2.3.1. 3-Bromo-4-[2-(4-methoxyphenyl)-1H-indole-3-yl]pyrrole-
2,5-dione (7a). Yield: 0.044 g (0.11 mmol) from 0.45 g
(2.0 mmol) of 2a [9] (5%), red crystals, m.p. 200 ꢁC. IR
6.2.3.6. 3-[2-(4-Benzyloxyphenyl)-1H-indole-3-yl]-4-bromo-
pyrrole-2,5-dione (7f). Yield: 0.23 g (0.5 mmol) from 0.6 g
(2.0 mmol) of 2f (25%), red crystals, m.p. 220 ꢁC. IR (KBr):
1
(KBr): n (cmꢀ1) ¼ 3376, 1771, 1721, 1609, 1580, 1495. H
NMR (DMSO-d6): d (ppm) ¼ 3.80 (s, 3H), 7.03 (d, 2H,
J ¼ 9.1 Hz), 7.09 (ddd, 1H, J ¼ 1.1, 7.3 Hz), 7.19 (ddd, 1H,
J ¼ 1.2, 7.1 Hz), 7.43 (d, 1H, J ¼ 7.2 Hz), 7.46 (d, 1H,
J ¼ 9.1 Hz), 7.50 (d, 2H, J ¼ 8.7 Hz), 11.26 (s, 1H), 12.03
n
(cmꢀ1) ¼ 3394, 3054, 1773, 1611, 1495. 1H NMR
(DMSO-d6): d (ppm) ¼ 5.14 (s, 2H), 7.05e7.21 (m, 4H),
ꢄ
7.33e7.51 (m, 9H). EI-MS (70 eV) m/z (%): 472 (28) [Mþ ].
Anal. (C25H17BrN2O3) C, H, N.
ꢄ
(s, 1H). EI-MS (70 eV) m/z (%): 398 (70) [Mþ ]. Anal.
(C19H13BrN2O3) C, H, N.
6.2.3.7. 3-Bromo-4-{2-[4-(naphthalen-1-ylmethoxy)-phenyl]-
1H-indole-3-yl}pyrrole-2,5-dione (7g). Yield: 0.27 g (0.51 mmol)
from 0.7 g (2.0 mmol) of 2g (26%), red crystals, m.p. 220 ꢁC.
6.2.3.2. 3-Bromo-4-[2-(4-butoxyphenyl)-1H-indole-3-yl]pyrrole-
2,5-dione (7b). Yield: 0.28 g (0.63 mmol) from 0.54 g
(2.0 mmol) of 2b (31%), red crystals, m.p. 220 ꢁC. IR
1
IR (KBr): n (cmꢀ1) ¼ 3386, 3241, 1775, 1609, 1495. H NMR
(DMSO-d6): d (ppm) ¼ 5.60 (s, 2H), 7.05e7.22 (m, 4H), 7.41e
7.62 (m, 7H), 7.70 (d, 1H, J ¼ 7.0 Hz), 7.93e8.00 (m, 2H),
8.10 (d, 1H, J ¼ 6.7 Hz). EI-MS (70 eV) m/z (%): 522 (10)
(KBr): n (cmꢀ1) ¼ 3365, 1773, 1709, 1609, 1543, 1495. H
1
NMR (DMSO-d6): d (ppm) ¼ 0.93 (t, 3H, J ¼ 7.3 Hz),
1.37e1.52 (m, 2H), 1.65e1.76 (m, 2H), 4.00 (t, 2H,
J ¼ 6.7 Hz), 7.01 (d, 2H, J ¼ 8.7 Hz), 7.07 (t, 1H,
J ¼ 7.9 Hz), 7.18 (1H, J ¼ 7.5 Hz), 7.42 (d, 1H, J ¼ 7.1 Hz),
7.46 (d, 1H, J ¼ 7.1 Hz), 7.47 (d, 2H, J ¼ 8.7 Hz), 11.32 (s,
ꢄ
[Mþ ], 141 (100) [C1ꢄ 1H9]þ. Anal. (C29H19BrN2O3$1/4pentane)
C, H, N.
6.2.4. Formation of the indoles 8aef and 9aee (Table 4)
The respective anilines (3 eq, 5aef) were dissolved in N,N-
dimethylaniline (DMA) and stirred at reflux in an N2 atmo-
sphere. A solution of 1 eq of 4a or 4b in xylene was added
dropwise to the hot solution and was subsequently stirred at
150 ꢁC for 15 h. The solution was cooled to 0 ꢁC and the precip-
itated crude product was filtered and washed with EE and meth-
anol. The crude product was purified by CC (DCM/EE ¼ 10/1).
ꢄ
1H), 12.01 (s, 1H). EI-MS (70 eV) m/z (%): 438 (68) [Mþ ],
260 (100). Anal. (C22H19BrN2O3) C, H, N.
6.2.3.3. 3-Bromo-4-[2-(4-pentyloxyphenyl)-1H-indole-3-yl]-
pyrrole-2,5-dione (7c). Yield: 0.15 g (0.33 mmol) from
0.56 g (2.0 mmol) of 2c (17%), red crystals, m.p. 200 ꢁC. IR
(KBr): n (cmꢀ1) ¼ 3361, 1773, 1709, 1605, 1495. H NMR
1
(DMSO-d6): d (ppm) ¼ 0.89 (t, 3H, J ¼ 7.1 Hz), 1.36e1.39
(m, 4H), 1.65e1.76 (m, 2H), 3.99 (t, 2H, J ¼ 6.3 Hz), 7.01
(d, 2H, J ¼ 8.7 Hz), 7.08 (t, 1H, J ¼ 7.9 Hz), 7.18 (1H,
J ¼ 7.5 Hz), 7.42 (d, 1H, J ¼ 7.1 Hz), 7.45 (d, 1H,
J ¼ 6.7 Hz), 7.47 (d, 2H, J ¼ 9.1 Hz), 11.25 (s, 1H), 12.01
6.2.4.1. 5-Methoxy-2-phenyl-1H-indole (8a) [9]. Yield: 4.0 g
(18 mmol) from 19.9 g (100 mmol) of 4a and 12.3 g
(100 mmol) of 4-methoxyphenylamine (5a) [24] (18%), col-
1
ourless crystals, m.p. 177e177.5 ꢁC. H NMR (DMSO-d6):
ꢄ
(s, 1H). EI-MS (70 eV) m/z (%): 452 (56) [Mþ ], 260 (100).
d (ppm) ¼ 3.75 (s, 3H), 6.72e7.00 (m, 3H), 7.26e7.64 (m,
Anal. (C23H21BrN2O3) C, H, N.
4H), 7.77e7.87 (m, 2H), 11.30 (s, 1H).

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
643
Table 4
Compounds 8aef, 9aee, 14aef, 15aef, 20aed, 21aee and 26aeh
J ¼ 7.4 Hz), 1.73 (m, 2H), 3.90 (t, 2H, J ¼ 6.5 Hz), 6.73 (dd,
1H, Jo ¼ 8.7 Hz, Jm ¼ 2.4 Hz), 6.78 (d, 1H, J ¼ 1.6 Hz), 7.00
(d, 1H, J ¼ 2.4 Hz), 7.26 (d, 1H, J ¼ 8.7 Hz), 7.29 (d, 1H,
J ¼ 7.5 Hz), 7.43 (m, 2H), 7.81 (d, 2H, J ¼ 7.7 Hz), 11.33 (s,
[M ꢀ Cꢄ3H6]þ. Anal. (C17H17NO) C, H, N.
R1
ꢄ
1H). EI-MS (70 eV) m/z (%): 251 (56) [Mþ ], 209 (44)
N
H
R2
6.2.4.4. 5-Butoxy-2-phenyl-1H-indole (8d). Yield: 3.1 g
(11.7 mmol) from 6.4 g (32.2 mmol) of 4a and 5.3 g
(32.2 mmol) of 4-butoxyphenylamine (5d) [26] (36%), yellow
crystals, m.p. 132 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3453, 2957, 1622,
Nr.
R1
R2
Nr.
R1
R2
8a
8b
8c
8d
8e
8f
OMe
OEt
H
14a
14b
14c
14d
14e
14f
Me
Et
H
H
H
OPr
H
Pr
H
1
OBu
OPen
OHex
OEt
H
Bu
Pen
Hex
Me
Et
H
1540, 1457, 1396. H NMR (DMSO-d6): d (ppm) ¼ 0.94 (t,
H
H
3H, J ¼ 7.3 Hz), 1.45 (m, 2H), 1.70 (m, 2H), 3.94 (t, 2H,
J ¼ 6.4 Hz), 6.72 (dd, 1H, Jo ¼ 8.7 Hz, Jm ¼ 2.4 Hz), 6.78 (d,
1H, J ¼ 1.6 Hz), 7.00 (d, 1H, J ¼ 2.4 Hz), 7.26 (d, 1H,
J ¼ 9.5 Hz), 7.29 (d, 1H, J ¼ 7.5 Hz), 7.43 (m, 2H), 7.81 (d,
2H, J ¼ 7.5 Hz), 11.33 (s, 1H). EI-MS (70 eV) m/z (%): 265
H
H
9a
9b
9c
9d
9e
OMe
OMe
OMe
OMe
OMe
15a
15b
15c
15d
15e
OMe
OMe
OMe
OMe
OMe
OPr
OBu
OPen
OHex
Pr
Bu
Pen
ꢄ
(64) [Mþ ], 209 (100) [M ꢀ C4ꢄ H8]þ. Anal. (C18H19NO)
C, H, N.
6.2.4.5. 5-Pentyloxy-2-phenyl-1H-indole (8e). Yield: 2.6 g
(9.3 mmol) from 6.4 g (32.2 mmol) of 4a and 5.7 g (32.2 mmol)
of 4-pentoxyphenylamine (5e) [24] (29%), yellow crystals,
m.p. 130 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3451, 2959, 1623, 1540,
1457, 1395. 1H NMR (DMSO-d6): d (ppm) ¼ 0.89 (t, 3H,
J ¼ 6.9 Hz), 1.38 (m, 4H), 1.71 (m, 2H), 3.93 (t, 2H,
J ¼ 6.5 Hz), 6.72 (dd, 1H, Jo ¼ 8.7 Hz, Jm ¼ 2.4 Hz), 6.78 (d,
1H, J ¼ 1.6 Hz), 6.99 (d, 1H, J ¼ 2.3 Hz), 7.28 (m, 2H), 7.43
(t, 2H, J ¼ 7.5 Hz), 7.81 (d, 2H, J ¼ 7.5 Hz), 11.33 (s, 1H).
N
H
R1
R2
20a
20b
20c
20d
Me
Et
H
21a
21b
21c
21d
21e
Me
Et
OMe
OMe
OMe
OMe
OMe
H
H
H
Bu
Pen
Pr
Bu
Hex
R1
ꢄ
EI-MS (70 eV) m/z (%): 279 (68) [Mþ ], 209 (100)
[M ꢀ Cꢄ5H10]þ. Anal. (C19H21NO$1/20EE) C, H, N.
N
H
6.2.4.6. 5-Hexyloxy-2-phenyl-1H-indole (8f). Yield: 3.4 g
(11.6 mmol) from 5.6 g (28.1 mmol) of 4a and 6.2 g
(28.1 mmol) of 4-hexoxyphenylamine (5f) [24] (41%), yellow
crystals, m.p. 135 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3451, 2927, 1625,
R2
26a
26b
26c
26d
OMe
OEt
OMe
OMe
OMe
OMe
26e
26f
26g
26h
Me
Et
OMe
OMe
OMe
OMe
1
1542, 1457, 1395. H NMR (DMSO-d6): d (ppm) ¼ 0.88 (t,
OBu
OHex
Bu
Hex
3H, J ¼ 6.9 Hz), 1.31 (m, 4H), 1.43 (m, 2H), 1.71 (m, 2H),
3.93 (t, 2H, J ¼ 6.3 Hz), 6.72 (dd, 1H, Jo ¼ 8.7 Hz,
Jm ¼ 2.4 Hz), 6.78 (d, 1H, J ¼ 1.6 Hz), 6.99 (d, 1H,
J ¼ 2.4 Hz), 7.27 (m, 2H), 7.43 (m, 2H), 7.81 (d, 2H,
J ¼ 7.1 Hz), 11.33 (s, 1H). EI-MS (70 eV) m/z (%): 293 (72)
6.2.4.2. 5-Ethoxy-2-phenyl-1H-indole (8b). Yield: 1.96 g
(8.3 mmol) from 4.9 g (24.6 mmol) of 4a and 3.4 g
(24.6 mmol) of 4-ethoxyphenylamine (5b) [24] (34%), yellow
crystals, m.p. 135 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3433, 2975, 1601,
ꢄ
[Mþ ], 209 (100) [M ꢀ C6ꢄ H12]þ. Anal. (C20H23NO) C, H, N.
6.2.4.7. 5-Ethoxy-2-(4-methoxyphenyl)-1H-indole (9a). Yield:
4.48 g (16.7 mmol) from 5.2 g (22.7 mmol) of 4b (74%), yel-
low crystals, m.p. 200 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3417, 2936,
1622, 1609, 1547, 1457, 1391. 1H NMR (DMSO-d6):
d (ppm) ¼ 1.32 (t, 3H, J ¼ 7.15 Hz), 3.79 (s, 3H), 3.99 (q,
2H, J ¼ 6.7 Hz), 6.64 (d, 1H, J ¼ 1.5 Hz), 6.68 (dd, 1H,
J ¼ 2.4, 8.7 Hz), 6.96 (d, 1H, J ¼ 2.4 Hz), 7.00 (d, 2H,
J ¼ 9.1 Hz), 7.22 (d, 1H, J ¼ 8.7 Hz), 7.74 (d, 2H,
1
1539, 1456, 1391. H NMR (DMSO-d6): d (ppm) ¼ 1.33 (t,
3H, J ¼ 7.0 Hz), 4.00 (q, 2H, J ¼ 6.9 Hz), 6.72 (dd, 1H,
Jo ¼ 8.9 Hz, Jm ¼ 2.5 Hz), 6.78 (d, 1H, J ¼ 1.6 Hz), 6.99 (d,
1H, J ¼ 2.4 Hz), 7.22e7.31 (m, 2H), 7.43 (m, 2H), 7.81 (d,
2H, J ¼ 7.2 Hz), 11.34 (s, 1H). EI-MS (70 eV) m/z (%): 223
(100) [Mþ ], 208 (44) [M ꢀ CꢄH3]þ. Anal. (C16H15NO) C, H, N.
ꢄ
ꢄ
6.2.4.3. 2-Phenyl-5-propoxy-1H-indole (8c). Yield: 2.0 g
(8.0 mmol) from 5.0 g (25 mmol) of 4a and 3.7 g (25 mmol)
of 4-propoxyphenylamine (5c) [25] (32%), yellow crystals,
m.p. 126 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3430, 2967, 1622, 1540,
1457, 1393. 1H NMR (DMSO-d6): d (ppm) ¼ 0.99 (t, 3H,
J ¼ 8.7 Hz). EI-MS (70 eV) m/z (%): 267 (100) [Mþ ]. Anal.
(C17H17NO2) C, H, N.
6.2.4.8. 2-(4-Methoxyphenyl)-5-propoxy-1H-indole (9b). Yield:
3.5 g (12.4 mmol) from 5.2 g (22.6 mmol) of 4b (55%), yellow

644
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
crystals, m.p. 170 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3419, 2938, 1623,
1609, 1549, 1457, 1389. 1H NMR (DMSO-d6): d (ppm) ¼ 0.99
(t, 3H, J ¼ 7.2 Hz), 1.72 (m, 2H), 3.79 (s, 3H), 3.87 (t, 2H,
J ¼ 6.3 Hz), 6.64 (d, 1H, J ¼ 1.6 Hz), 6.69 (dd, 1H, J ¼ 2.4,
8.7 Hz), 6.96 (d, 1H, J ¼ 2.3 Hz), 7.00 (d, 2H, J ¼ 9.1 Hz),
7.23 (d, 1H, J ¼ 8.7 Hz), 7.74 (d, 2H, J ¼ 9.1 Hz), 11.2 (s,
Table 5
TBS
N
H
N
O
O
O
O
Br
R1
Br
R1
ꢄ
1H). EI-MS (70 eV) m/z (%): 281 (100) [Mþ ], 239 (88).
N
N
H
H
Anal. (C18H19NO2) C, H, N.
R2
R2
Nr.
R1
R2
Nr.
