3-Bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione derivatives as new lead compounds for antibacterially active substances

Article abstract of DOI:10.1016/j.ejmech.2005.10.006

A number of new 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, Mycobacterium smegmatis and some other Gram positive bacte

Full text of DOI:10.1016/j.ejmech.2005.10.006

European Journal of Medicinal Chemistry 41 (2006) 176–191
http://france.elsevier.com/direct/ejmech
Original article
3-Bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrroledione
derivatives as new lead compounds
for antibacterially active substances
Siavosh Mahboobi a,*, Emerich Eichhorn a, Alfred Popp a, Andreas Sellmer a,
Sigurd Elz a, Ute Möllmann b
a Department of Pharmaceutical Chemistry I, University of Regensburg, D-93040 Regensburg, Germany
b Hans Knöll Institut für Naturstofforschung, Abtlg. Mikrobielle Infektionsbiologie, D-07745 Jena, Germany
Received 18 July 2005; received in revised form 26 September 2005; accepted 6 October 2005
Available online 10 January 2006
Abstract
A number of new 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, Mycobacterium smegmatis and some other Gram positive bacteria. The investigated
compounds exhibit minimal inhibition concentrations (MIC’s) lower than those of ciprofloxacin, vancomycin and doxycycline resp. A different
spectrum of activity, suggests a mechanism of action different to vancomycin and doxycycline. This might be important in circumventing existing
resistance mechanisms. Here we report about the synthesis and on the antibacterial activity in a structure activity relationship study.
© 2005 Elsevier SAS. All rights reserved.
Keywords: SAR-study; Antibacterial; Indole derivatives; Resistant Staphylococcus aureus; Mycobacterium smegmatis
1. Introduction
tein kinase C (PKC)-inhibitors [9]. Recently we reported on the
antimicrobial activity of pyrrole-substituted 2,5-dihydro-1H-
2,5-pyrrolediones (e.g. 1h, 1i), developed by our group [10].
The emergence of bacterial resistance to the available anti-
biotics of various structural classes has become a problem in the
medical world. While use of antibiotics allowed physicians to
successfully treat numerous diseases over the last decades, al-
most all bacteria treated with antibiotics have developed at least
some degree of resistance against these drugs [1]. In many
countries, an increasing number of clinical isolates of multire-
sistant Staphylococcus aureus strains has been observed [2] and
the pathogenetic potential in nosocomial and community ac-
quired infections is well known [3]. Substituted 2,5-dihydro-
1H-2,5-pyrrolediones and their reduced derivatives 1a–g have
interesting biological activities. For example, arcyriarubin A
(1a) (Fig. 1) and related compounds, in which one indole sub-
stituent can be replaced by various heterocycles, show high
antimicrobial [4] and antiviral [5–8] activity and are potent pro-
As announced, we carried out further investigations that led
to indole-substituted 2,5-dihydro-1H-2,5-pyrrolediones exhibit-
ing even higher antimicrobial activities. These compounds are
derivatives of 3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-
pyrroledione with variable substituents in indole 2-position
(R1) (Fig. 2).
In the present work we demonstrate the results of a structure-
activity investigation of this new class of compounds.
2. Chemistry
2.1. Synthesis of the compounds
The preparation of compounds comprises two main steps.
The first part leads to a 2-substituted indole, using 2-methylani-
line and carboxylic acid derivatives as starting materials. In the
second part we linked a 3,4-dibromo-2,5-dihydro-1H-2,5-pyrro-
* Corresponding author. Tel.: +49 941 943 4824; fax: +49 941 943 1737.
E-mail address: siavosh.mahboobi@chemie.uni-regensburg.de
(S. Mahboobi).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.10.006

S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
177
Scheme 1. Formation of the 2-alkyl- and 2-methoxyphenyl indoles according to
Smith [11,12].
methylanilides from the dicarboxylic acid monoesters or
monoester halides 4a–f and 2-methylaniline. These ester 2-
methylanilides 5 had to be N-metallated with n-BuLi before
being reacted with Li2TMSOT. Otherwise, the amide H proto-
nates the Li2TMSOT, regenerating its methyl group and so is
preventing the indole formation. Therefore, we added one
equivalent of n-BuLi at –78 °C before we added the Li2TMSOT
suspension. Using this procedure, we got the desired indoles
6a–f in yields of about 10–20%.
Fig. 1. Chemical structure of arcyriarubin A (1a) and related biological active
compounds.
Several authors described the introduction of 3,4-dibromo-
2,5-dihydro-1H-2,5-pyrroledione 7 at the indole-3-position
(Scheme 3) in the lit. According to Brenner [13], the indole
was metallated by Grignard’s reagent to form a nucleophile at
C-3 position. This nucleophile can undergo a SN reaction with 7
Fig. 2. General structure of 3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-
pyrrolediones investigated.
ledione derivative to the indole-3-position to give the title com-
pounds.
One series of compounds consists of simple 2-alkylindoles.
We prepared the indoles 3a–h in analogy to the protocols of
Smith et al. (Scheme 1) [11,12]. Thus, N-trimethylsilyl-2-tolui-
dine (TMSOT) was lithiated with two equivalents of n-BuLi
leading to metallation at the NH–Si– and the methyl group.
This product acts as a strong nucleophile. We reacted the
Li2TMSOT suspension, after cooling to –78 °C, with car-
boxylic acid esters to give the desired 2-substituted indoles.