R1
R2
6.2.4.9. 5-Butoxy-2-(4-methoxyphenyl)-1H-indole (9c). Yield:
5.21 g (17.7 mmol) from 7.4 g (32.3 mmol) of 4b (55%), yel-
low crystals, m.p. 165 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3417, 2930,
1623, 1609, 1549, 1457, 1389. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.94 (t, 3H, J ¼ 7.3 Hz), 1.45 (m, 2H), 1.69 (m,
2H), 3.79 (s, 3H), 3.93 (t, 2H, J ¼ 6.4 Hz), 6.64 (d, 1H,
J ¼ 1.1 Hz), 6.68 (dd, 1H, J ¼ 2.4 Hz, J ¼ 8.7 Hz), 6.97 (d,
1H, J ¼ 2.4 Hz), 7.00 (d, 2H, J ¼ 8.7 Hz), 7.22 (d, 1H,
J ¼ 8.7 Hz), 7.74 (d, 2H, J ¼ 8.7 Hz), 11.20 (s, 1H). EI-MS
10a
10b
10c
10d
10e
10f
5-OMe
5-OEt
5-OPr
5-OBu
5-OPen
5-OHex
5-OEt
5-OPr
5-OBu
5-OPen
5-OHex
5-Me
5-Et
H
H
H
H
H
H
12a
12b
12c
12d
12e
12f
5-OMe
5-OEt
5-OPr
5-OBu
5-OPen
5-OHex
5-OEt
5-OPr
5-OBu
5-OPen
5-OHex
5-Me
5-Et
H
H
H
H
H
H
11a
11b
11c
11d
11e
16a
16b
16c
16d
16e
16f
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
13a
13b
13c
13d
13e
18a
18b
18c
18d
18e
18f
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
ꢄ
(70 eV) m/z (%): 295 (100) [Mþ ], 239 (64). Anal.
(C19H21NO2$1/4H2O) C, H, N.
H
H
5-Pr
5-Bu
H
5-Pr
5-Bu
H
6.2.4.10. 2-(4-Methoxyphenyl)-5-pentyloxy-1H-indole (9d).
Yield: 1.5 g (4.9 mmol) from 5.7 g (24.8 mmol) of 4b (19%),
yellow crystals, m.p. 196 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3415,
H
H
5-Pen
5-Hex
5-Me
5-Et
H
5-Pen
5-Hex
5-Me
5-Et
H
H
H
1
17a
17b
17c
17d
17e
17f
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
19a
19b
19c
19d
19e
19f
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
2956, 1620, 1611, 1549, 1456, 1389. H NMR (DMSO-d6):
d (ppm) ¼ 0.90 (t, 3H, J ¼ 7.0 Hz), 1.38 (m, 4H), 1.69 (m,
2H), 3.79 (s, 3H), 3.92 (t, 2H, J ¼ 6.5 Hz), 6.64 (d, 1H,
J ¼ 1.2 Hz), 6.68 (dd, 1H, J ¼ 2.4 Hz, J ¼ 8.7 Hz), 6.96 (d,
1H, J ¼ 2.4 Hz), 7.00 (d, 2H, J ¼ 8.7 Hz), 7.22 (d, 1H,
J ¼ 8.7 Hz), 7.74 (d, 2H, J ¼ 8.7 Hz), 11.19 (s, 1H). EI-MS
5-Pr
5-Bu
5-Pr
5-Bu
5-Pen
5-Hex
7-Me
7-Et
5-Pen
5-Hex
7-Me
7-Et
22a
22b
22c
22d
23a
23b
23c
23d
23e
27a
27b
27c
27d
27e
27f
24a
24b
24c
24d
25a
25b
25c
25d
25e
28a
28b
28c
28d
28e
28f
ꢄ
(70 eV) m/z (%): 309 (90) [Mþ ], 239 (100). Anal.
H
H
7-Bu
H
7-Bu
H
(C20H23NO2) C, H, N.
7-Pen
7-Me
7-Et
H
7-Pen
7-Me
7-Et
H
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
6.2.4.11. 5-Hexyloxy-2-(4-methoxyphenyl)-1H-indole (9e).
Yield: 1.0 g (3.1 mmol) from 5.7 g (24.8 mmol) of 4b (12%),
yellow crystals, m.p. 185 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3415,
2927, 1622, 1611, 1456, 1302. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.87 (t, 3H, J ¼ 6.7 Hz), 1.31 (m, 4H), 1.43 (m,
2H), 1.70 (m, 2H), 3.79 (s, 3H), 3.92 (t, 2H, J ¼ 6.5 Hz),
6.64 (d, 1H, J ¼ 1.5 Hz), 6.68 (dd, 1H, J ¼ 2.4, 8.7 Hz),
6.96 (d, 1H, J ¼ 2.4 Hz), 7.00 (d, 2H, J ¼ 8.7 Hz), 7.22 (d,
1H, J ¼ 8.7 Hz), 7.74 (d, 2H, J ¼ 9.1 Hz), 11.21 (s, 1H). EI-
7-Pr
7-Bu
7-Pr
7-Bu
7-Hex
5-OMe
5-OEt
5-OBu
5-OHex
5-Me
5-Et
7-Hex
5-Ome
5-Oet
5-Obu
5-OHex
5-Me
5-Et
27g
27h
5-Bu
5-Hex
28g
28h
5-Bu
5-Hex
ꢄ
MS (70 eV) m/z (%): 323 (100) [Mþ ]. Anal. (C21H25NO2)
C, H, N.
6.2.5. Condensation of TBSedibromomaleinimide with
indole derivatives (10aef and 11aee, Table 5)
6.2.6. Removal of the silyl-protecting group to give 12aef
and 13aee (Table 5)
The respective indoles (8aef and 9aee) were dissolved in
dry THF and cooled under argon to ꢀ20 ꢁC. Then LiHMDS
(2 eq, 1 M in THF) was slowly added. After stirring the solu-
tion for 45 min, TBSedibromomaleinimide (1 eq) in THF was
added within 3 h. The solution was stirred for 15 min at
ꢀ20 ꢁC, poured into sat. aq. NH4Cl, extracted with ethyl ace-
tate, dried over Na2SO4 and concentrated in vacuo. The crude
products were processed to 12aef and 13aee without further
purification.
The raw silyl-protected indoleemaleinimides (10aef and
11aee) were dissolved in THF under N2, tetrabutylammonium
fluoride trihydrate (1.3 eq) was added, and the mixture was
stirred for 2 h, poured into ice, mixed with saturated NH4Cl
solution and extracted with ethyl acetate. The extract was
dried over Na2SO4, the solvent was removed in vacuo and
the remaining oil was purified by CC (DCM) and crystallized
from pentane.

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
645
6.2.6.1. 3-Bromo-4-(5-methoxy-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (12a). Yield: 0.080 g (0.2 mmol) from 0.45 g
(2.0 mmol) of 8a (10%), red crystals, m.p. 250 ꢁC decomp.
IR (KBr): n (cmꢀ1) ¼ 3340, 1721, 1622, 1485. 1H NMR
(CDCl3): d (ppm) ¼ 3.87 (s, 3H), 6.95 (d, 1H, 8.7 Hz), 6.98
(s, 1H), 7.34e7.67 (m, 6H), 11.29 (s, 1H), 11.98 (s, 1H).
ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 398
(100) [M þ H]þ. Anal. (C19H13BrN2O3) C, H, N.
(m, 6H), 8.56 (s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l
NH4Ac) m/z (%): 467 (100) [M þ H]þ. Anal. (C24H23BrN2O3)
C, H, N.
6.2.6.7. 3-Bromo-4-[5-ethoxy-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (13a). Yield: 0.16 g (0.36 mmol) from
0.54 g (2.0 mmol) of 9a (18%), red crystals, m.p. 190 ꢁC. IR
1
(KBr): n (cmꢀ1) ¼ 3390, 1779, 1715, 1613, 1474. H NMR
(CDCl3): d (ppm) ¼ 1.33 (t, 3H, J ¼ 7.0 Hz), 3.78 (s, 3H),
3.99 (q, 2H, J ¼ 6.9 Hz), 6.80 (dd, 1H, J ¼ 2.4, 8.7 Hz), 6.89
(d, 1H, J ¼ 2.4 Hz), 7.01 (d, 2H, J ¼ 8.7 Hz), 7.33 (d, 1H,
J ¼ 8.7 Hz), 7.45 (d, 2H, J ¼ 8.7 Hz), 11.27 (s, 1H), 11.86
(s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z
(%): 441 (100) [M þ H]þ. Anal. (C21H17BrN2O4) C, H, N.
6.2.6.2. 3-Bromo-4-(5-ethoxy-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (12b). Yield: 0.10 g (0.2 mmol) from 0.47 g
(2.0 mmol) of 8b (10%), red crystals, m.p. 235 ꢁC. IR (KBr): n
(cmꢀ1) ¼ 3421, 3214, 1775, 1719, 1632, 1476. 1H NMR
(CDCl3): d (ppm) ¼ 1.34 (t, 3H, J ¼ 7.0 Hz), 4.00 (q, 2H,
J ¼ 7.1 Hz), 6.83 (dd, 1H, J ¼ 2.4, 8.7 Hz), 6.92 (d, 1H,
J ¼ 2.4 Hz), 7.32e7.54 (m, 6H), 11.29 (s, 1H), 11.98 (s, 1H).
ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 413 (100)
[M þ H]þ. Anal. (C20H15BrN2O3$1/10pentane) C, H, N.
6.2.6.8. 3-Bromo-4-[2-(4-methoxyphenyl)-5-propoxy-1H-indole-
3-yl]pyrrole-2,5-dione (13b). Yield: 0.13 g (0.28 mmol) from
0.57 g (2 mmol) of 9b (14%), red crystals, m.p. 185 ꢁC. IR
1
(KBr): n (cmꢀ1) ¼ 3392, 3288, 1779, 1713, 1613, 1483. H
6.2.6.3. 3-Bromo-4-(2-phenyl-5-propoxy-1H-indole-3-yl)pyrrole-
2,5-dione (12c). Yield: 0.12 g (0.28 mmol) from 0.5 g
(2.0 mmol) of 8c (14%), red crystals, m.p. 222 ꢁC. IR (KBr): n
(cmꢀ1) ¼ 3409, 3232, 1780, 1711, 1619, 1457. 1H NMR
(CDCl3): d (ppm) ¼ 0.98 (t, 3H, J ¼ 7.3 Hz), 1.74 (m, 2H),
3.90 (t, 2H, J ¼ 6.3 Hz), 6.84 (dd, 1H, J ¼ 2.4, 8.7 Hz), 6.93 (d,
1H, J ¼ 2.4 Hz), 7.32e7.54 (m, 6H), 11.29 (s, 1H), 11.98 (s,
1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 425
(100) [M þ H]þ. Anal. (C21H17BrN2O3$1/5pentane) C, H, N.
NMR (CDCl3): d (ppm) ¼ 0.98 (t, 3H, J ¼ 7.3 Hz), 1.74 (m,
2H), 3.79 (s, 3H), 3.89 (t, 2H, J ¼ 6.5 Hz), 6.81 (dd, 1H,
J ¼ 2.4, 8.7 Hz), 6.89 (d, 1H, J ¼ 2.0 Hz), 7.01 (d, 2H,
J ¼ 9.1 Hz), 7.32 (d, 1H, J ¼ 8.7 Hz), 7.45 (d, 2H,
J ¼ 8.7 Hz), 11.26 (s, 1H), 11.85 (s, 1H). ES-MS (DCM/
MeOH þ 10 mmol/l NH4Ac) m/z (%): 457 (100) [M þ H]þ.
Anal. (C22H19BrN2O4) C, H, N.
6.2.6.9. 3-Bromo-4-[5-butoxy-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (13c). Yield: 0.27 g (0.57 mmol) from
0.59 g (2.0 mmol) of 9c (29%), red crystals, m.p. 230 ꢁC. IR
6.2.6.4. 3-Bromo-4-(5-butoxy-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (12d). Yield: 0.4 g (0.9 mmol) from 0.53 g
(2.0 mmol) of 8d (45%), red crystals, m.p. 220 ꢁC. IR (KBr):
n (cmꢀ1) ¼ 3382, 3195, 1775, 1717, 1611, 1464. 1H NMR
(CDCl3): d (ppm) ¼ 0.93 (t, 3H, J ¼ 7.3 Hz), 1.44 (m, 2H),
1.69 (m, 2H), 3.94 (t, 2H, J ¼ 6.4 Hz), 6.84 (dd, 1H, J ¼ 2.4,
8.7 Hz), 6.93 (d, 1H, J ¼ 2.0 Hz), 7.32e7.54 (m, 6H), 11.29
(s, 1H), 11.97 (s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l
NH4Ac) m/z (%): 441 (100) [M þ H]þ. Anal. (C22H19BrN2O3)
C, H, N.
1
(KBr): n (cmꢀ1) ¼ 3392, 1779, 1713, 1613, 1580, 1483. H
NMR (CDCl3): d (ppm) ¼ 0.93 (t, 3H, J ¼ 7.3 Hz), 1.44 (m,
2H), 1.69 (m, 2H), 3.78 (s, 3H), 3.94 (t, 2H, J ¼ 6.4 Hz),
6.80 (dd, 1H, J ¼ 2.4, 8.7 Hz), 6.89 (d, 1H, J ¼ 2.4 Hz), 7.01
(d, 2H, J ¼ 9.1 Hz), 7.32 (d, 1H, J ¼ 8.7 Hz), 7.45 (d, 2H,
J ¼ 8.7 Hz), 11.26 (s, 1H), 11.85 (s, 1H). ES-MS (DCM/
MeOH þ 10 mmol/l NH4Ac) m/z (%): 471 (100) [M þ H]þ.
Anal. (C23H21BrN2O4) C, H, N.
6.2.6.10.
3-Bromo-4-[2-(4-methoxyphenyl)-5-pentyloxy-1H-
6.2.6.5. 3-Bromo-4-(5-pentyloxy-2-phenyl-1H-indole-3-yl)pyr-
role-2,5-dione (12e). Yield: 0.44 g (0.97 mmol) from 0.56 g
(2.0 mmol) of 8e (48%), red crystals, m.p. 205 ꢁC. IR (KBr):
indole-3-yl]pyrrole-2,5-dione (13d). Yield: 0.47 g (1.0 mmol)
from 0.62 (2.0 mmol) of 9d (50%), red crystals, m.p.
220 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3392, 1779, 1713, 1611, 1483.
1H NMR (CDCl3): d (ppm) ¼ 0.89 (t, 3H, J ¼ 7.1 Hz), 1.37
(m, 4H), 1.72 (m, 2H), 3.78 (s, 3H), 3.93 (t, 2H,
J ¼ 6.7 Hz), 6.80 (dd, 1H, J ¼ 2.4, 8.7 Hz), 6.89 (d, 1H,
J ¼ 2.4 Hz), 7.01 (d, 2H, J ¼ 8.7 Hz), 7.34 (d, 1H,
J ¼ 8.7 Hz), 7.45 (d, 2H, J ¼ 8.7 Hz), 11.27 (s, 1H), 11.85
(s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z
(%): 485 (100) [M þ H]þ. Anal. (C24H23BrN2O4) C, H, N.
1
n (cmꢀ1) ¼ 3403, 3226, 1780, 1713, 1620, 1474. H NMR
(CDCl3): d (ppm) ¼ 0.94 (t, 3H, J ¼ 6.9 Hz), 1.44 (m, 4H),
1.81 (m, 2H), 4.00 (t, 2H, J ¼ 6.6 Hz), 6.94 (dd, 1H, J ¼ 2.4,
8.7 Hz), 6.98 (d, 1H, J ¼ 2.0 Hz), 7.26e7.47 (m, 6H), 8.57
(s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z
(%): 455 (100) [M þ H]þ. Anal. (C23H21BrN2O3) C, H, N.
6.2.6.6. 3-Bromo-4-(5-hexyloxy-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (12f). Yield: 0.21 g (0.45 mmol) from 0.59 g
(2.0 mmol) of 8f (22%), red crystals, m.p. 195 ꢁC. IR (KBr): n
(cmꢀ1) ¼ 3399, 3201, 1781, 1713, 1620, 1474. 1H NMR
(CDCl3): d (ppm) ¼ 0.91 (t, 3H, J ¼ 6.7 Hz), 1.36 (m, 4H),
1.49 (m, 2H), 1.82 (m, 2H), 4.00 (t, 2H, J ¼ 6.6 Hz), 6.95
(dd, 1H, J ¼ 2.4, 8.7 Hz), 6.97 (d, 1H, J ¼ 2.4 Hz), 7.26e7.46
6.2.6.11. 3-Bromo-4-[5-hexyloxy-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (13e). Yield: 0.3 g (0.6 mmol) from
0.48 g (2.0 mmol) of 9e (30%), red crystals, m.p. 200 ꢁC. IR
1
(KBr): n (cmꢀ1) ¼ 3392, 2933, 1779, 1713, 1611, 1484. H
NMR (CDCl3): d (ppm) ¼ 0.87 (t, 3H, J ¼ 7.1 Hz), 1.32 (m,
4H), 1.42 (m, 2H), 1.71 (m, 2H), 3.78 (s, 3H), 3.93 (t, 2H,

646
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
J ¼ 6.5 Hz), 6.80 (dd, 1H, J ¼ 2.4, 8.8 Hz), 6.89 (d, 1H,
J ¼ 2.4 Hz), 7.01 (d, 2H, J ¼ 9.1 Hz), 7.32 (d, 1H,
J ¼ 8.7 Hz), 7.45 (d, 2H, J ¼ 8.7 Hz), 11.30 (s, 1H), 11.85
(s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z
(%): 499 (25) [M þ H]þ. Anal. (C25H25BrN2O4) C, H, N.
6.2.7.5. 5-Pentyl-2-phenyl-1H-indole (14e). Yield: 3.3 g
(12.5 mmol) from 6.1 g (30.6 mmol) of 4a (41%), colourless
crystals, m.p. 130 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3429, 2950, 1603,
1542, 1495, 1403. 1H NMR (DMSO-d6): d (ppm) ¼ 0.85
(t, 3H, J ¼ 6.7 Hz), 1.20e1.40 (m, 4H), 1.52e1.65 (m, 2H),
2.61 (t, 2H, J ¼ 7.5 Hz), 6.80 (d, 1H, J ¼ 1.6 Hz), 6.93 (dd,
1H, Jo ¼ 8.3 Hz, Jm ¼ 1.6 Hz), 7.25e7.31 (m, 3H), 7.44
(t, 2H, J ¼ 7.5 Hz), 7.82 (d, 2H, J ¼ 7.1 Hz), 11.37 (s, 1H).
6.2.7. Formation of the indoles 14aef and 15aef (Table 4)
The respective anilines (5gel, 3 eq) were dissolved in
DMA and stirred at reflux in an N2 atmosphere. A solution
of 1 eq of 4a or 4b in hot xylene (70 ꢁC) was slowly added
dropwise to the hot solution which was subsequently stirred
at 150 ꢁC for 15 h. The solution was cooled to 0 ꢁC and the
precipitated crude product was filtered and washed with ethyl
acetate and methanol. The crude product was purified by CC
(DCM) and crystallized from pentane.
ꢄ
EI-MS (70 eV) m/z (%): 263 (68) [Mþ ], 206 (100)
ꢄ
[M ꢀ C4H9]þ. Anal. (C19H21N) C, H, N.
6.2.7.6. 5-Hexyl-2-phenyl-1H-indole (14f). Yield: 5.9 g
(21 mmol) from 7.5 g (37.6 mmol) of 4a (56%), colourless
crystals, m.p. 130 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3438, 2952,
1603, 1542, 1472, 1403. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.85 (t, 3H, J ¼ 6.7 Hz), 1.20e1.40 (m, 6H),
1.50e1.70 (m, 2H), 2.61 (t, 2H, J ¼ 7.5 Hz), 6.80 (d, 1H,
J ¼ 1.6 Hz), 6.92 (dd, 1H, Jo ¼ 8.3 Hz, Jm ¼ 1.6 Hz), 7.25e
7.31 (m, 3H), 7.44 (t, 2H, J ¼ 7.5 Hz), 7.82 (d, 2H,
J ¼ 7.1 Hz), 11.37 (s, 1H). EI-MS (70 eV) m/z (%): 277 (74)
6.2.7.1. 5-Methyl-2-phenyl-1H-indole (14a). Yield: 6.05 g
(29 mmol) from 10 g (50 mmol) of 4a (58%), colourless crys-
tals, m.p. 210 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3405, 2859, 1613,
1
1551, 1506, 1391. H NMR (DMSO-d6): d (ppm) ¼ 2.49 (s,
ꢄ
ꢄ
[Mþ ], 206 (100) [M ꢀ C5H11]þ. Anal. (C20H23N) C, H, N.
3H), 6.79 (d, 1H, J ¼ 1.6 Hz), 6.91 (dd, 1H, Jo ¼ 7.9 Hz, Jm ¼
1.6 Hz), 7.26e7.31 (m, 3H), 7.44 (t, 2H, J ¼ 7.5 Hz), 7.83 (d,
2H, J ¼ 7.9 Hz), 11.37 (s, 1H). EI-MS (70 eV) m/z (%): 207
6.2.7.7. 5-Methyl-2-(4-methoxyphenyl)-1H-indole (15a). Yield:
5.7 g (25 mmol) from 11.5 g (50 mmol) of 4b (50%), colourless
crystals, m.p. 220 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3436, 2919, 1609,
ꢄ
(100) [Mþ ], 206 (60) [M ꢀ H]þ. Anal. (C15H13N) C, H, N.
1
1547, 1503, 1398. H NMR (DMSO-d6): d (ppm) ¼ 2.34 (s,
6.2.7.2. 5-Ethyl-2-phenyl-1H-indole (14b). Yield: 2.00 g
(9 mmol) from 4.9 g (24 mmol) of 4a (36%), colourless crys-
tals, m.p. 151 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3432, 2961, 1603,
3H), 3.78 (s, 3H), 6.64 (d, 1H, J ¼ 1.6 Hz), 6.87 (dd, 1H,
Jo ¼ 7.9 Hz, Jm ¼ 1.6 Hz), 7.00 (d, 2H, J ¼ 8.7 Hz), 7.24 (d,
1H, J ¼ 7.2 Hz), 7.26 (s, 1H), 7.75 (d, 2H, J ¼ 9.0 Hz), 11.24
1
ꢄ
(s, 1H). EI-MS (70 eV) m/z (%): 237 (100) [Mþ ], 222 (52)
1541, 1503, 1402. H NMR (DMSO-d6): d (ppm) ¼ 1.21 (t,
[M ꢀ CꢄH3]þ. Anal. (C16H15NO) C, H, N.
3H, J ¼ 7.5 Hz), 2.65 (q, 2H, J ¼ 7.6 Hz), 6.80 (d, 1H,
J ¼ 1.6 Hz), 6.95 (dd, 1H, Jo ¼ 7.9 Hz, Jm ¼ 1.6 Hz), 7.25e
7.31 (m, 3H), 7.43 (t, 2H, J ¼ 7.7 Hz), 7.83 (d, 2H,
J ¼ 7.1 Hz), 11.37 (s, 1H). EI-MS (70 eV) m/z (%): 221 (84)
6.2.7.8. 5-Ethyl-2-(4-methoxyphenyl)-1H-indole (15b). Yield:
3.65 g (14.5 mmol) from 5.7 g (25 mmol) of 4b (58%), colour-
less crystals, m.p. 200 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3435, 2963,
1609, 1547, 1503, 1399. 1H NMR (DMSO-d6):
d (ppm) ¼ 1.20 (t, 3H, J ¼ 7.7 Hz), 2.64 (q, 2H, J ¼ 7.5 Hz),
3.79 (s, 3H), 6.66 (d, 1H, J ¼ 1.9 Hz), 6.91 (dd, 1H,
Jo ¼ 8.1 Hz, Jm ¼ 1.4 Hz), 7.01 (d, 2H, J ¼ 8.7 Hz), 7.26 (d,
1H, J ¼ 8.3 Hz), 7.28 (s, 1H), 7.75 (d, 2H, J ¼ 8.7 Hz),
ꢄ
ꢄ
[Mþ ], 206 (100) [M ꢀ CH3]þ. Anal. (C16H15N) C, H, N.
6.2.7.3. 5-Propyl-2-phenyl-1H-indole (14c). Yield: 3.8 g
(16 mmol) from 7.1 g (35 mmol) of 4a (45%), colourless crys-
tals, m.p. 133 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3430, 2954, 1603,
1541, 1506, 1401. 1H NMR (DMSO-d6): d (ppm) ¼ 0.90
(t, 3H, J ¼ 7.3 Hz), 1.54e1.68 (m, 2H), 2.59 (t, 2H,
J ¼ 7.5 Hz), 6.80 (d, 1H, J ¼ 1.6 Hz), 6.93 (dd, 1H, Jo ¼ 8.3 Hz,
Jm ¼ 1.6 Hz), 7.25e7.31 (m, 3H), 7.44 (t, 2H, J ¼ 7.5 Hz),
7.83 (d, 2H, J ¼ 7.7 Hz), 11.38 (s, 1H). EI-MS (70 eV)
ꢄ
11.25 (s, 1H). EI-MS (70 eV) m/z (%): 251 (100) [Mþ ], 236
ꢄ
(68) [M ꢀ CH3]þ. Anal. (C17H17NO) C, H, N.
6.2.7.9. 5-Propyl-2-(4-methoxyphenyl)-1H-indole (15c). Yield:
4.3 g (16.2 mmol) from 6.2 g (27 mmol) of 4b (59%), colour-
less crystals, m.p. 192 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3409, 2952,
1609, 1549, 1505, 1397. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.89 (t, 3H, J ¼ 7.3 Hz), 1.56e1.65 (m, 2H), 2.59
(t, 2H, J ¼ 7.3 Hz), 3.79 (s, 3H), 6.65 (d, 1H, J ¼ 1.6 Hz),
6.88 (dd, 1H, Jo ¼ 8.5 Hz, Jm ¼ 1.4 Hz), 7.01 (d, 2H,
J ¼ 8.7 Hz), 7.23e7.27 (m, 2H), 7.75 (d, 2H, J ¼ 8.7 Hz),
ꢄ
ꢄ
m/z (%): 235 (60) [Mþ ], 206 (100) [M ꢀ C2H5]þ. Anal.
(C17H17N) C, H, N.
6.2.7.4. 5-Butyl-2-phenyl-1H-indole (14d). Yield: 1.85 g
(7.4 mmol) from 6.4 g (32 mmol) of 4a (23%), colourless
crystals, m.p. 148 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3433, 2954, 1603,
1542, 1497, 1403. 1H NMR (DMSO-d6): d (ppm) ¼ 0.90
(t, 3H, J ¼ 7.3 Hz), 1.27e1.36 (m, 2H), 1.52e1.61 (m, 2H),
2.62 (t, 2H, J ¼ 7.5 Hz), 6.80 (d, 1H, J ¼ 1.6 Hz), 6.93 (dd,
1H, Jo ¼ 8.3 Hz, Jm ¼ 1.6 Hz), 7.25e7.31 (m, 3H), 7.44
(t, 2H, J ¼ 7.5 Hz), 7.84 (d, 2H, J ¼ 7.5 Hz), 11.37 (s, 1H).
ꢄ
11.25 (s, 1H). EI-MS (70 eV) m/z (%): 265 (100) [Mþ ], 236
ꢄ
(88) [M ꢀ C2H5]þ. Anal. (C18H19NO) C, H, N.
6.2.7.10. 5-Butyl-2-(4-methoxyphenyl)-1H-indole (15d). Yield:
4.8 g (17 mmol) from 7.4 g (32 mmol) of 4b (53%), colourless
crystals, m.p. 195 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3436, 2956, 1609,
ꢄ
EI-MS (70 eV) m/z (%): 249 (66) [Mþ ], 206 (100)
ꢄ
[M ꢀ C3H7]þ. Anal. (C18H19N) C, H, N.

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
647
1
1549, 1505, 1397. H NMR (DMSO-d6): d (ppm) ¼ 0.89 (t,
6.2.9.1. 3-Bromo-4-(5-methyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (18a). Yield: 0.32 g (0.84 mmol) from 0.420 g
(2 mmol) of 14a (41%), red crystals, m.p. 240 ꢁC. IR (KBr): n
(cmꢀ1) ¼ 3444, 3208, 1771, 1711, 1619, 1478. 1H NMR
(DMSO-d6): d (ppm) ¼ 2.38 (s, 3H), 7.03 (dd, 1H, J ¼ 1.4,
8.3 Hz), 7.24 (s, 1H), 7.32e7.56 (m, 6H), 11.32 (s, 1H), 12.01
(s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%):
381 (100) [M þ H]þ. Anal. (C19H13BrN2O2) C, H, N.
3H, J ¼ 7.5 Hz), 1.24e1.38 (m, 2H), 1.51e1.63 (m, 2H),
2.61 (t, 2H, J ¼ 7.5 Hz), 3.79 (s, 3H), 6.65 (d, 1H,
J ¼ 1.6 Hz), 6.88 (dd, 1H, Jo ¼ 8.3 Hz, Jm ¼ 1.6 Hz), 7.01
(d, 2H, J ¼ 9.1 Hz), 7.23e7.27 (m, 2H), 7.75 (d, 2H,
J ¼ 8.7 Hz), 11.24 (s, 1H). EI-MS (70 eV) m/z (%):
ꢄ
ꢄ
279 (92) [Mþ ], 236 (100) [M ꢀ C3H7]þ. Anal. (C19H21NO)
C, H, N.
6.2.9.2. 3-Bromo-4-(5-ethyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (18b). Yield: 0.36 g (0.91 mmol) from 2.0 mmol
of 14b (45%), red crystals, m.p. 205.3 ꢁC. IR (KBr): n
(cmꢀ1) ¼ 3374, 3189, 1771, 1711, 1613, 1478. 1H NMR
(DMSO-d6): d (ppm) ¼ 1.21 (t, 3H, J ¼ 7.7 Hz), 2.67 (q, 2H,
J ¼ 7.5 Hz), 7.07 (dd, 1H, J ¼ 1.6, 8.3 Hz), 7.26 (s, 1H),
7.32e7.56 (m, 6H), 11.32 (s, 1H), 12.01 (s, 1H). ES-MS
(DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 395 (100)
[M þ H]þ. Anal. (C20H15BrN2O2$1/2pentane) C, H, N.
6.2.7.11. 5-Pentyl-2-(4-methoxyphenyl)-1H-indole (15e). Yield:
4.9 g (16.7 mmol) from 6.5 g (28 mmol) of 4b (59%), colour-
less crystals, m.p. 175 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3434, 2929,
1609, 1547, 1503, 1397. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.85 (t, 3H, J ¼ 6.5 Hz), 1.24e1.38 (m, 4H),
1.51e1.63 (m, 2H), 2.60 (t, 2H, J ¼ 7.5 Hz), 3.79 (s, 3H),
6.65 (d, 1H, J ¼ 1.6 Hz), 6.88 (dd, 1H, Jo ¼ 8.3 Hz,
Jm ¼ 1.6 Hz), 7.01 (d, 2H, J ¼ 8.7 Hz), 7.23e7.27 (m, 2H),
7.75 (d, 2H, J ¼ 8.7 Hz), 11.25 (s, 1H). EI-MS (70 eV) m/z
ꢄ
ꢄ
(%): 293 (100) [Mþ ], 236 (68) [M ꢀ C4H9]þ. Anal.
6.2.9.3. 3-Bromo-4-(5-propyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (18c). Yield: 0.39 (0.95 mmol) from 0.47 g
(2.0 mmol) of 14c (47%), red crystals, m.p. 198.2 ꢁC. IR
(C20H23NO) C, H, N.
6.2.7.12. 5-Hexyl-2-(4-methoxyphenyl)-1H-indole (15f). Yield:
2.9 g (9.4 mmol) from 4.3 g (18.8 mmol) of 4b (50%), colour-
less crystals, m.p. 183 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3436, 2929,
1609, 1549, 1503, 1399. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.84 (t, 3H, J ¼ 6.8 Hz), 1.24e1.38 (m, 6H),
1.51e1.63 (m, 2H), 2.60 (t, 2H, J ¼ 7.5 Hz), 3.79 (s, 3H),
6.66 (d, 1H, J ¼ 1.6 Hz), 6.88 (dd, 1H, Jo ¼ 8.3 Hz,
Jm ¼ 1.6 Hz), 7.01 (d, 2H, J ¼ 8.7 Hz), 7.23e7.27 (m, 2H),
7.75 (d, 2H, J ¼ 8.7 Hz), 11.25 (s, 1H). EI-MS (70 eV) m/z
1
(KBr): n (cmꢀ1) ¼ 3359, 3191, 1773, 1711, 1611, 1476. H
NMR (DMSO-d6): d (ppm) ¼ 0.90 (t, 3H, J ¼ 7.3 Hz), 1.57e
1.65 (m, 2H), 2.62 (t, 2H, J ¼ 7.3 Hz), 7.04 (dd, 1H, J ¼ 1.6,
8.3 Hz), 7.25 (s, 1H), 7.32e7.56 (m, 6H), 11.31 (s, 1H), 12.02
(s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%):
409 (100) [M þ H]þ. Anal. (C21H17BrN2O2) C, H, N.