Analogously 2-phenylindoles were available using substituted
benzoic acid esters.
We got another series of compounds by linking a 2-methy-
lanilide substructure to the indole-2-position by an alkyl spacer.
We had to modify Smith’s [11,12] method to prepare the spacer
linked indole-2-methylanilides 6a–f. We prepared the ester 2-
Scheme 2. Conditions: (i) X = Cl: 2-methylaniline, NEt3, Δ, 12h; for X = OH:
2-methylaniline, dicyclohexylcarbodiimide, p-TosOH, pyridine, 12h; (ii) n-
BuLi, Li2TMSOT,–78 °C > RT.

178
S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
Scheme 3. Conditions: (I) TBSCl, NaH, THF; (II) DMS, acetone, K2CO3; (III) indole derivative (for R1 and n see Table 1), LiHMDS, THF, –20 °C; (IV) NBu4F,
THF; (V) DMS, BuLi, THF.
substituting one bromide to form the final product. In our
hands, however, this method led to low yields and products that
were difficult to purify. We got better results using a modified
method, described by Murase et al. [14]: First we protected the
N of 7 by a tert-butyl-dimethylsilyl group (TBS) and got the
product 8 [14]. The indole reactant was metallated with lithium
hexamethyldisilazane LiHMDS [15] (Scheme 3). The reaction
of the lithiated indole and 8 led to silyl-protected products,
which we could only isolate as raw materials containing re-
maining indoles. After removal of the silyl protecting group
by tetrabutylammonium fluoride [14], we could easily isolate
the final products.
moving the silyl protecting group. The main formation path-
ways are shown in Scheme 3. A survey of the final products
is presented in table 1.
To show the importance of the bromine substituent, we hy-
drogenated the double bond of the 2,5-dihydro-1H-2,5-pyrrole-
dione core of 12a. The reaction was accompanied by loss of the
bromine substituent to give the indole substituted pyrrolidine-
dione 14. This we further processed to 15, regenerating the for-
mer double bond by an oxidative dehydrogenation with DDQ in
the presence of a catalytic amount of 4-toluenesulfonic acid
(Scheme 4).
3. Pharmacology
In order to study the effects of the N-hydrogen bond on its
biological effect, we masked the imide NH as well as the indole
NH by methylation. We accomplished the formal methylation
of the imide NH by reacting the substituted indoles with 1-
methyl-3,4-dibromo-2,5-dihydro-1H-2,5-pyrroledione (9) [16].
For the methylation of the indole NH, the silyl-protected raw
materials were reacted with dimethylsulfate (DMS) prior to re-
3.1. General antimicrobial properties
The compounds 12a and 12l are two typical substances of
the synthesized series. Their antibacterial activities against
some Gram positive and Gram negative bacteria are shown in

S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
179
Table 1
Substituents for the compounds, described in Scheme 3
Compound
R2 = H
R3 = CH3
10a
10b
10c
10d
10e
10f
R1
Compound
R2 = H
R3 = H
11a
11b
11c
11d
11e
11f
Na
Compound
R2 = H
R3 = H
12a
12b
12c
12d
12e
12f
R1
Compound
R2 = CH3
R3 = H
13a
13b
13c
R1
H
Methyl
Ethyl
Propyl
Butyl
Pentyl
2
3
4
5
6
7
H
Methyl
Ethyl
Propyl
Butyl
Pentyl
Methyl
Butyl
Hexyl
Phenyl
Ph-4-OMe
13d
13e
10g
Hexyl
12g
Hexyl
10h
10i
10j
10k
Heptyl
Phenyl
ph-2-OMe
ph-3-OMe
ph-4-OMe
12h
12i
12j
12k
Heptyl
Phenyl
Ph-2-OMe
Ph-3-OMe
Ph-4-OMe
10l
12l
a
For R1 and N see scheme 3.
Scheme 4. Conditions: (i) Pd/C, H2 CH3OH; (ii) 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), 4-toluenesulfonic acid, benzene, RT.
Table 2 in comparison to the activities of therapeutically used
antibiotics in terms of minimal inhibitory concentrations (MIC)
(determination see Section 6).
Among the Gram positive bacteria the epidemic strain S.
aureus 134/93 strain is resistant to ciprofloxacin (Cip) and
methicillin (Meth). S. aureus SG 511 is a laboratory strain,
sensitive to all compounds used. Enterococcus faecalis 1528
and Mycobacterium smegmatis SG 987 are resistant to Meth.
E. faecalis 1528 additionally to vancomycin (Vanc). The Gram
negative bacteria Escherichia coli SG 458 and Pseudomonas
aeruginosa SG are resistant to Meth, Vanc, 12a, and 12l,
P. aeruginosa SG 137 additionally to doxycycline (Dox).
Against the multiresistant S. aureus 134/93 12a is in the ac-
tivity range of Dox and Vanc. 12l and some other compounds
of the synthesized series (see Tables 3 and 4) were more active
against S. aureus 134/93 than Dox and Vanc. The synthesized
compounds show lower activities against other Gram positive
bacteria and unlike Dox they are inactive against Gram negative
bacteria. 12a has the simplest structure within the group of
synthesized and tested compounds, showing characteristic ac-
Table 2
Antimicrobial activity of 12a and some of its derivatives against various Gram positive and Gram negative bacteria. MIC values for Ciprofloxacin (Cip), Methicillin
(Meth), Docycycline (Dox) and Vancomycine (Vanc) are given for comparison
MIC (μg ml–1
)
Compound
S. aureus
134/93
3.12
0.13
25
> 100
6.25
1.56
S. aureus
SG.511
1.56
< 0.05
< 0.05
0.8
E. faecalis
1528
12.5
12.5
0.4
50
12.5
> 100
M. smegma-
tis SG 987
12.5
13.1
0.2
> 100
< 0.05
25
E. coli
SG 458
> 50
> 50
< 0.05
50
P. aeruginosa
SG 137
50
50
0.1
> 100
> 100
> 100
12aa
12la
Cipa
Metha
Doxa
Vanca
< 0.05
0.4
0.4
100
MIC [10–6 M]
12ab
10.6
0.33
82.6
> 265
13.7
1.1
5.3
42.6
31.3
1.3
133
27.5
70
42.6
30.0
0.66
> 265
< 0.11
17.5
> 170
> 125
< 0.16
133
0.88
70
170
125
0.33
265
> 220
> 70
12lb
< 0.12
< 0.16
2.12
< 0.11
0.28
Cipb
Methb
Doxb
Vancb

180
S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
Table 3
Activity of compounds 12b–12h against S. aureus 134/93
Compound
12b
12c
12d
12e
12f
12g
12h
R1
MIC μg–1 ml–1
0.39
1.09
0.32
0.235
0.14
0.095
0.075
MIC per 10−6
1.28
3.41
0.96
0.68
0.38
0.253
0.193
M
pMIC
5.8
5.5
6.0
6.2
6.3
6.6
6.7
Δ
log(P)
2.26
2.41
2.58
2.84
3.08
3.35
3.65
Methyl
Ethyl
Propyl
Butyl
Pentyl
Hexyl
Heptyl
0.1
–0.3
0.1
0.1
0.0
0.1
–0.1
Table 4
Antibacterial activities of compounds 10a–l, 11a–f, 12a, 12i–l and 13a–e against S. aureus 134/93
Compound
10a
10b
10c
10d
10e
10f
10g
10h
10i
R1
H
Methyl
Ethyl
Propyl
Butyl
MIC μg–1 ml–1
0.76
12.5
6.25
3.125
0.4
MIC per 10−6
2.49
39.16
18.76
9.00
1.11
2.13
2.05
3.97
1.02
0.93
0.93
0.38
39.16
0.28
0.80
0.51
0.38
1.08
0.32
0.28
0.47
1.10
0.38
10.7
0.95
M
pMIC
5.6
4.4
4.7
5.1
6.0
5.7
5.7
5.4
6.0
6.0
6.0
6.4
4.4
6.6
6.1
6.3
6.4
6.0
6.5
6.6
6.3
6.0
6.4
5.0
6.0
6.0
6.6
6.5
Δ
log(P)
2.94
2.73
2.87
3.06
3.35
3.63
3.84
4.19
3.03
2.86
2.99
3.03
2.69
3.28
3.84
3.11
3.15
2.58
2.60
2.65
2.74
2.91
3.07
2.34
2.58
2.34
2.54
2.59
–0.6
–1.6
–1.4
–1.2
–0.5
–1.1
–1.2
–1.8
–0.3
–0.1
–0.2
0.1
–1.6
0.1
–0.8
0.0
0.1
0.1
0.6
0.6
0.3
–0.2
0.1
–0.7
0.1
0.3
0.7
0.6
Pentyl
Hexyl
0.8b
0.8b
Heptyl
Phenyl
ph-2-OMe
ph-3-OMe
ph-4-OMe
Methyl
Butyl
1.6b
0.39
0.4
0.4
0.156
12.5
0.1
0.312
0.20
0.156
0.49
0.15
0.13
0.23
0.56
0.2
10j
10k
10l
13a
13b
13c
13d
13e
11a
11b
11c
11d
11e
11f
12a
12i
12j
12k
12l
Hexyl
Phenyl
ph-4-OMe
N = 2a
N = 3a
N = 4a
N = 5a
N = 6a
N = 7a
H
Phenyl
ph-2-OMe
ph-3-OMe
ph-4-OMe
3.12
0.35
0.4
0.96
0.24
0.33
0.1
0.13c
a
For R1 and N see scheme 3.
The compounds haven’t been completely soluble in the testing procedure.
b
tivities against the different strains of microorganisms. There-
fore, we selected 12a as a lead for a structure activity study.
system and describes the hydrophobic properties of a com-
pound. Linear regression led to the function
pMIC¼ 0:79 logðPÞ þ 3:87
(2)
3.2. Structure activity relationship for S. aureus 134/93
with a correlation coefficient of 94%. The experimental error,
estimated from the dilution steps used in the antimicrobial tests
(see Section 6), is
The compounds 14 and 15 and all indoles, which we pre-
pared according to Scheme 2, are inactive against S. aureus
134/93. Therefore, we regard 12a to be the simplest active prin-
ciple, the bromine substituent in pyrrole-3-position seems to be
necessary for the activity. Table 3 shows the MIC’s for the
homologous series of the 2-alkylated derivatives of 12a (12b–
12h). The activity of the compounds increases with the length
of the alkyl substituent. If we define
ΔpMIC ¼ :3
(3)
The results of multiple MIC-determinations with the same
compounds were all within that limit. Δ describes the deviation
of an observed pMIC (pMIC(obs)) to the value, expected from
the log(P)-function (2) (pMIC(cal)), that is
pMIC ¼ ꢀlogðMIC=mollꢀ1
Þ
(1)
Δ ¼ pMICðobsÞ ꢀ pMICðcalÞ
(4)
we find a linear correlation between pMIC and log(P). P is the
partition coefficient of the compound in the n-octanol/water
The MIC’s of the other compounds are listed in Table 4.