6.2.9.4. 3-Bromo-4-(5-butyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (18d). Yield: 0.40 g (0.95 mmol) from 0.50 g
(2 mmol) of 14d (47%), red crystals, m.p. 200.2 ꢁC. IR (KBr):
ꢄ
ꢄ
(%): 307 (100) [Mþ ], 236 (68) [M ꢀ C5H11]þ. Anal.
(C21H25NO) C, H, N.
1
n (cmꢀ1) ¼ 3378, 2954, 1775, 1726, 1613, 1464. H NMR
(DMSO-d6): d (ppm) ¼ 0.89 (t, 3H, J ¼ 7.3 Hz), 1.27e1.36
(m, 2H), 1.52e1.61 (m, 2H), 2.64 (t, 2H, J ¼ 7.5 Hz), 7.04
(dd, 1H, J ¼ 1.6, 8.3 Hz), 7.24 (s, 1H), 7.32e7.56 (m, 6H),
11.31 (s, 1H), 12.01 (s, 1H). ES-MS (DCM/MeOH þ 10 m-
mol/l NH4Ac) m/z (%): 423 (100) [M þ H]þ. Anal.
(C22H19BrN2O2$1/6DCM) C, H, N.
6.2.8. Condensation of TBSedibromomaleinimide with
indole derivatives (16aef and 17aef) (Table 5)
The respective indoles (14aef and 15aef) were dissolved
in dry THF, and the solution was cooled under argon to
ꢀ20 ꢁC. Then LiHMDS (2 eq, 1 M in THF) was slowly added.
After stirring the solution for 45 min at ꢀ20 ꢁC, TBSedibro-
momaleinimide (1 eq) in THF was added within 3 h. The so-
lution was stirred for 15 min, poured into sat. aq. NH4Cl,
extracted with ethyl acetate, dried over Na2SO4 and concen-
trated in vacuo. The crude products were processed to 18ae
f and 19aef without further purification.
6.2.9.5. 3-Bromo-4-(5-pentyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (18e). Yield: 0.40 g (0.91 mmol) from 0.53 g
(2.0 mmol) of 14e (45%), red crystals, m.p. 185 ꢁC. IR
1
(KBr): n (cmꢀ1) ¼ 3399, 2927, 1771, 1709, 1615, 1460. H
NMR (DMSO-d6): d (ppm) ¼ 0.85 (t, 3H, J ¼ 6.7 Hz),
1.27e1.31 (m, 4H), 1.50e1.70 (m, 2H), 2.63 (t, 2H,
J ¼ 7.5 Hz), 7.04 (dd, 1H, J ¼ 1.6, 8.3 Hz), 7.24 (s, 1H),
7.32e7.56 (m, 6H), 11.31 (s, 1H), 12.01 (s, 1H). ES-MS
(DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 437 (100)
[M þ H]þ. Anal. (C23H21BrN2O2) C, H, N.
6.2.9. Removal of the silyl-protecting group to give 18aef
and 19aef (Table 5)
The raw silyl-protected indoleemaleinimides (16aef and
17aef) were dissolved in THF under N2, tetrabutylammonium
fluoride trihydrate (1.3 eq) was added, and the mixture was
stirred for 2 h at room temperature, poured into ice, mixed
with saturated NH4Cl solution and extracted with ethyl ace-
tate. The extract was dried over Na2SO4, the solvent was re-
moved in vacuo and the remaining oil was purified by CC
(DCM) and crystallized from pentane.
6.2.9.6. 3-Bromo-4-(5-hexyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (18f). Yield: 0.35 g (0.77 mmol) from 0.550 g
(1.98 mmol) of 14f (39%), red crystals, m.p. 175 ꢁC. IR
1
(KBr): n (cmꢀ1) ¼ 3438, 2954, 1773, 1713, 1617, 1462. H
NMR (DMSO-d6): d (ppm) ¼ 0.84 (t, 3H, J ¼ 6.7 Hz), 1.27e
1.31 (m, 6H), 1.50e1.70 (m, 2H), 2.63 (t, 2H, J ¼ 7.5 Hz),

648
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
7.04 (dd, 1H, J ¼ 1.6, 8.3 Hz), 7.24 (s, 1H), 7.32e7.56 (m, 6H),
11.31 (s, 1H), 12.01 (s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l
NH4Ac) m/z (%): 451 (100) [M þ H]þ. Anal. (C24H23BrN2O2)
C, H, N.
(s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z
(%): 467 (100) [M þ H]þ. Anal. (C24H23BrN2O3) C, H, N.
6.2.9.12. 3-Bromo-4-[5-hexyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (19f). Yield: 0.43 g (0.9 mmol) from
0.60 g (2.0 mmol) of 15f (45%), red crystals, m.p. 205 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3371, 2927, 1709, 1609, 1447. 1H
NMR (DMSO-d6): d (ppm) ¼ 0.83 (t, 3H, J ¼ 7.1 Hz),
1.20e1.40 (m, 6H), 1.50e1.70 (m, 2H), 2.62 (t, 2H,
J ¼ 7.5 Hz), 3.79 (s, 3H), 6.98e7.07 (m, 3H), 7.20 (s,
1H), 7.34 (d, 1H, J ¼ 8.3 Hz), 7.46 (d, 2H, J ¼ 8.7 Hz),
11.29 (s, 1H), 11.90 (s, 1H). ES-MS (DCM/MeOH þ
10 mmol/l NH4Ac) m/z (%): 481 (100) [M þ H]þ. Anal.
(C25H25BrN2O3) C, H, N.
6.2.9.7. 3-Bromo-4-[5-methyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (19a). Yield: 0.44 g (1.1 mmol) from
0.48 g (2.0 mmol) of 15a (53%), red crystals, m.p. 260 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3380, 2936, 1711, 1611, 1449. 1H
NMR (DMSO-d6): d (ppm) ¼ 2.37 (s, 3H), 3.79 (s, 3H),
6.99e7.04 (m, 3H), 7.20 (s, 1H), 7.33 (d, 1H, J ¼ 8.3 Hz),
7.47 (d, 2H, J ¼ 8.7 Hz), 11.30 (s, 1H), 11.98 (s, 1H). ES-
MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 411 (100)
[M þ H]þ. Anal. (C20H15BrN2O3) C, H, N.
6.2.9.8. 3-Bromo-4-[5-ethyl-2-(4-methoxyphenyl)-1H-indole-3-
yl]pyrrole-2,5-dione (19b). Yield: 0.42 g (1.0 mmol) from
0.50 g (2.0 mmol) of 15b (50%), red crystals, m.p. 245 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3363, 2927, 1707, 1609, 1491. 1H
NMR (DMSO-d6): d (ppm) ¼ 1.20 (t, 3H, J ¼ 7.5 Hz), 2.66
(q, 2H, J ¼ 7.5 Hz), 3.79 (s, 3H), 7.00e7.06 (m, 3H), 7.23
(s, 1H), 7.36 (d, 1H, J ¼ 8.3 Hz), 7.47 (d, 2H, J ¼ 9.1 Hz),
11.29 (s, 1H), 11.90 (s, 1H). ES-MS (DCM/MeOH þ 10 m-
mol/l NH4Ac) m/z (%): 425 (100) [M þ H]þ. Anal.
(C21H17BrN2O3) C, H, N.
6.2.10. Formation of the indoles 20aed and 21aee (Table 4)
The respective anilines (5mer, 3 eq) were dissolved in
DMA and stirred at reflux in an N2 atmosphere. A solution
of 1 eq of 4a or 4b in xylene was added dropwise to the hot
solution, which was subsequently stirred at 150 ꢁC for 15 h.
The solution was cooled to 0 ꢁC, and the precipitated crude
product was filtered and washed with EE and methanol. The
crude product was purified by CC (DCM) and crystallized
from pentane.
6.2.10.1. 7-Methyl-2-phenyl-1H-indole (20a). Yield: 3.75 g
(18 mmol) from 6.1 g (30 mmol) of 4a (59%), colourless crys-
tals, m.p. 110 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3450, 1667, 1448,
6.2.9.9. 3-Bromo-4-[5-propyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (19c). Yield: 0.44 g (1 mmol) from
0.53 g (2.0 mmol) of 15c (50%), red crystals, m.p. 230 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3349, 2957, 1709, 1607, 1491. 1H
NMR (DMSO-d6): d (ppm) ¼ 0.89 (t, 3H, J ¼ 7.5 Hz),
1.56e1.65 (m, 2H), 2.61 (t, 2H, J ¼ 7.3 Hz), 3.79 (s, 3H),
6.90e7.05 (m, 3H), 7.21 (s, 1H), 7.35 (d, 1H, J ¼ 8.3 Hz),
7.47 (d, 2H, J ¼ 8.7 Hz), 11.29 (s, 1H), 11.90 (s, 1H). ES-
MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 439 (100)
[M þ H]þ. Anal. (C22H19BrN2O3$1/5H2O) C, H, N.
1
1301. H NMR (DMSO-d6): d (ppm) ¼ 2.53 (s, 3H), 6.87 (d,
1H, J ¼ 3.0 Hz), 6.88e6.98 (m, 2H), 7.27e7.36 (m, 2H),
7.42e7.48 (m, 2H), 7.90e7.95 (m, 2H), 11.04 (s, 1H). EI-MS
ꢄ
(70 eV) m/z (%): 207 (100) [Mþ ]. Anal. (C15H13N) C, H, N.
6.2.10.2. 7-Ethyl-2-phenyl-1H-indole (20b). Yield: 5.12 g
(23 mol) from 6.1 g (31 mmol) of 4a (75%), colourless crys-
tals, m.p. 55 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3454, 1601, 1450,
1296. 1H NMR (DMSO-d6):
d
(ppm) ¼ 1.28 (t, 3H,
6.2.9.10. 3-Bromo-4-[5-butyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (19d). Yield: 0.36 g (0.8 mmol) from
0.56 g (2.0 mmol) of 15d (50%), red crystals, m.p. 230 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3349, 2929, 1711, 1607, 1439. 1H
NMR (DMSO-d6): d (ppm) ¼ 0.89 (t, 3H, J ¼ 7.3 Hz),
1.27e1.36 (m, 2H), 1.50e1.60 (m, 2H), 2.62 (t, 2H,
J ¼ 7.5 Hz), 3.79 (s, 3H), 6.98e7.05 (m, 3H), 7.22 (s, 1H),
7.34 (d, 1H, J ¼ 7.9 Hz), 7.49 (d, 2H, J ¼ 8.7 Hz), 11.29 (s,
1H), 11.90 (s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l
NH4Ac) m/z (%): 453 (100) [M þ H]þ. Anal. (C23H21BrN2O3)
C, H, N.
J ¼ 7.3 Hz), 2.95 (q, 2H, J ¼ 7.5 Hz), 6.87 (d, 1H,
J ¼ 2.0 Hz), 6.88e6.97 (m, 2H), 7.27e7.36 (m, 2H), 7.45
(t, 2H, J ¼ 7.5 Hz), 7.93 (d, 2H, J ¼ 7.9 Hz), 11.03 (s, 1H).
ꢄ
EI-MS (70 eV) m/z (%): 221 (100) [Mþ ], 206 (76)
ꢄ
[M ꢀ CH3]þ. Anal. (C17H15N) C, H, N.
6.2.10.3. 7-Butyl-2-phenyl-1H-indole (20c). Yield: 4.5 g
(18 mmol) from 6.1 g (31 mmol) of 4a (59%), oil. IR (KBr):
n
(cmꢀ1) ¼ 3450, 2928, 1605, 1451, 1303. 1H NMR
(CDCl3): d (ppm) ¼ 0.98 (t, 3H, J ¼ 7.3 Hz), 1.40e1.55 (m,
2H), 1.70e1.82 (m, 2H), 2.87 (t, 2H, J ¼ 7.7 Hz), 6.83 (d,
1H, J ¼ 2.1 Hz), 6.99e7.11 (m, 2H), 7.29e7.38 (m, 2H),
7.42e7.49 (m, 2H), 7.67e7.78 (m, 2H), 8.20 (s, 1H). EI-MS
6.2.9.11. 3-Bromo-4-[5-pentyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (19e). Yield: 0.41 g (0.89 mmol) from
0.59 (2.0 mmol) of 15e (44%), red crystals, m.p. 215 ꢁC. IR
ꢄ
ꢄ
(70 eV) m/z (%): 249 (83) [Mþ ], 206 (100) [M ꢀ C3H7]þ.
Anal. (C18H19N$1/10pentane) C, H, N.
1
(KBr): n (cmꢀ1) ¼ 3390, 2927, 1711, 1611, 1447. H NMR
(DMSO-d6): d (ppm) ¼ 0.85 (t, 3H, J ¼ 7.3 Hz), 1.27e1.37
(m, 4H), 1.50e1.70 (m, 2H), 2.62 (t, 2H, J ¼ 7.3 Hz), 3.79
(s, 3H), 6.98e7.05 (m, 3H), 7.21 (s, 1H), 7.34 (d, 1H,
J ¼ 7.9 Hz), 7.46 (d, 2H, J ¼ 9.1 Hz), 11.29 (s, 1H), 11.90
6.2.10.4. 7-Pentyl-2-phenyl-1H-indole (20d). Yield: 4.6 g
(17 mmol) from 4.5 g (23 mmol) of 4a (77%), oil. IR (KBr):
n
(cmꢀ1) ¼ 3450, 2928, 1605, 1452, 1302. 1H NMR
(CDCl3): d (ppm) ¼ 0.92 (t, 3H, J ¼ 7.0 Hz), 1.33e1.67 (m,

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
649
4H), 1.72e1.84 (m, 2H), 2.87 (t, 2H, J ¼ 7.7 Hz), 6.83 (d, 1H,
J ¼ 1.8 Hz), 6.99e7.11 (m, 2H), 7.29e7.35 (m, 2H), 7.42e
7.49 (m, 2H), 7.67e7.78 (m, 2H), 8.20 (s, 1H). EI-MS
J ¼ 8.7 Hz), 10.88 (s, 1H). EI-MS (70 eV) m/z (%): 307 (100)
ꢄ
ꢄ
[Mþ ], 236 (52) [M ꢀ C5H11]þ. Anal. (C21H25NO$1/20DCM)
C, H, N.
ꢄ
ꢄ
(70 eV) m/z (%): 263 (78) [Mþ ], 206 (100) [M ꢀ C4H9]þ.
Anal. (C19H21N$1/6H2O) C, H, N.
6.2.11. Condensation of TBSedibromomaleinimide with
indole derivatives (22aed and 23aee) (Table 5)
6.2.10.5. 7-Methyl-2-(4-methoxyphenyl)-1H-indole (21a). Yield:
3.5 g (15 mmol) from 6.5 g (28.4 mmol) of 4b (53%), colourless
crystals, m.p. 125 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3400, 1608, 1550,
The respective indoles (20aed and 21aee) were dissolved
in dry THF and cooled under argon to ꢀ20 ꢁC. Then LiHMDS
(2 eq, 1 M in THF) was slowly added. After stirring the solu-
tion for 45 min at ꢀ20 ꢁC, TBSedibromomaleinimide (1 eq)
in THF was added within 3 h. The solution was stirred for
15 min, poured into sat. aq. NH4Cl, extracted with ethyl ace-
tate, dried over Na2SO4 and concentrated in vacuo. The crude
products were processed to 24aed and 25aee without further
purification.
1506, 1355. 1H NMR (DMSO-d6):
d
(ppm) ¼
2.52 (s, 3H), 3.80 (s, 3H), 6.73 (d, 1H, J ¼ 2.1 Hz), 6.82e6.91
(m, 2H), 7.02 (d, 2H, J ¼ 8.8 Hz), 7.30 (dd, 1H, Jo ¼ 7.2 Hz,
Jm ¼ 1.4 Hz), 7.85 (d, 2H, J ¼ 8.8 Hz), 10.93 (s, 1H). EI-MS
ꢄ
ꢄ
(70 eV) m/z (%): 237 (100) [Mþ ], 222 (58) [M ꢀ CH3]þ. Anal.
(C16H15NO) C, H, N.
6.2.10.6. 7-Ethyl-2-(4-methoxyphenyl)-1H-indole (21b). Yield:
3.8 g (15 mmol) from 6.5 g (28.4 mmol) of 4b (53%), colourless
crystals, m.p. 120 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3454, 2964, 1613,
1506, 1350. 1H NMR (DMSO-d6): d (ppm) ¼ 1.28 (t, 3H,
J ¼ 7.5 Hz), 2.94 (q, 2H, J ¼ 7.5 Hz), 3.80 (s, 3H), 6.73 (d,
1H, J ¼ 2.0 Hz), 6.85e6.94 (m, 2H), 7.02 (d, 2H, J ¼ 8.7 Hz),
7.30 (dd, 1H, Jo ¼ 6.9 Hz, Jm ¼ 1.8 Hz), 7.85 (d, 2H,
J ¼ 8.7 Hz), 10.92 (s, 1H). EI-MS (70 eV) m/z (%): 251 (100)
6.2.12. Removal of the silyl-protecting group to give
24aed and 25aee (Table 5)
The raw silyl-protected indoleemaleinimides (22aed and
23aee) were dissolved in THF under N2, tetrabutylammonium
fluoride trihydrate (1.3 eq) was added, and the mixture was
stirred for 2 h, poured into ice, mixed with saturated NH4Cl
solution and extracted with ethyl acetate. The extract was
dried over Na2SO4, the solvent was removed in vacuo and
the remaining oil was purified by CC (DCM) and crytallized
from pentane.
ꢄ
ꢄ
[Mþ ], 236 (56) [M ꢀ CH3]þ. Anal. (C17H17NO) C, H, N.
6.2.10.7. 7-Propyl-2-(4-methoxyphenyl)-1H-indole (21c).
Yield: 2.45 g (9.2 mmol) from 6.5 g (28.4 mmol) of 4b
(32%), colourless crystals, m.p. 100 ꢁC. IR (KBr): n (cmꢀ1) ¼
3450, 2953, 1613, 1505, 1352. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.97 (t, 3H, J ¼ 7.3 Hz), 1.62e1.74 (m, 2H), 2.89
(t, 2H, J ¼ 7.6 Hz), 3.80 (s, 3H), 6.72 (d, 1H, J ¼ 2.0 Hz),
6.85e6.93 (m, 2H), 7.02 (d, 2H, J ¼ 8.8 Hz), 7.30 (dd, 1H,
Jo ¼ 7.3 Hz, Jm ¼ 1.3 Hz), 7.85 (d, 2H, J ¼ 8.8 Hz), 10.89 (s,
6.2.12.1. 3-Bromo-4-(7-methyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (24a). Yield: 0.24 g (0.63 mmol) from 0.42 g
(2.0 mmol) of 20a (32%), red crystals, m.p. 250 ꢁC. IR
1
(KBr): n (cmꢀ1) ¼ 3367, 1705, 1602, 1456, 1330. H NMR
(DMSO-d6): d (ppm) ¼ 2.55 (s, 3H), 7.00 (d, 2H, 6.1 Hz),
7.25e7.28 (m, 1H), 7.35e7.48 (m, 3H), 7.55e7.72 (m, 2H),
11.31 (s, 1H), 11.81 (s, 1H). ES-MS (DCM/MeOH þ 10 m-
mol/l NH4Ac) m/z (%): 381 (100) [M þ H]þ. Anal.
(C19H13BrN2O2) C, H, N.
ꢄ
1H). EI-MS (70 eV) m/z (%): 265 (100) [Mþ ], 236 (57)
ꢄ
[M ꢀ C2H5]þ. Anal. (C18H19NO) C, H, N.
6.2.10.8. 7-Butyl-2-(4-methoxyphenyl)-1H-indole (21d). Yield:
3.8 g (14 mmol) from 6.5 g (28.4 mmol) of 4b (49%), col-
ourless crystals, m.p. 85 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3431,
2928, 1608, 1508, 1356. 1H NMR (DMSO-d6):
d (ppm) ¼ 0.92 (t, 3H, J ¼ 7.3 Hz), 1.32e1.47 (m, 2H),
1.59e1.72 (m, 2H), 2.91 (t, 2H, J ¼ 7.5 Hz), 3.80 (s, 3H),
6.72 (d, 1H, J ¼ 2.0 Hz), 6.83e6.93 (m, 2H), 7.02 (d, 2H,
J ¼ 8.7 Hz), 7.30 (dd, 1H, Jo ¼ 7.3 Hz, Jm ¼ 1.3 Hz), 7.85
(d, 2H, J ¼ 8.7 Hz), 10.88 (s, 1H). EI-MS (70 eV) m/z
6.2.12.2. 3-Bromo-4-(7-ethyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (24b). Yield: 0.35 g (0.88 mmol) from 0.44 g
(2.0 mmol) of 20b (44%), red crystals, m.p. 228 ꢁC. IR (KBr):
1
n (cmꢀ1) ¼ 3357, 1770, 1716, 1616, 1456, 1328. H NMR
(DMSO-d6): d (ppm) ¼ 1.34 (t, 3H, J ¼ 7.5 Hz), 3.02 (q, 2H,
J ¼ 6.2 Hz), 7.06e7.12 (m, 2H), 7.31e7.37 (m, 1H), 7.40e
7.51 (m, 3H), 7.53e7.63 (m, 2H), 11.36 (s, 1H), 11.72 (s, 1H).
ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 395
(100) [M þ H]þ. Anal. (C20H15BrN2O2$H2O) C, H, N.
ꢄ
ꢄ
(%): 279 (100) [Mþ ], 236 (55) [M ꢀ C3H7]þ. Anal.
(C19H21NO$1/12DCM) C, H, N.
6.2.12.3. 3-Bromo-4-(7-butyl-2-phenyl-1H-indole-3-yl)pyrrole-
2,5-dione (24c). Yield: 0.36 g (0.85 mmol) from 0.50 g
(2.0 mmol) of 20c (42%), red crystals, m.p. 229 ꢁC. IR
6.2.10.9. 7-Hexyl-2-(4-methoxyphenyl)-1H-indole (21e). Yield:
4.6 g (15 mmol) from 6.4 g (27.9 mmol) of 4b (54%), colour-
less crystals, m.p. 100 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3435, 2925,
1
(KBr): n (cmꢀ1) ¼ 3381, 1770, 1706, 1619, 1453, 1333. H
NMR (DMSO-d6): d (ppm) ¼ 0.98 (t, 3H, J ¼ 7.3 Hz),
1.41e1.51 (m, 2H), 1.66e1.77 (m, 2H), 2.99 (t, 2H,
J ¼ 6.8 Hz), 7.04e7.11 (m, 2H), 7.31e7.35 (m, 1H), 7.38e
7.45 (m, 3H), 7.49e7.62 (m, 2H), 11.35 (s, 1H), 11.85 (s,
1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%):
423 (100) [M þ H]þ. Anal. (C22H19BrN2O2) C, H, N.
1608, 1504, 1352. 1H NMR (DMSO-d6):
d
(ppm) ¼
0.85 (t, 3H, J ¼ 3.2 Hz), 1.20e1.40 (m, 6H), 1.50e1.70 (m,
2H), 2.91 (t, 2H, J ¼ 7.5 Hz), 3.80 (s, 3H), 6.72 (d, 1H,
J ¼ 2.0 Hz), 6.83e6.93 (m, 2H), 7.02 (d, 2H, J ¼ 8.7 Hz),
7.30 (dd, 1H, Jo ¼ 7.3 Hz, Jm ¼ 1.3 Hz), 7.85 (d, 2H,

650
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
6.2.12.4. 3-Bromo-4-(7-pentyl-2-phenyl-1H-indole-3-yl)pyr-
role-2,5-dione (24d). Yield: 0.25 g (0.57 mmol) from 0.53 g
(2.0 mmol) of 20d (29%), red crystals, m.p. 223 ꢁC. IR (KBr):
from 0.62 g (2.0 mmol) of 21e (36%), red crystals, m.p.
217 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3383, 2930, 1772, 1719,
1
1612, 1493, 1450, 1331. H NMR (DMSO-d6): d (ppm) ¼
1
n (cmꢀ1) ¼ 3364, 1768, 1705, 1618, 1454, 1330. H NMR
0.92 (t, 3H, J ¼ 6.8 Hz), 1.30e1.50 (m, 6H), 1.60e1.80
(m, 2H), 2.97 (t, 2H, J ¼ 5.5 Hz), 3.84 (s, 3H), 6.01e7.10
(m, 4H), 7.28 (dd, 1H, Jo ¼ 6.1 Hz, Jm ¼ 1.5 Hz), 7.53 (d,
2H, J ¼ 7.3 Hz), 11.34 (s, 1H), 11.72 (s, 1H). ES-MS
(DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 481 (100)
[M þ H]þ. Anal. (C25H25BrN2O3$1/6H2O) C, H, N.
(DMSO-d6): d (ppm) ¼ 0.87 (t, 3H, J ¼ 5.9 Hz), 1.20e1.50
(m, 4H), 1.60e1.80 (m, 2H), 2.93 (t, 2H, J ¼ 6.5 Hz), 6.98e
7.05 (m, 2H), 7.24e7.28 (m, 1H), 7.35e7.40 (m, 3H), 7.44e
7.56 (m, 2H), 11.31 (s, 1H), 11.79 (s, 1H). ES-MS (DCM/
MeOH þ 10 mmol/l NH4Ac) m/z (%): 437 (100) [M þ H]þ.
Anal. (C23H21BrN2O2$3/2DCM) C, H, N.
6.2.13. Formation of the 5-alkyl/5-alkyloxy- and
6.2.12.5. 3-Bromo-4-[7-methyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (25a). Yield: 0.36 g (0.88 mmol) from
0.48 g (2.0 mmol) of 21a (44%), red crystals, m.p. 250 ꢁC. IR
2-methoxyphenyl indoles 26aeh (Table 4)
2-Bromo-30-methoxyacetophenone (4c) and the respective
aniline (2.5 eq) were dissolved in DMF and heated to reflux
for 24 h. After cooling to room temperature, HCl was added
and the crude product extracted with EE. The products were
purified by CC (DCM) and dried in vacuo.
1
(KBr): n (cmꢀ1) ¼ 3340, 1727, 1611, 1494, 1450, 1326. H
NMR (DMSO-d6): d (ppm) ¼ 2.54 (s, 3H), 3.79 (s, 3H),
6.97e7.05 (m, 4H), 7.24 (dd, 1H, Jo ¼ 6.5 Hz, Jm ¼ 2.6 Hz),
7.50 (d, 2H, J ¼ 8.7 Hz), 11.30 (s, 1H), 11.71 (s, 1H). ES-MS
(DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 411 (100)
[M þ H]þ. Anal. (C20H15BrN2O3) C, H, N.
6.2.13.1. 5-Methoxy-2-(3-methoxyphenyl)-1H-indole (26a)
[27]. Yield: 1.9 g (7.5 mmol) from 2.05 g (9.0 mmol) of 4c
1
(83%), yellow crystals, m.p. 143.7 ꢁC. H NMR (DMSO-d6):
6.2.12.6. 3-Bromo-4-[7-ethyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (25b). Yield: 0.48 g (1.12 mmol) from
0.5 g (2.0 mmol) of 21b (56%), red crystals, m.p. 220 ꢁC. IR
(KBr): n (cmꢀ1) ¼ 3348, 1769, 1716, 1611, 1489, 1446, 1323.
1H NMR (DMSO-d6): d (ppm) ¼ 1.29 (t, 3H, J ¼ 7.5 Hz),
2.96 (q, 3H, J ¼ 7.5 Hz), 3.79 (s, 3H), 6.98e7.05 (m, 4H),
7.24 (dd, 1H, Jo ¼ 6.4 Hz, Jm ¼ 2.8 Hz), 7.50 (d, 2H,
J ¼ 8.7 Hz), 11.29 (s, 1H), 11.70 (s, 1H). ES-MS (DCM/
MeOH þ 10 mmol/l NH4Ac) m/z (%): 425 (100) [M þ H]þ.
Anal. (C21H17BrN2O3$1/3H2O) C, H, N.
d (ppm) ¼ 3.76 (s, 3H), 3.84 (s, 3H), 6.74 (dd, 1H, J ¼ 2.5,
8.7 Hz), 6.83 (d, 1H, J ¼ 1.6 Hz), 6.87 (m, 1H), 7.02 (d, 1H,
J ¼ 2.4 Hz), 7.28 (d, 1H, J ¼ 8.8 Hz), 7.35 (t, 1H,
J ¼ 7.9 Hz), 7.41 (dd, 2H, J ¼ 1.5, 7.5 Hz), 11.36 (s, 1H).
6.2.13.2. 5-Ethoxy-2-(3-methoxyphenyl)-1H-indole (26b). Yield:
1.35 g (5.1 mmol) from 5.1 g (22.2 mmol) of 4c (23%), yellow
crystals, m.p. 155.7 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3428, 3300, 3064,
1
1673, 1610, 1478. H NMR (CDCl3): d (ppm) ¼ 1.44 (t, 3H,
J ¼ 7.0 Hz), 3.88 (s, 3H), 4.08 (q, 2H, J ¼ 7.0 Hz), 6.74 (m,
1H), 6.86 (dd, 1H, J ¼ 2.4, 8.7 Hz), 6.87 (m, 1H), 7.08 (d, 1H,
J ¼ 2.4 Hz), 7.17 (m, 1H), 7.23 (m, 1H), 7.28 (d, 1H,
J ¼ 8.8 Hz), 7.35 (t, 1H, J ¼ 7.9 Hz), 8.22 (s, 1H). CI-MS
(NH3) m/z (%): 268 (100) [M þ Hþ]. Anal. (C17H17NO2$1/
7MeOH) C, H, N.
6.2.12.7. 3-Bromo-4-[7-propyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (25c). Yield: 0.44 g (0.99 mmol) from
0.53 g (2.0 mmol) of 21c (49%), red crystals, m.p. 203 ꢁC. IR
(KBr): n (cmꢀ1) ¼ 3373, 1770, 1707, 1608, 1489, 1448, 1332.
1H NMR (DMSO-d6): d (ppm) ¼ 0.98 (t, 3H, J ¼ 7.3 Hz),
1.60e1.80 (m, 2H), 2.91 (t, 2H, J ¼ 7.3 Hz), 3.79 (s, 3H),
6.97e7.05 (m, 4H), 7.24 (dd, 1H, Jo ¼ 6.4 Hz, Jm ¼ 2.8 Hz),
7.50 (d, 2H, J ¼ 8.7 Hz), 11.29 (s, 1H), 11.70 (s, 1H). ES-MS
(DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 439 (100)
[M þ H]þ. Anal. (C22H19BrN2O3$1/4H2O) C, H, N.
6.2.13.3. 5-Butoxy-2-(3-methoxyphenyl)-1H-indole (26c). Yield:
2.2 g (7.4 mmol) from 4.9 g (21.8 mmol) of 4c (34%), yellow
crystals, m.p. 82.5 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3429, 1609,
1579. 1H NMR (CDCl3): d (ppm) ¼ 0.98 (t, 3H, J ¼
7.3 Hz), 1.51 (qd, 2H, J ¼ 7.3, 14.5 Hz), 1.79 (m, 2H), 3.84
(s, 3H), 4.00 (t, 2H, J ¼ 6.6 Hz), 6.72 (d, 1H, J ¼ 1.5 Hz),
6.83 (m, 1H), 6.86 (m, 1H), 7.07 (d, 1H, J ¼ 2.4 Hz), 7.15
(m, 1H), 7.20 (m, 1H), 7.23 (m, 1H), 7.31 (t, 1H,
J ¼ 7.9 Hz), 8.26 (s, 1H). CI-MS (NH3) m/z (%): 296 (100)
[M þ Hþ]. Anal. (C19H21NO2$1/4H2O) C, H, N.
6.2.12.8. 3-Bromo-4-[7-butyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (25d). Yield: 0.38 g (0.84 mmol) from
0.56 g (2.0 mmol) of 21d (42%), red crystals, m.p. 217 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3365, 1768, 1705, 1613, 1491, 1449,
1331. 1H NMR (DMSO-d6):
d
(ppm) ¼ 0.92 (t, 3H,
J ¼ 7.3 Hz), 1.35e1.45 (m, 2H), 1.60e1.72 (m, 2H), 2.93 (t,
2H, J ¼ 5.5 Hz), 3.79 (s, 3H), 6.97e7.05 (m, 4H), 7.23 (dd,
1H, Jo ¼ 6.0 Hz, Jm ¼ 1.5 Hz), 7.48 (d, 2H, J ¼ 7.3 Hz),
11.28 (s, 1H), 11.68 (s, 1H). ES-MS (DCM/MeOH þ 10 m-
mol/l NH4Ac) m/z (%): 453 (100) [M þ H]þ. Anal.
(C23H21BrN2O3$1/4H2O) C, H, N.
6.2.13.4. 5-Hexyloxy-2-(3-methoxyphenyl)-1H-indole (26d).