S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
181
Compounds 10b–10h are a homologous series of 2-alkyl-de-
3.3. Structure activity relationship for M. smegmatis SG 987
rivatives, which are all methylated at the imide-N-position
(R3 = CH3). With the only exception that 10a shows a greater
activity than 12a, this methylation usually reduces the activity
of the materials. The activity of 10b–10h is on average 10 times
smaller than expected from eq. (2). The effect of imide-N-
methylation is much smaller in the case of the phenyl substi-
tuted derivatives 10i–10l. If we compare the MIC’s of the com-
pounds 10i–10l with the MIC’s of the corresponding non
methylated compounds 12i–12l, we observe a reduction in ac-
tivity only in the case of 10k. The methylated compounds, how-
ever, are more hydrophobic than the non methylated ones. If we
take the different log(P) values into account and compare the Δ
values instead of the MIC’s, the compounds 10i, 10j and 10l
show a reduction in activity slightly above the limit of experi-
mental error.
The compounds 13a–13e are methylated at the indole N-po-
sition (R2 = CH3). The effect of this derivatization is not uni-
form. With 13b and 13d the methylation shows no effect. The
alkyl derivatives 13a and 13c show low activity, and the 4-
methoxyphenyl-derivative 13e shows a reduction in activity
only in Δ (relative to Δ of 12l) but not in MIC. From these
results we can only draw the conclusion that the indole-N-
methylation usually does not improve the activity.
Compound 11d was a side product of a target compound in
another study and we tested it as a mater of routine. Because we
have found 11d to be an active material, we synthesized the
homologous series 11a–11f in which we varied the length of
the alkyl spacer (expressed by n, see scheme 3). The MIC’s
do not strongly depend on the spacer length. If we use the Δ’s
for analysis, however, we found the compounds 11b and 11c
more active than expected from eq. (2) while all other com-
pounds of this series have pMIC’s fitting to the log(P) function.
Obviously, we observe a maximum in Δ, if the alkyl spacer
consists of three or four methylene units. We find a similar
dependence in the series of the 2-methoxyphenyl derivatives.
The distance of the methoxy group from the indole-2-position
increases in the sequence 12j < 12k < 12l. The compounds 12k
and 12l are more active than 12i, but 12j is not. In this series,
the activity depends also on the distance of a polar substituent
to the indol-2-position. This dependence is still, but only partly
recognizable in the series of the imide-N-methylated methoxy-
phenyl derivatives 10j–10l. 10l is more active than 10i, but 10j
and 10k are not. Finally, the effect of the methoxy group is
extinguished in the indole-N-methylated derivative 13e. 13e
shows the same MIC as 13d and the methoxy group does not
improve the activity in this case.
The compounds 12a and 12l show only moderate activities
against the Gram positive bacteria E. faecalis 1528 and
M. smegmatis SG 987 (see Table 2). In the case of
M. smegmatis SG 987, however, we have found also a linear
correlation between pMIC of the compounds 12b–12h and log
(P) as we have observed with S. aureus 134/93. Linear regres-
sion led to the function
pMIC ¼ 1:63 logðPÞ þ 0:57
(5)
with a correlation coefficient of 95%. The activity increases of
about 100 times if we vary the alkyl group to make the materi-
als more hydrophobic (see Table 5).
Consequently, we have included M. smegmatis SG 987 in
our study, and we give the results of the other compounds in
Table 6.
Methylation of the imid-N-position led on average to a 10-
fold reduction in activity. This effect is considerably strong
with the indole-2-alkylated derivatives 10a–10h. With the phe-
nyl substituted compounds 10i–10l we find a reduction in ac-
tivity only in Δ but not in MIC. Methylation of the indole-N-
position (13a–13e) led in all cases to a reduction in activity if
we use Δ for analysis. The compounds 13a and 13e, however,
show the same MIC’s as their non methylated derivatives 12b
and 12l, respectively. In the homologous series 11a–11f the 2-
methylanilide substructure also increases the activity against
M. smegmatis SG 987 relative to the expected values of eq.
(5) in some cases. We found this effect with 11e (N = 6) and
11f (N = 7). Compound 11b (N = 3) shows also a slightly larger
activity than the compounds 11a, 11c and 11d. Among the com-
pounds 12j–12l, compound 12k shows a larger activity than
12i. Among the compounds 10j–10l, compound 10k shows a
larger activity than 10i.
4. Discussion
The results, shown in Table 2, demonstrate that the deriva-
tives of 12a are antibacterial principles, showing selective ac-
tivity against different bacterial strains. The fact that they have
a spectrum of activity against the investigated bacteria different
to Dox and Vanc indicates a different mechanism of action.
This might be important in circumventing existing resistance
mechanisms. The activities of the compounds 12b–12h depend
on their hydrophobicities. Correlation between log(P) and bio-
logical activity has been frequently observed [17]. One possible
Table 5
Activity of compounds 12b–12h against M. smegmatis SG 987
Compound
12b
12c
12d
12e
12f
12g
12h
R1
MIC μg–1 ml–1
25.0
7.95
8.3
2.17
0.56
0.14
0.30
MIC per 10−6
82
25
25
6.25
1.55
0.37
0.77
M
PMIC
4.1
4.6
4.6
5.2
5.8
6.4
6.1
Δ
log(P)
2.26
2.41
2.58
2.84
3.08
3.35
3.65
Methyl
Ethyl
Propyl
Butyl
Pentyl
Hexyl
Heptyl
–0.1
0.1
–0.2
0.0
0.2
0.4
–0.4

182
S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
Table 6
Antibacterial activities of compounds 10a–l, 11a–f, 12a, 12i–l and 13a–e against M. smegmatis SG 987
Compound
10a
10b
10c
10d
10e
10f
10g
10h
10i
R1
H
Methyl
Ethyl
Propyl
Butyl
MIC μg–1 ml–1
6.25
50
50
MIC per 10−6
20.5
157
150
72
69
33
8.0
–
32.8
15.0
7.5
30.4
39
17
–
–
30.3
55.3
17.1
52.0
25.3
0.49
0.78
43
50
33
7.5
30.0
M
pMIC
4.7
3.8
3.8
4.1
4.2
4.5
5.1
–
4.5
4.8
5.1
4.5
4.4
4.8
–
Δ
log(P)
2.89
2.73
2.87
3.06
3.35
3.63
3.84
4.19
3.03
2.86
2.99
3.03
2.69
3.28
3.84
3.11
3.15
2.58
2.60
2.65
2.74
2.91
3.07
2.34
2.58
2.34
2.54
2.59
–0.6
–1.2
–1.4
–1.4
–1.8
–2.0
–1.7
–
–1.0
–0.4
–0.3
–1.0
–0.5
–1.1
–
25
25
Pentyl
Hexyl
12b
3.12b
No activityb
12.5
Heptyl
Phenyl
ph-2-OMe
ph-3-OMe
ph-4-OMe
Methyl
Butyl
10j
10k
10l
6.25
3.125
12.5
12.5
6.25
No activity
No activity
12.5
25.0
8.0
25
12.5
0.25
0.41
12.5
18.4
12.5
3.125
13.1
13a
13b
13c
13d
13e
11a
11b
11c
11d
11e
11f
12a
12i
12j
12k
12l
Hexyl
Phenyl
ph-4-OMe
N = 2a
N = 3a
N = 4a
N = 5a
N = 6a
N = 7a
Hc
Phenyl
ph-2-OMe
ph-3-OMe
ph-4-OMe
–
–
4.5
4.3
4.8
4.3
4.6
6.3
6.1
4.4
4.3
4.5
5.1
4.5
–1.2
–0.5
–0.1
–0.6
–0.4
1.0
0.5
0.0
–0.5
0.1
0.4
–0.3
a
For R1 and N see Scheme 3.
The compounds haven’t been completely soluble in the testing procedure.
b
explanation is that the active materials have to permeate the
hydrophobic double layer of a cell membrane to reach their
target inside the cell [18]. In the case of M. smegmatis SG
987, the slope of the log(P) function (eq. (5)) is two times larger
than in the case of S. aureus 134/93 (eq.(2)). This indicates that
hydrophobic materials can invade the cells of M. smegmatis SG
987 easier than those of S. aureus 134/93. This result is easy to
understand, because pathogenic mycobacteria are wrapped by a
high amount of mycolic acid esters [19], making their cell sur-
face more hydrophobic than those of most other bacteria.
Therefore, the experimental observations are in good agreement
with the hypothesis that the permeation properties of the active
materials are reflected by the observed log(P) functions indicat-
ing a predominant lipid pathway [20]. In this case, however, the
hydrophobicity of the active materials should influence the ac-
tivity of all investigated compounds and the effect should not
be limited to the compounds 12a–12h. If we want to take into
account the effect of the different hydrophobicities of our com-
pounds, we can use the Δ’s for analysis instead of the pMIC’s.
Although the most important conclusions of our study do not
strongly depend on it, there are some indications that the use of
the Δ’s is justified. The pMIC’s of 10a–10h also depend on log
(P) but the limited solubility of some of this compounds in the
testing procedure affects the quantitative correlation in this ser-
ies. Finally, compounds 11a, 11d–11f, 12i and 12j have activ-
ities against S. aureus 134/93 fitting to eq. (2) although they are
not 2-alkylated derivatives of 12a.
If a derivatization causes a deviation of Δ > +/–0.3 from the
log(P) function (or from Δ of a fitting reference, if more than
one derivatization is made) in several derivatives, it is very un-
likely that only different permeation properties cause this effect.
We have to suspect a special effect on physiological processes
inside the bacterial cell.