Yield: 3.8 g (11.7 mmol) from 4.7 g (20.9 mmol) of 4c
(56%), yellow crystals, m.p. 58.9 ꢁC. IR (KBr): n (cmꢀ1) ¼
3435, 3400, 2946, 2923, 1609, 1452. 1H NMR (CDCl3):
d (ppm) ¼ 0.90 (t, 3H, J ¼ 7.0 Hz), 1.34 (m, 4H), 1.47 (m,
2H), 1.79 (m, 2H), 3.83 (s, 3H), 3.99 (t, 2H, J ¼ 6.6 Hz),
6.71 (dd, 1H, J ¼ 0.7, 2.1 Hz), 6.85 (dd, 1H, J ¼ 2.5,
8.8 Hz), 6.83 (m, 1H), 7.07 (d, 1H, J ¼ 2.3 Hz), 7.14 (m,
1H), 7.18 (m, 1H), 7.22 (d, 1H, J ¼ 8.8 Hz), 7.30 (t, 1H,
6.2.12.9. 3-Bromo-4-[7-hexyl-2-(4-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (25e). Yield: 0.35 g (0.73 mmol)

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
651
J ¼ 7.9 Hz), 8.21 (s, 1H). CI-MS (NH3) m/z (%): 324 (100)
6.2.15. Removal of the sylil-protecting group to give 28aeh
(Table 5)
[M þ Hþ]. Anal. (C21H25NO2) C, H, N.
The raw silyl-protected indoleemaleinimides (27aeh)
were dissolved in THF under N2, tetrabutylammonium fluo-
ride trihydrate (1.3 eq) was added, and the mixture was stirred
for 2 h at room temperature, poured into ice, mixed with sat-
urated NH4Cl solution and extracted with ethyl acetate. The
extract was dried over Na2SO4, the solvent was removed in
vacuo and the remaining oil was purified by CC (DCM).
6.2.13.5. 2-(3-Methoxyphenyl)-5-methyl-1H-indole (26e).
Yield: 1.8 g (7.6 mmol) from 7.1 g (31.7 mmol) of 4c (24%),
yellow crystals, m.p. 126.6 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3436,
1
1609. H NMR (DMSO-d6): d (ppm) ¼ 2.37 (s, 3H), 3.84 (s,
3H), 6.82 (dd, 1H, J ¼ 0.6, 2.2 Hz), 6.87 (m, 1H), 6.92 (dd,
1H, J ¼ 1.4, 8.3 Hz), 7.28 (m, 2H), 7.35 (t, 1H, J ¼ 8.1 Hz),
7.42 (m, 2H), 11.38 (s, 1H). EI-MS (70 eV) m/z (%): 237
ꢄ
(100) [Mþ ]. Anal. (C16H15NO$1/6H2O) C, H, N.
6.2.15.1.
3-Bromo-4-[5-methoxy-2-(3-methoxyphenyl)-1H-
indole-3-yl]pyrrole-2,5-dione (28a). Yield: 0.21 g (0.5 mmol)
from 1.9 g (7.5 mmol) of 26a (6.6%), red crystals, m.p.
105.1 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3379, 3209, 1779, 1714,
1609, 1577, 1535. 1H NMR (DMSO-d6): d (ppm) ¼ 3.80
(s, 3H), 3.84 (s, 3H), 6.90 (dd, 1H, J ¼ 2.5, 8.8 Hz), 6.99
(m, 2H), 7.10 (m, 1H), 7.14 (m, 1H), 7.40 (d, 1H,
J ¼ 1.8 Hz), 7.43 (d, 1H, J ¼ 2.7 Hz), 11.39 (s, 1H), 12.05
(s, 1H). EI-MS (70 eV) m/z (%): 426 (10) [M þ Hþ]. Anal.
(C20H15BrN2O4$6/5H2O) C, H, N.
6.2.13.6. 5-Ethyl-2-(3-methoxyphenyl)-1H-indole (26f). Yield:
2.5 g (9.9 mmol) from 5.3 g (23.0 mmol) of 4c (43%), yellow
crystals, m.p. 106.2 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3431, 2963,
1611, 1544. 1H NMR (DMSO-d6): d (ppm) ¼ 1.22 (t, 3H,
J ¼ 7.6 Hz), 2.66 (q, 2H, J ¼ 7.5 Hz), 3.84 (s, 3H), 6.84 (d,
1H, J ¼ 1.5 Hz), 6.85e6.89 (m, 1H), 6.96 (dd, 1H, J ¼ 1.6,
8.3 Hz), 7.28e7.38 (m, 3H), 7.40e7.44 (m, 2H), 11.38 (s,
ꢄ
1H). EI-MS (70 eV) m/z (%): 251 (100) [Mþ ], 236 (95)
ꢄ
[M ꢀ CH3]þ. Anal. (C17H17NO$1/4H2O) C, H, N.
6.2.15.2. 3-Bromo-4-[5-ethoxy-2-(3-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (28b). Yield: 0.1 g (0.2 mmol) from
1.35 g (5.1 mmol) of 26b (4%), red crystals, m.p. 205.3 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3390, 3211, 1777, 1714, 1580, 1485.
1H NMR (DMSO-d6): d (ppm) ¼ 1.34 (t, 3H, J ¼ 6.9 Hz),
3.80 (s, 3H), 4.02 (q, 2H, J ¼ 7.1 Hz), 6.85 (dd, 1H, J ¼ 2.4,
8.7 Hz), 6.94 (m, 2H), 7.06 (m, 1H), 7.09 (m, 1H), 7.35 (m,
2H), 11.98 (s, 1H). CI-MS (NH3) m/z (%): 440 (100)
[M þ Hþ]. Anal. (C21H17BrN2O4$3/2H2O) C, H, N.
6.2.13.7. 5-Butyl-2-(3-methoxyphenyl)-1H-indole (26g). Yield:
5.9 g (21.1 mmol) from 5.3 g (22.9 mmol) of 4c (92%), yellow
crystals, m.p. 50.9 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3442, 2953, 1667.
1H NMR (CDCl3): d (ppm) ¼ 0.93 (t, 3H, J ¼ 7.3 Hz), 1.38
(qd, 2H, J ¼ 7.3, 14.4 Hz), 1.64 (m, 2H), 2.69 (m, 2H), 3.85
(s, 3H), 6.74 (dd, 1H, J ¼ 0.7, 2.1 Hz), 6.85 (ddd, 1H,
J ¼ 0.8, 2.5, 8.2 Hz), 7.02 (dd, 1H, J ¼ 1.6, 8.3 Hz), 7.16 (m,
1H), 7.21 (m, 1H), 7.27 (m, 1H), 7.33 (t, 1H, J ¼ 7.9 Hz),
7.41 (s, 1H), 8.22 (s, 1H). EI-MS (70 eV) m/z (%): 279 (64)
ꢄ
ꢄ
[Mþ ], 236 (84) [M ꢀ C3H7]þ, Anal. (C19H21NO) C, H, N.
6.2.15.3. 3-Bromo-4-[5-butoxy-2-(3-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (28c). Yield: 0.2 g (0.4 mmol) from
2.2 g (7.4 mmol) of 26c (5%), red crystals, m.p. 143.0 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3392, 3239, 2957, 1778, 1719, 1611,
1579, 1484. 1H NMR (CDCl3): d (ppm) ¼ 0.99 (t, 3H,
J ¼ 7.4 Hz), 1.50 (m, 2H), 1.81 (m, 2H), 3.83 (s, 3H), 4.01
(t, 2H, J ¼ 6.5 Hz), 6.93 (m, 2H), 6.98 (m, 2H), 7.02 (m,
2H), 7.39 (m, 1H), 7.41 (s, 1H), 8.55 (s, 1H). CI-MS (NH3)
m/z (%): 469 (75) [M þ Hþ]. Anal. (C23H21BrN2O4) C, H, N.
6.2.13.8.
5-Hexyl-2-(3-methoxyphenyl)-1H-indole
(26h).
Yield: 7.3 g (21.7 mmol) from 5.5 g (24.0 mmol) of 4c
(90%), yellow crystals, m.p. 76.1 ꢁC. IR (KBr): n (cmꢀ1) ¼
1
3440, 2921, 2852, 1730, 1667, 1609, 1437, 1044. H NMR
(CDCl3): d (ppm) ¼ 0.88 (t, 3H, J ¼ 6.9 Hz), 1.32 (m, 6H),
1.7 (m, 2H), 2.69 (m, 2H), 3.86 (s, 3H), 6.75 (m, 1H), 6.85
(ddd, 1H, J ¼ 0.8, 2.5, 8.2 Hz), 7.03 (dd, 1H, J ¼ 1.6,
8.3 Hz), 7.17 (m, 1H), 7.22 (m, 1H), 7.29 (d, 1H,
J ¼ 8.3 Hz), 7.34 (t, 1H, J ¼ 7.9 Hz), 7.41 (s, 1H), 8.23 (s,
6.2.15.4. 3-Bromo-4-[5-hexyloxy-2-(3-methoxyphenyl)-1H-indole-
3-yl]pyrrol-2,5-dione (28d). Yield: 0.15 g (0.3 mmol) from
3.8 g (11.7 mmol) of 26d (3%), red crystals, m.p. 168.7 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3312, 2918, 1712, 1605. 1H NMR
(DMSO-d6): d (ppm) ¼ 0.88 (t, 3H, J ¼ 7.0 Hz), 1.31 (m,
4H), 1.43 (m, 2H), 1.73 (m, 2H), 3.80 (s, 3H), 3.94 (t, 2H,
J ¼ 6.4 Hz), 6.85 (dd, 1H, J ¼ 2.4, 8.8 Hz), 6.94 (dd, 2H,
J ¼ 2.1, 7.7 Hz), 7.06 (m, 1H), 7.09 (m, 1H), 7.36 (m, 2H),
11.33 (s, 1H), 11.98 (s, 1H). ES-MS (DCM/MeOH þ 10 m-
mol/l NH4Ac) m/z (%): 497 (33) [M þ Hþ]. Anal.
(C25H25BrN2O4) C, H, N.
ꢄ
1H). EI-MS (70 eV) m/z (%): 307 (95) [Mþ ], 236 (100)
ꢄ
[M ꢀ C5H11]þ. Anal. (C21H25NO) C, H, N.
6.2.14. Condensation of TBSedibromomaleinimide with
indole derivatives (27aeh) (Table 5)
The indole derivatives (26aeh) were dissolved in dry THF
and cooled under argon to ꢀ20 ꢁC. Then LiHMDS (2 eq, 1 M
in THF) was slowly added. After stirring the solution for
45 min at ꢀ20 ꢁC, TBSedibromomaleinimide (1 eq) in THF
was added within 3 h. The solution was stirred for 15 min,
poured into sat. aq. NH4Cl, extracted with ethyl acetate, dried
over Na2SO4, concentrated in vacuo and processed to 28aeh
without further purification.
6.2.15.5. 3-Bromo-4-[2-(3-methoxyphenyl)-5-methyl-1H-indole-
3-yl]pyrrole-2,5-dione (28e). Yield: 0.15 g (0.4 mmol) from
1.8 g (7.6 mmol) of 26e (5%), red crystals, m.p. 187.3 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3302, 3174, 3071, 1772, 1712, 1605,

652
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
1484. 1H NMR (CDCl3): d (ppm) ¼ 2.48 (s, 3H), 3.83 (s, 3H),
6.93 (ddd, 1H, J ¼ 0.8, 2.5, 8.2 Hz), 6.99 (m, 1H), 7.03 (m,
1H), 7.12 (dd, 1H, J ¼ 1.5, 8.1 Hz), 7.33 (m, 1H), 7.36 (m,
1H), 7.40 (m, 1H), 8.57 (s, 1H). CI-MS (NH3) m/z (%): 411
(92) [M þ Hþ]. Anal. (C20H15BrN2O3$5/3H2O) C, H, N.
Table 6
Compounds 31aeh and 32aeh
O
O
HN
C
R3
N
H
N
H
R3
R3
n
n
H2
MeO
O
Nr.
n
Nr.
n
R3
6.2.15.6. 3-Bromo-4-[5-ethyl-2-(3-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (28f). Yield: 0.17 g (0.4 mmol) from
5.9 g (9.9 mmol) of 26f (4%), red crystals, m.p. 211.2 ꢁC. IR
(KBr): n (cmꢀ1) ¼ 3306, 1711, 1606, 1532. 1H NMR
(CDCl3): d (ppm) ¼ 1.29 (t, 3H, J ¼ 7.6 Hz), 2.77 (q, 2H,
J ¼ 7.6 Hz), 3.83 (s, 3H), 6.93 (ddd, 1H, J ¼ 0.8, 2.5,
8.3 Hz), 7.00 (m, 1H), 7.03 (m, 1H), 7.16 (dd, 1H, J ¼ 1.5,
8.4 Hz), 7.36 (m, 3H), 7.53 (s, 1H), 8.64 (s, 1H). CI-MS
(NH3) m/z (%): 425 (93) [M þ Hþ]. Anal. (C21H17BrN2O3$
3/2H2O) C, H, N.
31a
2
3
4
5
6
3
3
3
H
32a
2
3
4
5
6
3
3
3
H
H
H
H
H
31b
31c
H
32b
32c
H
31d
31e
H
32d
32e
H
31f
31g
4-Me
3-Me
2-Me
32f
32g
4-Me
3-Me
2-Me
31h [5]
32h [5]
6.2.16.2. 4-Phenylcarbamoylbutyric acid ethylester [29] (31b).
Yield: 12.0 g (51.0 mmol) from 5.2 g (56.0 mmol) of 30a
(91%), m.p. 70 ꢁC. 1H NMR (DMSO-d6): d (ppm) ¼ 1.18
(t, 3H, J ¼ 7.1 Hz), 2.34 (t, 4H, J ¼ 7.5 Hz), 4.06 (q, 2H,
J ¼ 7.1 Hz), 7.01 (t, 1H, J ¼ 6.3 Hz), 7.28 (t, 2H,
J ¼ 8.7 Hz), 7.58 (d, 1H, J ¼ 7.5 Hz), 9.88 (s, 1H).
6.2.15.7. 3-Bromo-4-[5-butyl-2-(3-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (28g). Yield: 0.11 g (0.3 mmol) from
5.9 g (21.1 mmol) of 26g (2%), red crystals, m.p. 193.5 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3301, 3176, 3069, 1711, 1604, 1482.
1H NMR (DMSO-d6): d (ppm) ¼ 0.90 (t, 3H, J ¼ 7.3 Hz),
1.33 (qd, 2H, J ¼ 7.3, 14.4 Hz), 1.59 (td, 2H, J ¼ 7.4,
15.1 Hz), 2.65 (t, 2H, J ¼ 7.5 Hz), 3.80 (s, 3H), 6.95 (dd,
1H, J ¼ 2.1, 8.0 Hz), 7.05 (m, 1H), 7.08 (m, 1H), 7.10 (m,
1H), 7.25 (s, 1H), 7.37 (d, 1H, J ¼ 3.2 Hz), 7.38 (m, 1H),
11.35 (s, 1H), 12.02 (s, 1H). CI-MS (NH3) m/z (%): 453
(100) [M þ Hþ]. Anal. (C23H21BrN2O3) C, H, N.
6.2.16.3. 5-Phenylcarbamoyl pentanoic acid methylester [28]
(31c). Yield: 11.8 g (50 mmol) from 5.8 g (62 mmol) of 30a
(81%), m.p. 48 ꢁC. 1H NMR (DMSO-d6): d (ppm) ¼ 1.57
(m, 4H), 2.31 (t, 2H, J ¼ 7.1 Hz), 2.34 (t, 2H, J ¼ 7.1 Hz),
3.58 (s, 3H), 7.01 (t, 1H, J ¼ 7.5 Hz), 7.28 (t, 2H,
J ¼ 8.7 Hz), 7.58 (d, 2H, J ¼ 7.9 Hz), 9.86 (s, 1H).
6.2.15.8. 3-Bromo-4-[5-hexyl-2-(3-methoxyphenyl)-1H-indole-
3-yl]pyrrole-2,5-dione (28h). Yield: 0.17 g (0.4 mmol) from
7.3 g (21.7 mmol) of 26h (2%), red crystals, m.p. 169.7 ꢁC.
IR (KBr): n (cmꢀ1) ¼ 3308, 2924, 1712, 1605. 1H NMR
(DMSO-d6): d (ppm) ¼ 0.85 (t, 3H, J ¼ 6.8 Hz), 1.29 (m,
6H), 1.60 (m, 2H), 2.64 (t, 2H, J ¼ 7.5 Hz), 3.80 (s, 3H),
6.95 (m, 1H), 7.05 (m, 1H), 7.08 (m, 1H), 7.10 (m, 1H),
7.25 (s, 1H), 7.32e7.40 (m, 2H), 11.35 (s, 1H), 12.02 (s,
1H). CI-MS (NH3) m/z (%): 481 (100) [M þ Hþ]. Anal.
(C25H25BrN2O3$1/2TBSH) C, H, N.
6.2.16.4. 6-Phenylcarbamoyl hexanoic acid methylester [28]
(31d). Yield: 3.6 g (13.7 mmol) from 3.9 g (41 mmol) of
30a (33%), m.p. 59 ꢁC. 1H NMR (DMSO-d6): d (ppm) ¼
1.16 (t, 3H, J ¼ 7.1 Hz), 1.31 (m, 2H), 1.57 (m, 4H), 2.28
(t, 4H, J ¼ 7.5 Hz), 7.01 (t, 1H, J ¼ 7.1 Hz), 7.27 (t, 2H,
J ¼ 8.3 Hz), 7.58 (d, 2H, J ¼ 7.5 Hz), 9.84 (s, 1H).
6.2.16.5. 7-Phenylcarbamoyl heptanoic acid methylester [28]
(31e). Yield: 5.74 g (21.8 mmol) from 2.25 g (24.3 mmol) of
30a (90%), m.p. 65 ꢁC. 1H NMR (DMSO-d6): d (ppm) ¼
1.2e1.35 (m, 4H), 1.45e1.60 (m, 4H), 2.24e2.31 (m, 4H),
3.56 (s, 3H), 7.00 (t, 1H, J ¼ 7.3 Hz), 7.26 (t, 2H,
J ¼ 7.9 Hz), 7.57 (d, 2H, J ¼ 8.1 Hz), 9.83 (s, 1H).
6.2.16. Formation of estereamides from carboxylic acids
and their chlorides and various anilines (31aeg) (Table 6)
The respective anilines (30aed) and triethylamine (1 eq)
were dissolved in dry CH2Cl2. The solution was cooled with
ice, and the acid chlorides or the acids (1 eq, 29aee) were
carefully added dropwise. Then the solution was heated to re-
flux for 12 h, cooled, the precipitated acid chloride was filtered
off, and the residue was purified by CC (DCM/EE ¼ 6:1). The
products were obtained as colourless powders.
6.2.16.6. 4-p-Tolylcarbamoyl butyric acid methylester [13]
(31f). Yield: 11.4 g (45.7 mmol) from 6.0 g (56 mmol) of
30b (82%), m.p. 95 ꢁC. 1H NMR (DMSO-d6): d (ppm) ¼
1.18 (t, 3H, J ¼ 7.1 Hz), 1.82 (quintett, 2H, J ¼ 7.1 Hz), 2.23
(s, 3H), 2.35 (t, 2H, J ¼ 7.5 Hz), 4.05 (q, 2H, J ¼ 7.1 Hz),
7.08 (d, 2H, J ¼ 8.3 Hz), 7.46 (t, 2H, J ¼ 8.3 Hz), 9.79
(s, 1H).
6.2.16.1. N-Phenylsuccinamic acid methylester [28] (31a).
Yield: 5.16 g (25 mmol) from 3.1 g (33 mmol) of 30a
(76%), white powder, m.p. 97 ꢁC. 1H NMR (CDCl3):
d (ppm) ¼ 2.65e2.69 (m, 2H), 2.73e2.78 (m, 2H), 3.71 (s,
3H), 7.09 (t, 1H, J ¼ 7.3 Hz), 7.31 (d, 2H, J ¼ 7.9 Hz), 7.50
(d, 2H, J ¼ 7.9 Hz), 7.60 (s, 1H).
6.2.16.7. 4-m-Tolylcarbamoyl butyric acid methylester [13]
(31g). Yield: 12.3 g (49.3 mmol) from 6.0 g (56.0 mmol) of
30c (88%), m.p. 55 ꢁC. 1H NMR (DMSO-d6): d (ppm) ¼
1.82 (quintett, 2H, J ¼ 7.5 Hz), 2.26 (s, 3H), 2.33 (t,
2H, J ¼ 7.5 Hz), 2.35 (t, 2H, J ¼ 7.5 Hz), 6.84 (d, 1H,

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
653
J ¼ 7.5 Hz), 7.15 (t, 1H, J ¼ 7.9 Hz), 7.35 (d, 1H, J ¼ 8.3 Hz),
2H), 1.59e1.77 (m, 4H), 2.30 (t, 2H, J ¼ 7.5 Hz), 2.71 (t,
2H, J ¼ 7.5 Hz), 6.12 (d, 1H, J ¼ 1.1 Hz), 6.90 (td, 1H,
Jo ¼ 7.2 Hz, Jm ¼ 1.2 Hz), 6.94e7.04 (m, 2H), 7.24e7.31
(m, 3H), 7.38 (d, 1H, J ¼ 7.5 Hz), 7.58 (d, 2H, J ¼ 8.3 Hz),
9.80 (s, 1H), 10.90 (s, 1H). EI-MS (70 eV) m/z (%): 307
(100) [M þ Hþ]. Anal. (C20H22N2O) C, H, N.
7.43 (s, 1H), 9.79 (s, 1H).
6.2.17. Formation of the indoles according to Smith
(32aeg) (Table 6)
Trimethylsilyl-o-toluidine (TMSOT) was dissolved in dry
hexane. Under N2 n-BuLi (2 eq, 1.6 M solution in hexane)
was added dropwise at room temperature. Then the solution
was heated to reflux for 4 h. During the reaction a red precip-
itate occurred, and the solution turned orange. The obtained
suspension was cooled to ꢀ78 ꢁC, and a solution of the respec-
tive ester (1 eq, 31aeg) in THF was added slowly, so that the
temperature did not rise above ꢀ70 ꢁC. After stirring over-
night, while slowly warming up to room temperature, the so-
lution was refluxed for 2 h, poured into ice and stirred until
most of the ice was molten. The mixture was extracted with
ethyl acetate, the extract was dried over Na2SO4 and concen-
trated in vacuo. The raw material was purified by CC (DCM).
We separated the indoleeamides as oils and processed them
without further purification. References are given for the char-
acterization of the products.
6.2.17.5. 3-(1H-Indole-2-yl)-N-phenylheptanamide (32e).
Yield: 0.67 g (2.1 mmol) from 3.8 g (14.4 mmol) of 31e
(19%), m.p. 90 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3382, 2923, 1667,
1
1599, 1532. H NMR (DMSO-d6): d (ppm) ¼ 1.30e1.40 (m,
4H), 1.50e1.75 (m, 4H), 2.28 (t, 2H, J ¼ 7.3 Hz), 2.69 (t,
2H, J ¼ 7.5 Hz), 6.12 (d, 1H, J ¼ 1.1 Hz), 6.90 (td, 1H,
Jo ¼ 7.2 Hz, Jm ¼ 1.2 Hz), 6.93e7.03 (m, 2H), 7.23e7.29
(m, 3H), 7.37 (d, 1H, J ¼ 7.1 Hz), 7.57 (d, 2H, J ¼ 7.5 Hz),
9.83 (s, 1H), 10.85 (s, 1H). EI-MS (70 eV) m/z (%): 321
(100) [M þ Hþ]. Anal. (C21H24N2O) C, H, N.
6.2.17.6. 3-(1H-Indole-2-yl)-N-(4-methyl-phenyl)-butanamide
(32f). Yield: 0.82 g (2.8 mmol) from 3.6 g (14.4 mmol) of
31f (19%), m.p. 133 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3311, 2932,
1
1680, 1595, 1524. H NMR (DMSO-d6): d (ppm) ¼ 1.96e
6.2.17.1. 3-(1H-Indole-2-yl)-N-phenylpropanamide (32a). Yield:
0.81 g (3 mmol) from 3.0 g (14.5 mmol) of 31a (21%),
m.p.152 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3386, 3319, 2905, 1655,
2.07 (m, 2H), 2.22 (s, 3H), 2.34 (t, 2H, J ¼ 7.5 Hz), 2.75 (t,
2H, J ¼ 7.3 Hz), 6.14 (d, 1H, J ¼ 1.1 Hz), 6.90 (td, 1H,
Jo ¼ 8.7 Hz, Jm ¼ 1.6 Hz), 6.98 (td, 1H, Jo ¼ 7.5 Hz, Jm ¼
1.5 Hz), 7.07 (d, 2H, J ¼ 8.3 Hz), 7.25 (d, 1H, J ¼ 7.9 Hz),
7.39 (d, 1H, J ¼ 7.1 Hz), 7.46 (d, 2H, J ¼ 8.3 Hz), 9.78 (s,
1H), 10.91 (s, 1H). EI-MS (70 eV) m/z (%): 293 (100)
[M þ Hþ]. Anal. (C19H20N2O$1/4H2O) C, H, N.
1
1597, 1550. H NMR (CDCl3): d (ppm) ¼ 1.58 (s, 1H), 2.77
(t, 2H, J ¼ 6.3 Hz), 3.16 (t, 2H, J ¼ 6.3 Hz), 6.25 (s, 1H),
7.01e7.16 (m, 4H), 7.28e7.36 (m, 3H), 7.44e7.54 (m, 3H),
8.8 (s, 1H). EI-MS (70 eV) m/z (%): 265 (100) [M þ Hþ].
Anal. (C17H16N2O) C, H, N.
6.2.17.7. 3-(1H-Indole-2-yl)-N-(3-methyl-phenyl)-butanamide
(32g). Yield: 0.92 g (3.1 mmol) from 3.6 g (14.4 mmol) of
31g (22%), m.p. 103 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3318, 2932,
6.2.17.2. 3-(1H-Indole-2-yl)-N-phenylbutanamide (32b). Yield:
0.7 g (2.5 mmol) from 3.4 g (14.5 mmol) of 31b (17%), oil.
IR (NaCl): n (cmꢀ1) ¼ 3341, 2963, 1717, 1690, 1597, 1542.
1H NMR (DMSO-d6): d (ppm) ¼ 1.95e2.07 (m, 2H), 2.37 (t,
2H, J ¼ 7.5 Hz), 2.77 (t, 2H, J ¼ 7.5 Hz), 6.16 (d, 1H,
J ¼ 1.0 Hz), 6.91 (td, 1H, Jo ¼ 7.3 Hz, Jm ¼ 1.2 Hz), 6.95e
7.04 (m, 2H), 7.25e7.31 (m, 3H), 7.41 (d, 1H, J ¼ 7.1 Hz),
7.59 (d, 2H, J ¼ 7.5 Hz), 9.9 (s, 1H), 10.9 (s, 1H). EI-MS
(70 eV) m/z (%): 279 (100) [M þ Hþ]. Anal. (C18H18N2O$1/
4H2O) C, H, N.
1
1688, 1611, 1533, 1490. H NMR (DMSO-d6): d (ppm) ¼
1.93e2.06 (m, 2H), 2.25 (s, 3H), 2.35 (t, 2H, J ¼ 7.3 Hz),
2.75 (t, 2H, J ¼ 7.3 Hz), 6.15 (d, 1H, J ¼ 1.1 Hz), 6.83 (d,
1H, J ¼ 7.5 Hz), 6.90 (td, 1H, Jo ¼ 7.3 Hz, Jm ¼ 1.2 Hz),
6.98 (td, 1H, Jo ¼ 7.4 Hz, Jm ¼ 1.2 Hz), 7.14 (d, 1H,
J ¼ 7.7 Hz), 7.26 (d, 1H, J ¼ 7.9 Hz), 7.34e7.43 (m, 3H),
9.80 (s, 1H), 10.92 (s, 1H). EI-MS (70 eV) m/z (%): 293
(100) [M þ Hþ]. Anal. (C19H20N2O) C, H, N.
6.2.17.3. 3-(1H-Indole-2-yl)-N-phenylpentanamide (32c). Yield:
0.87 g (3.0 mmol) from 3.4 g (14.5 mmol) of 31c (21%), m.p.
100 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3386, 2940, 1713, 1667, 1599,
6.2.18. Condensation of TBSedibromomaleinimide with
indole derivatives (33aeg, Scheme 5)
The respective indoles (32aeg) were dissolved in dry THF
and cooled under argon to ꢀ20 ꢁC. Then LiHMDS (2 eq, 1 M
in THF) was slowly added. After stirring the solution for
45 min at ꢀ20 ꢁC, TBSedibromomaleinimide (1 eq) in THF
was added within 3 h. The solution was stirred for 15 min,
poured into sat. aq. NH4Cl, extracted with ethyl acetate, dried
over Na2SO4 and concentrated in vacuo. The crude products
were processed to 33aeg without further purification.
1
1530. H NMR (DMSO-d6): d (ppm) ¼ 1.50e1.80 (m, 4H),
2.35 (t, 2H, J ¼ 6.7 Hz), 2.74 (t, 2H, J ¼ 7.1 Hz), 6.13 (d, 1H,
J ¼ 1.0 Hz), 6.90 (td, 1H, Jo ¼ 7.3 Hz, Jm ¼ 1.2 Hz), 6.94e
7.04 (m, 2H), 7.24e7.31 (m, 3H), 7.39 (d, 1H, J ¼ 7.1 Hz),
7.58 (d, 2H, J ¼ 7.9 Hz), 9.90 (s, 1H), 10.90 (s, 1H). EI-MS
(70 eV) m/z (%): 293 (100) [M þ Hþ]. Anal. (C19H20N2O$1/
2H2O) C, H, N.
6.2.17.4.
3-(1H-Indole-2-yl)-N-phenylhexanamide
(32d).
6.2.19. Removal of the silyl-protecting group to give 34aeg
(Scheme 5)
The raw silyl-protected indoleemaleinimide (33aeg) was
dissolved in THF under N2, tetrabutylammonium fluoride
Yield: 0.87 g (2.8 mmol) from 3.8 g (14.4 mmol) of 31d
(19%), m.p. 118 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3344, 2940, 1636,
1
1599, 1532. H NMR (DMSO-d6): d (ppm) ¼ 1.33e1.42 (m,

654
S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
trihydrate (1.3 eq) was added, and the mixture was stirred for
2 h, poured into ice, mixed with saturated NH4Cl solution and
extracted with ethyl acetate. The extract was dried over
Na2SO4, the solvent was removed in vacuo and the remaining
oil was purified by CC (DCM) and in some cases crystallized
from EE.
(0.44 mmol) from 0.61 g (2.0 mmol) of 32e (22%), m.p.
145 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3336, 3062, 2932, 1773, 1719,
1
1625, 1601. H NMR (DMSO-d6): d (ppm) ¼ 1.20e1.40 (m,
4H), 1.50e1.80 (m, 4H), 2.26 (t, 2H, J ¼ 7.3 Hz), 2.72 (t,
2H, J ¼ 7.4 Hz), 6.97e7.04 (m, 2H), 7.10 (dd, 1H,
Jo ¼ 7.9 Hz, Jm ¼ 1.2 Hz), 7.23e7.37 (m, 4H), 7.55 (d, 2H,
J ¼ 7.5 Hz), 9.81 (s, 1H), 11.36 (s, 1H), 11.68 (s, 1H). ES-
MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 494 (100)
[M þ H]þ. Anal. (C25H24BrN3O3$1/3H2O) C, H, N.
6.2.19.1. 3-(3-(4-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-yl)-
1H-indole-2-yl)-N-phenyl-propanamide (34a). Yield: 0.15 g
(0.34 mmol) from 0.5 g (2.0 mmol) of 32a (17%), m.p.
194 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3340, 3226, 1773, 1719, 1626,
1605. 1H NMR (DMSO-d6): d (ppm) ¼ 2.73 (t, 2H, J ¼
7.5 Hz), 3.0e3.2 (m, 2H), 6.98e7.06 (m, 2H), 7.12 (dd, 1H,
Jo ¼ 7.5 Hz, Jm ¼ 1.7 Hz), 7.26 (t, 2H, J ¼ 7.9 Hz), 7.34 (d,
1H, J ¼ 7.9 Hz), 7.37 (d, 1H, J ¼ 7.5 Hz), 7.49 (d, 2H, J ¼
7.5 Hz), 9.89 (s, 1H), 11.34 (s, 1H), 11.75 (s, 1H). EI-MS
(70 eV) m/z (%): 439 (5) [M þ Hþ]. Anal. (C21H16BrN3O3$
1/6H2O) C, H, N.
6.2.19.6. 3-(3-(4-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-
1H-indol-2-yl)-N-(4-methyl-phenyl)-butanamide (34f). Yield:
0.15 g (0.31 mmol) from 0.61 g (1.98 mmol) of 32f (15%),
m.p. 145 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3335, 3060, 2927, 1773,
1
1723, 1625, 1603. H NMR (DMSO-d6): d (ppm) ¼ 1.95e
2.01 (m, 2H), 2.22 (s, 3H), 2.26 (t, 2H, J ¼ 7.1 Hz), 2.70e
2.85 (m, 2H), 6.99e7.14 (m, 4H), 7.32e7.44 (m, 4H), 9.75
(s, 1H), 11.36 (s, 1H), 11.73 (s, 1H). ES-MS (DCM/
MeOH þ 10 mmol/l NH4Ac) m/z (%): 466 (100) [M þ H]þ.