We have observed two of such derivatization effects in our
study, which we consider to be important. One of them is the
reduction of activity in the case of imide-N-methylation. It is
observed with S. aureus 134/93 and M. smegmatis SG 987 to
approximately the same extent. Therefore, the imide NH is im-
portant for the activity against both microorganisms. Another
derivatization effect is the increase of activity by polar substi-
tuents linked by a spacer to the indole-2-position. The com-
pounds 11b, 11c, 12k and 12l show higher activities against
S. aureus 134/93 than expected from eq. (2). All these com-
pounds have hydrogen-bond-acceptors (CO in the case of 11b,
11c and OCH3 in the case of 12k, 12l) linked in a distance of
three (11b, 12k) or four (11c, 12l) C–C bond lengths to the
indole-2-position. Possibly the carbonyl and methoxy-groups
produce the observed effect by a similar interaction inside the
bacteria cell. In the case of M. smegmatis SG 987, the com-
pounds 11e and 11f have shown higher pMIC’s than expected
from eq. (5). Their 2-methylanilide substructures are situated at
larger distances from the indole-2-position than in the case of
S. aureus 134/93. On the other hand, 11b shows a slightly lar-
ger activity than 11a and 11c, and 10k as well as 12k show

S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
183
larger activities against M. smegmatis SG 987 than the simple
6.2. Chemistry
phenyl derivatives 10i and 12i, respectively. All this com-
pounds have their hydrogen bond acceptors in nearly the same
distance from the indole-2-position and most of them show an
improved activity also against S. aureus 134/93. Also in the
case of M. smegmatis SG 987, we could improve the activity
by linking hydrogen bond acceptors by spacers to the indol-2-
position. In this respect, both microorganisms have shown
again similar results in the structure activity relationship, pre-
sented here.
Melting points were recorded on a Büchi 512 heating stage
and are not corrected. Proton Nuclear magnetic resonance spec-
tra were recorded on a Bruker AC 250 (250 MHz) spectro-
meter. DMSO-d6 was used as solvent if not stated otherwise.
FT-IR-spectroscopy was performed on a Nicolet 410 FT-IR-
spectrometer. Microanalyses were performed by Analytisches
Lab. Univ. Regensburg and were within 0.4% of the theore-
tical values. Thin layer chromatography (TLC) was carried out
on Al-sheets coated with 60 F245 silica. Column chromatogra-
phy (CC) was carried out using Merck 60 (70–230 mesh
ASTM) silica. Solvents and commercially available reagents
were dried and purified before use according to standard proce-
dures.
5. Conclusion
The new compounds described were found to have antibac-
terial activity against resistant strains of S. aureus,
M. smegmatis and some other Gram positive bacteria whereas
they are inactive against Gram negative bacteria.
log(P)-values were determined using HPLC retention data
[17]. All compounds were dissolved in methanol and subjected
to HPLC:
Some of our new compounds show minimal inhibition con-
centrations (MIC’s) against resistant strains lower than those of
ciprofloxacin, vancomycin and doxycycline resp., which are
widely used in antiinfective therapy. Furthermore, they show a
different spectrum of activity against the investigated bacteria
suggesting a mechanism of action different to vancomycin and
doxycycline. This might be important in circumventing existing
resistance mechanisms.
In most cases, the activity of our compounds against
S. aureus and M. smegamtis improves by increasing hydropho-
bic properties as well as by hydrogen bond acceptors, depend-
ing on their distance from the indole-2-position. Methylation of
the imide-NH reduces the activity. The extent depends on the
nature of the substituent in indole-2-position, which we consid-
er to be important.
column: LiChrospher 100 RP-18 (5 μm) 250 × 4 mm, Merck
Art. 50983; eluent: methanol/water/acetic acid (80 + 20 + 0.1),
adjusted with ammonia to pH 5.5; flow: 1.00 ml min–1; detec-
tion: 254 nm; temperature: 25 °C. From the retention data, the
capacity factor k′ is calculated according to eq. (6):
k0¼ log ððtR=toÞ ꢀ 1Þ
(6)
with tR = retention time of the compound, and to = retention
time of methanol. From k′ we have determined log(P) using a
linear function which was calibrated with the following refer-
ence substances: 4-nitrophenole (log(P) = 1.91 [22]), 4-chloro-
phenole (log(P) = 2.39 [22]), benzophenone (log(P) = 3.18
[23]), naphthalene (log(P) = 3.44 [24]) and anthracene (log(P)
= 4.49 [24]). We have carried out two series of determinations,
using two different specimen of columns and separately mixed
eluents. Every log(P) value, given in tables, is an average value
of two estimations. The deviation was on average 0.03 and in
no time larger than 0.1 log(P) units.
6. Experimental
6.1. Biological testing procedure
6.2.1. Formation of ester-amides from carboxylic acid
chlorides and 2-methylaniline (5a; 5b; 5e)
The in vitro antibacterial activities were assessed by determi-
nation of minimal inhibitory concentrations (MIC’s) using a
standard micro broth dilution method in Mueller Hinton med-
ium (DIFCO) according to the NCCLS-guidelines [21]. The test
and reference compounds were stepwise diluted in the culture
medium in a range from 100 to 0.05 μg ml–1. In every dilution
step the concentration was reduced to half of the amount before.
The Gram positive (S. aureus SG 511, M. smegmatis SG 987)
and Gram negative (E. coli SG 458, P. aeruginosa SG 137) test
organisms were obtained from the stock of the Hans Knöll In-
stitute or were clinical isolates (S. aureus 134/93, E. faecalis
1528), kindly provided by W. Witte (Robert Koch-Institute,
Werningerode Branch, Germany). Inocula of test organisms
were adjusted to approximately 105 CFU ml–1 (CFU = colony
forming units). After strains were incubated for 18–20 h
(M. smegmatis SG 987 for 48 h) at 37 °C, the MIC’s were read
as the lowest concentration of compound allowing no visible
growth.
We dissolved 2-methylaniline (0.066 mol) and triethylamine
(0.066 mol) in dry CH2Cl2 (200 ml). The solution was cooled
with ice, and the acid chloride (0.066 mol) was carefully added
dropwise. Then the solution was heated to reflux for 12 h,
cooled, the precipitated triethylammonium chloride was filtered
off, and the residue was purified by CC (CH2Cl2/ethyl acetate
6:1). The products were obtained as colorless powders.