Anal. (C23H20BrN3O3$1/6pentane) C, H, N.
6.2.19.2. 3-(3-(4-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-yl)-
1H-indol-2-yl)-N-phenyl-butanamide (34b). Yield: 0.25 g
(0.55 mmol) from 0.55 g (1.99 mmol) of 32b (27%), m.p.
130 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3359, 2962, 1771, 1723, 1624,
6.2.19.7. 3-(3-(4-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-yl)-
1H-indol-2-yl)-N-(3-methyl-phenyl)-butanamide (34g). Yield:
0.28 g (0.6 mmol) from 0.58 g (2.0 mmol) of 32g (30%),
m.p. 155 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3394, 3143, 3066, 2956,
1599. 1H NMR (DMSO-d6):
d
(ppm) ¼ 2.01 (t, 2H,
J ¼ 7.3 Hz), 2.30 (t, 2H, J ¼ 7.3 Hz), 2.74e2.90 (m, 2H),
6.98e7.06 (m, 2H), 7.12 (dd, 1H, Jo ¼ 7.5 Hz, Jm ¼ 1.7 Hz),
7.27 (t, 2H, J ¼ 7.9 Hz), 7.33 (m, 2H), 7.55 (d, 2H,
J ¼ 7.5 Hz), 9.85 (s, 1H), 11.36 (s, 1H), 11.75 (s, 1H). ES-
MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 466 (100)
[M þ H]þ. Anal. (C22H18BrN3O3$2/3EE) C, H, N.
1
1767, 1717, 1676, 1609. H NMR (DMSO-d6): d (ppm) ¼
1.95e2.01 (m, 2H), 2.24 (s, 3H), 2.27 (t, 2H, J ¼ 7.5 Hz),
2.70e2.85 (m, 2H), 6.81 (d, 1H, J ¼ 7.1 Hz), 6.99e7.14 (m,
3H), 7.31e7.39 (m, 4H), 9.76 (s, 1H), 11.37 (s, 1H), 11.74
(s, 1H). ES-MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z
(%): 466 (100) [M þ H]þ. Anal. (C24H22BrN3O3) C, H, N.
6.2.19.3. 3-(3-(4-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-yl)-
1H-indol-2-yl)-N-phenyl-pentanamide (34c). Yield: 0.2 g
(0.43 mmol) from 0.58 g (1.98 mmol) of 32c (22%), m.p.
100 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3384, 3060, 2960, 1771, 1725,
Appendix A. Additional information: compound
number combustion elemental analysis
1
1622, 1601. H NMR (DMSO-d6): d (ppm) ¼ 1.58e1.72 (m,
4H), 2.29 (t, 2H, J ¼ 7.1 Hz), 2.75 (t, 2H, J ¼ 7.3 Hz),
6.97e7.04 (m, 2H), 7.10 (dd, 1H, Jo ¼ 7.9 Hz, Jm ¼ 1.7 Hz),
7.22e7.37 (m, 4H), 7.55 (d, 2H, J ¼ 7.5 Hz), 9.83 (s, 1H),
11.36 (s, 1H), 11.68 (s, 1H). ES-MS (DCM/MeOH þ 10 m-
mol/l NH4Ac) m/z (%): 464 (100) [M þ H]þ. Anal.
(C23H20BrN3O3$5/7EE) C, H, N.
Table A1 Analysis
2b
2c
2d
2e
2f
Calc. C 81.47, H 7.22, N 5.28
Calc. C 81.68, H 7.58, N 5.01
Calc. C 82.20, H 8.47, N 4.36
Calc. C 82.47, H 8.94, N 4.01
Calc. C 84.25, H 5.72, N 4.68
Calc. C 85.93, H 5.48, N 4.01
Calc. C 57.43, H 3.27, N 7.05
Calc. C 60.15, H 4.36, N 6.38
Calc. C 60.94, H 4.67, N 6.18
Calc. C 63.03, H 5.49, N 5.65
Calc. C 64.25, H 5.97, N 5.35
Calc. C 63.44, H 3.62, N 5.92
Calc. C 67.11, H 4.10, N 5.17
Calc. C 80.69, H 5.87, N 6.27
Calc. C 80.98, H 6.37, N 5.90
Calc. C 81.24, H 6.82, N 5.57
Calc. C 81.47, H 7.22, N 5.28
Calc. C 81.26, H 7.60, N 4.94
Calc. C 81.87, H 7.90, N 4.77
Calc. C 76.38, H 6.41, N 5.24
Calc. C 76.84, H 6.81, N 4.98
Calc. C 76.10, H 7.23, N 4.67
Calc. C 77.64, H 7.49, N 4.53
Found: C 81.30, H 7.26, N 5.07
Found: C 81.42, H 7.95, N 4.75
Found: C 81.52, H 8.63, N 4.14
Found: C 82.16, H 9.13, N 3.86.
Found: C 84.18, H 5.73, N 4.46
Found: C 85.55, H 5.60, N 3.57
Found: C 57.55, H 3.59, N 6.87
Found: C 60.49, H 4.64, N 6.20
Found: C 60.67, H 4.59, N 5.99
Found: C 62.77, H 5.32, N 5.50
Found: C 64.33, H 6.07, N 5.26
Found: C 63.01, H 3.86, N 5.62
Found: C 67.20, H 3.80, N 4.96
Found: C 80.49, H 5.57, N 5.90
Found: C 80.96, H 6.42, N 5.59
Found: C 81.56, H 6.78, N 5.41
Found: C 81.50, H 7.19, N 5.00
Found: C 81.49, H 7.51, N 4.74
Found: C 81.74, H 7.96, N 4.48
Found: C 76.57, H 6.45, N 5.07
Found: C 76.58, H 6.69, N 4.70
Found: C 76.43, H 6.96, N 4.38
Found: C 77.73, H 7.31, N 4.23
2g
7a
7b
7c
7d
7e
7f
6.2.19.4. 3-(3-(4-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-yl)-
1H-indol-2-yl)-N-phenyl-hexanamide (34d). Yield: 0.15 g
(0.48 mmol) from 0.61 g (2.0 mmol) of 32d (24%), m.p.
120 ꢁC. IR (KBr): n (cmꢀ1) ¼ 3374, 3060, 2932, 1773, 1723,
1
1625, 1599. H NMR (DMSO-d6): d (ppm) ¼ 1.20e1.40 (m,
7g
8a
8b
8c
8d
8e
8f
2H), 1.50e1.80 (m, 4H), 2.26 (t, 2H, J ¼ 7.3 Hz), 2.73 (t,
2H, J ¼ 7.4 Hz), 6.97e7.04 (m, 2H), 7.10 (dd, 1H,
Jo ¼ 7.5 Hz, Jm ¼ 1.2 Hz), 7.22e7.37 (m, 4H), 7.55 (d, 2H,
J ¼ 7.5 Hz), 9.81 (s, 1H), 11.35 (s, 1H), 11.68 (s, 1H). ES-
MS (DCM/MeOH þ 10 mmol/l NH4Ac) m/z (%): 480 (100)
[M þ H]þ. Anal. (C24H22BrN3O3$1/7pentane) C, H, N.
9a
9b
9c
9d
6.2.19.5. 3-(3-(4-Bromo-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-yl)-
1H-indol-2-yl)-N-phenyl-heptanamide (34e). Yield: 0.22 g

S. Mahboobi et al. / European Journal of Medicinal Chemistry 43 (2008) 633e656
Table A1 (continued)
655
Table A1 (continued)
9e
Calc. C 77.98, H 7.79, N 4.33
Found: C 77.91, H 7.91, N 4.10
Found: C 57.39, H 3.60, N 6.91
Found: C 58.96, H 3.92, N 6.58
Found: C 60.01, H 4.15, N 6.39
Found: C 60.02, H 4.50, N 6.22
Found: C 61.16, H 4.78, N 6.08
Found: C 61.79, H 4.96, N 5.77
Found: C 57.23, H 4.08, N 6.35
Found: C 58.26, H 4.46, N 6.04
Found: C 58.83, H 4.60, N 5.75
Found: C 59.68, H 4.92, N 5.64
Found: C 60.36, H 5.11, N 5.46
Found: C 86.97, H 6.30, N 6.51
Found: C 86.78, H 6.75, N 6.22
Found: C 86.61, H 7.21, N 5.71
Found: C 86.71, H 7.88, N 5.34
Found: C 86.44, H 7.73, N 4.91
Found: C 86.82, H 8.57, N 4.70
Found: C 81.03, H 6.62, N 5.74
Found: C 81.24, H 6.84, N 5.50
Found: C 81.36, H 7.40, N 5.17
Found: C 81.86, H 7.73, N 4.80
Found: C 81.79, H 7.57, N 4.37
Found: C 82.11, H 8.01, N 4.17
Found: C 59.81, H 3.49, N 7.25
Found: C 62.60, H 4.62, N 6.42
Found: C 61.67, H 4.26, N 6.73
Found: C 61.01, H 4.05, N 6.91
Found: C 63.13, H 4.98, N 6.17
Found: C 64.01, H 5.25, N 6.01
Found: C 58.49, H 3.75, N 6.59
Found: C 59.23, H 4.00, N 6.21
Found: C 59.50, H 4.49, N 6.25
Found: C 60.99, H 4.86, N 6.07
Found: C 61.55, H 5.00, N 5.82
Found: C 62.28, H 5.41, N 5.71
Found: C 86.81, H 6.72, N 5.96
Found: C 87.12, H 6.53, N 6.68
Found: C 86.59, H 7.56, N 5.06
Found: C 85.54, H 8.31, N 5.11
Found: C 80.85, H 6.43, N 5.74
Found: C 80.91, H 6.70, N 5.41
Found: C 81.17, H 7.01, N 5.04
Found: C 80.40, H 7.23, N 4.69
Found: C 81.43, H 8.16, N 4.27
Found: C 59.48, H 3.55, N 7.25
Found: C 58.23, H 3.96, N 6.72
Found: C 62.34, H 4.63, N 6.45
Found: C 57.36, H 4.37, N 6.06
Found: C 58.08, H 3.81, N 6.64
Found: C 58.58, H 4.21, N 6.31
Found: C 59.61, H 4.48, N 6.24
Found: C 60.34, H 4.75, N 5.93
Found: C 61.95, H 5.52, N 5.50
Found: C 76.11, H 6.91, N 4.79
Found: C 76.42, H 7.31, N 4.29
Found: C 77.60, H 7.46, N 4.01
Found: C 80.38, H 6.85, N 5.64
Found: C 79.82, H 6.54, N 5.18
Found: C 81.33, H 7.49, N 4.62
Found: C 81.66, H 8.02, N 4.22
Found: C 53.47, H 4.08, N 5.86
Found: C 55.51, H 4.11, N 5.90
Found: C 59.11, H 4.70, N 5.89
Found: C 60.13, H 5.54, N 5.21
Found: C 56.73, H 4.23, N 6.16
28f
Calc. C 58.69, H 4.10, N 6.52
Calc. C 60.94, H 4.97, N 6.18
Calc. C 62.38, H 5.23, N 5.82
Calc. C 77.25, H 6.10, N 10.60
Calc. C 76.43, H 6.59, N 9.90
Calc. C 75.72, H 7.02, N 9.29
Calc. C 78.40, H 7.24, N 9.14
Calc. C 78.71, H 7.55, N 8.74
Calc. C 76.87, H 6.96, N 9.44
Calc. C 78.05, H 6.89, N 9.58
Calc. C 57.16, H 3.73, N 9.52
Calc. C 57.97, H 4.60, N 8.22
Calc. C 58.68, H 4.90, N 7.94
Calc. C 60.50, H 4.87, N 8.56
Calc. C 60.01, H 4.97, N 8.40
Calc. C 59.84, H 4.64, N 8.78
Calc. C 59.24, H 4.32, N 9.01
Found: C 58.91, H 4.57, N 6.43
12a
12b
12c
12d
12e
12f
Calc. C 57.45, H 3.30, N 7.05
Calc. C 58.84, H 3.90, N 6.69
Calc. C 60.09, H 4.45, N 6.39
Calc. C 60.15, H 4.36, N 6.38
Calc. C 60.94, H 4.67, N 6.18
Calc. C 61.68, H 4.96, N 5.99
Calc. C 57.16, H 3.88, N 6.35
Calc. C 58.04, H 4.21, N 6.15
Calc. C 58.86, H 4.51, N 5.97
Calc. C 59.64, H 4.80, N 5.80
Calc. C 60.37, H 5.07, N 5.63
Calc. C 86.92, H 6.32, N 6.76
Calc. C 86.84, H 6.83, N 6.33
Calc. C 86.77, H 7.28, N 5.95
Calc. C 86.70, H 7.68, N 5.62
Calc. C 86.65, H 8.04, N 5.32
Calc. C 86.59, H 8.36, N 5.05
Calc. C 80.98, H 6.37, N 5.90
Calc. C 81.24, H 6.82, N 5.57
Calc. C 81.47, H 7.22, N 5.28
Calc. C 81.68, H 7.58, N 5.01
Calc. C 81.87, H 7.90, N 4.77
Calc. C 82.04, H 8.20, N 4.56
Calc. C 59.86, H 3.44, N 7.35
Calc. C 62.65, H 4.91, N 6.49
Calc. C 61.63, H 4.19, N 6.84
Calc. C 60.86, H 4.45, N 6.40
Calc. C 63.17, H 4.84, N 6.41
Calc. C 63.86, H 5.14, N 6.21
Calc. C 58.41, H 3.68, N 6.81
Calc. C 59.31, H 4.03, N 6.59
Calc. C 59.66, H 4.41, N 6.32
Calc. C 60.94, H 4.67, N 6.18
Calc. C 61.68, H 4.96, N 5.99
Calc. C 62.38, H 5.23, N 5.82
Calc. C 86.84, H 6.83, N 6.33
Calc. C 86.92, H 6.32, N 6.76
Calc. C 86.60, H 7.94, N 5.46
Calc. C 85.67, H 8.07, N 5.26
Calc. C 80.98, H 6.37, N 5.90
Calc. C 81.24, H 6.82, N 5.57
Calc. C 81.47, H 7.22, N 5.28
Calc. C 80.01, H 7.45, N 4.59
Calc. C 81.12, H 8.12, N 4.49
Calc. C 59.86, H 3.44, N 7.35
Calc. C 58.13, H 4.14, N 6.78
Calc. C 62.42, H 4.52, N 6.62
Calc. C 57.55, H 4.56, N 5.67
Calc. C 58.41, H 3.68, N 6.81
Calc. C 58.48, H 4.13, N 6.50
Calc. C 59.54, H 4.43, N 6.31
Calc. C 60.34, H 4.73, N 6.12
Calc. C 61.99, H 5.27, N 5.78
Calc. C 75.73, H 6.51, N 5.15
Calc. C 76.10, H 7.23, N 4.67
Calc. C 77.98, H 7.79, N 4.33
Calc. C 79.97, H 6.43, N 5.83
Calc. C 79.81, H 6.89, N 5.48
Calc. C 81.68, H 7.58, N 5.01
Calc. C 82.04, H 8.20, N 4.56
Calc. C 53.52, H 3.91, N 6.24
Calc. C 55.64, H 4.08, N 6.18
Calc. C 58.86, H 4.51, N 5.97
Calc. C 60.37, H 5.07, N 5.63
Calc. C 56.91, H 3.87, N 6.64
28g
28h
32a
32b
32c
32d
32e
32f
Found: C 60.80, H 5.38, N 5.83
Found: C 62.73, H 5.50, N 5.98
Found: C 77.04, H 6.30, N 10.47
Found: C 76.66, H 6.41, N 9.64
Found: C 75.91, H 7.32, N 9.39
Found: C 78.05, H 7.17, N 8.92
Found: C 78.53, H 7.56, N 8.60
Found: C 77.17, H 6.81, N 9.04
Found: C 77.91, H 6.97, N 9.21
Found: C 57.12, H 3.96, N 9.31
Found: C 58.02, H 4.84, N 7.92
Found: C 58.30, H 4.66, N 8.32
Found: C 60.11, H 5.20, N 8.16
Found: C 60.15, H 4.83, N 8.35
Found: C 59.48, H 4.84, N 8.54
Found: C 58.93, H 4.34, N 9.01
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
14f
32g
34a
34b
34c
34d
34e
34f
34g
15a
15b
15c
15d
15e
15f
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