6.2.1.1. Methyl 4-(2-methylphenyl)amino-4-oxobutanoate (5a)
[25]. Yield: 13.8 g (62 mmol; 94% from methyl 4-chloro-4-
oxo-butanoate); m.p. 72 °C (Lit. 78 °C [25]); IR (KBr) ν:
3355, 2929–2857, 1705, 1659, 1588, 1493, 1458; 747 cm−1.
6.2.1.2. Methyl 5-(2-methylphenyl)amino-5-oxopentanoate (5b).
Yield: 13.52 g (57 mmol; 86% from methyl 5-chloro-5-oxo-
1
pentanoate); m.p. 60 °C; H-NMR δ 1.84 (m, 2 H), 2.18 (s; 3
H, CH3), 2.37 (t; J = 7.4 Hz, 2 H), 2.38 (t, J = 7.4 Hz, 2 H),

184
S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
3.60 (s; 3 H, OCH3), 7.06 (m; 1 H, 4-H), 7.15 (m; 1 H, 5-H),
7.19 (d; Jo = 7.1 Hz, 1 H, 3-H), 7.35 (d; Jo = 7.5 Hz, 1 H, 6-H),
9.26 (s; 1 H, NH); IR (KBr) ν: 3450, 3245–2960, 1736, 1651,
1613, 1584, 1541, 750 cm−1. Anal. (C13H17NO3) C, H, N.
Yield: 7.0 g (27 mmol; 20%); m.p. 60 °C; Rf 0.23 (CH2Cl2/
ethylacetate 9:1); H-NMR: δ 1.31 (m; 2 H), 1.57 (m; 4 H),
1
2.17 (s; 1 H, CH3), 2.30 (t; J = 7.3 Hz, 4 H), 3.57 (s; 3 H,
OCH3), 7.04 (m; 1 H, 4-H), 7.13 (m; 1 H, 5-H), 7.17 (d;
Jo = 7.5 Hz, 1 H, 3-H), 7.33 (d; Jo = 7.35 Hz, 1 H, 6-H), 9.21
(s; 1 H, NH); IR (KBr) ν: 3295, 2929–2361, 1732, 1651, 1588,
1530, 1258, 1175; 756 cm−1. Anal. (C15H20NO). C, H, N.
6.2.1.3. Methyl 8-(2-methylphenyl)amino-8-oxooctanoate (5e).
Yield: 5.93 g (21 mmol; 64% from 33 mmol methyl 8-chloro-
8-oxo-octanoate); m.p. 68 °C; Rf 0.21 (CH2Cl2/ethyl acetate 9:
1); 1H-NMR δ 1.30 (m; 4 H), 1.56 (m; 4 H), 2.18 (s; 3 H, CH3),
2.30 (t; J = 7.5 Hz, 4 H), 3.58 (s; 3 H, OCH3), 7.06 (m; 1 H, 4-
H), 7.14 (m; 1 H, 5-H), 7.19 (d; Jo = 7.9 Hz, 1 H, 3-H), 7.34 (d;
Jo = 7.1 Hz, 1 H, 6-H), 9.21 (s; 1 H, NH); IR (KBr) ν: 3295,
3023–2853, 1734, 1659, 1611, 1588, 1524; 758 cm−1. Anal.
(C16H23NO3) C, H, N.
6.2.4. Formation of the 2-alkyl- and 2-methoxyphenyl indoles
according to Smith [11,12] (3a–3h)
Trimethylsilyl-o-toluidine (TMSOT, 0.0145 mol) [11] was
dissolved in dry hexane (60 ml). Under N2 n-BuLi
(0.029 mol, 1.6 M solution in hexane) was added dropwise at
RT. Then the solution was heated to reflux for 4 h. During the
reaction a red precipitate occurred, and the solution turned or-
ange. The metallated TMSOT might burn when it is exposed to
air.
6.2.2. Formation of ester amides from dicarboxylic acid
monomethyl esters and 2-methylaniline (5c; 5f)
Dicarboxylic acid monomethyl ester (0.03 mol), 2-methyla-
niline (0.03 mol), N,N′-dicyclohexylcarbodiimide (0.03 mol)
and p-toluenesulphonic acid monohydrate (0.003 mol) were
dissolved in pyridine (50 ml) and stirred for 12 h. Precipitated
N,N-dicyclohexylurea was filtered off, the solvent was removed
in vacuo, and the remaining oil was dissolved in CH2Cl2 and
purified by CC (CH2Cl2/ethyl acetate 6:1). The products were
obtained as colorless powders.
The obtained suspension was cooled to –78 °C, and then a
solution of 0.014 mol of ester in 30 ml THF was added slowly,
so that the temperature did not rise above –70 °C. After stirring
overnight, while slowly warming up to RT, the solution was
refluxed for 2 h, poured on ice (200 g) and stirred until most
of the ice was molten. The mixture was extracted with ethyl
acetate (4 × 100 ml), the extract was dried over Na2SO4 and
concentrated in vacuo. The indole spot on TLC acquires a yel-
low color after several h. The raw material was purified by CC
(CH2Cl2). We separated the alkylindoles as oils and processed
them without further purification. References are given for the
characterization of the products.
6.2.2.1. Methyl 6-(2-methylphenyl)amino-6-oxohexanoate (5c).
Yield: 6.1 g (24 mmol; 80% from methyl 6-methoxy-6-oxo-
hexanic acid; m.p. 61 °C; Rf 0.38 (CH2Cl2/ethyl acetate 6:1);
1H-NMR δ 1.60 (m; 4 H), 2.18 (s; 3 H, CH3), 2.35 (m; 4 H),
3.59 (s; 3 H, OCH3), 7.07 (m; 1 H, 4-H), 7.14 (m; 1 H, 5-H),
7.19 (d; Jo = 7.9 Hz, 1 H, 3-H), 7.35 (d; Jo = 7.5 Hz, 6-H), 9.24
(s; 1 H, NH); IR (KBr) ν: 3287, 3027–2851, 1736, 1651, 1588,
1533, 760 cm−1. Anal. (C14H19NO3) C, H, N.
6.2.4.1. 2-Ethyl-1H-indole (3a) [26]. Yield: 0.64 g (4.4 mmol;
30% from 2a); Rf 0.83 (CH2Cl2).
6.2.4.2. 2-Propyl-1H-indole (3b) [27]. Yield: 0.62 g (3.9 mmol;
27% from 2b); Rf 0.81 (CH2Cl2).
6.2.2.2. Methyl 9-(2-methylphenyl)amino-9-oxononanoate (5f).
Yield: 12.8 g (44 mmol; 73% from 60 mmol 8-methoxy-9-ox-
ononanoic acid; m.p. 45 °C; Rf 0.6 (CH2Cl2/ethyl acetate 9:1);
1H-NMR δ 1.30 (m; 6 H), 1.55 (m; 4 H), 2.18 (s; 3 H, CH3),
2.30 (m; 4 H), 3.58 (s; 3 H, OCH3), 7.07 (m; 1 H, 4-H), 7.13
(m; 1 H, 5-H), 7.19 (d; Jo = 7.5 Hz, 1 H, 3-H), 7.34 (d;
Jo = 7.5 Hz, 1 H, 6-H), 9.21 (NH); IR (KBr) ν: 3288, 2935–
2854, 1738, 1652, 1588, 1532, 754 cm−1. Anal. (C17H25NO3)
C, H, N.
6.2.4.3. 2-Buthyl-1H-indole (3c) [28]. Yield: 0.43 g (2.5 mmol;
18% from 2c); Rf 0.88 (CH2Cl2).
6.2.4.4. 2-Pentyl-1H-indole (3d) [29]. Yield: 0.28 g (1.5 mmol;
10% from 2d); Rf 0.90 CH2Cl2).
6.2.4.5. 2-Hexyl-1H-indole (3e) [29]. Yield: 0.65 g (3.2 mmol;
22% from 2e); Rf 0.95 (CH2Cl2).
6.2.3. Preparation of methyl 7-(2-methylphenyl)amino-7-
oxoheptanoate (5d)
6.2.4.6. 2-Heptyl-1H-indole (3f) [30]. Yield: 0.78 g (3.6 mmol;
25% from 2f); Rf 0.88 (CH2Cl2).
Triethylamine (0.26 mol) and 2-methylaniline (0.13 mol)
were dissolved in 100 ml of methanol. Pimeoylchloride
(0.13 mol) was carefully added and the mixture was refluxed
overnight, than the solvent was removed in vacuo. Water
(100 ml) was added to the residue, than the products were ex-
tracted with ethyl acetate, dried with Na2SO4 and concentrated
in vacuo. The residue was dissolved in CH2Cl2 (50 ml). Most
of the bis toluyl side product precipitated and was filtered off.
The solution was purified by CC on SiO2; CH2Cl2.
6.2.4.7. 2-(2-Methoxyphenyl)-1H-indole (3g). Yield: 0.77 g
(3.45 mmol; 24% from methyl-2-methoxybenzoate); Rf 0.7
1
(CH2Cl2); m.p. 83 °C; H-NMR δ 3.37 (s; 3 H, OCH3), 6.94
(d; J = 2 Hz, 1 H, ind 3-H), 6.97–7.15 (m; 4 H, ind 5-H, ph 4-
H, ph 5-H, ph 6-H), 7.30 (m; 1 H, ind 6-H), 7.44 (d;
Jo = 8.3 Hz, 1 H, ind 7-H), 7.52 (d; Jo = 7.5 Hz, 1 H, ind 4-
H), 7.80 (m; 1 H, ph 3-H), 11.18 (s; 1 H, NH); IR (KBr) ν:

S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
185
3446, 3041−2842, 1476, 1464, 1451, 1435, 1360, 1342, 1310,
3395, 3295, 3054–2800, 1653, 1588, 1530; 752 cm−1. Anal.
(C19H20N2O) C, H, N.
1236 cm−1. Anal. (C15H13NO) C, H, N.
6.2.5.3. 5-(1H-2-Indolyl)-N-(o-methylphenyl)pentanoylamide
(6c). Yield: 0.79 g (2.58 mmol; 18% from 5c); m.p. 153 °C; Rf
0.33 (CH2Cl2/ethyl acetate 8:1); 1H-NMR δ 1.71 (m; 4 H), 2.17
(s; 3 H, CH3), 2.38 (t; Jo = 6.7 Hz, 2 H), 2.75 (t; J = 6.7 Hz, 2
H) 6.13 (s; 1 H, ind 3-H), 6.91 (m; 1 H, ind 5-H), 6.98 (m; 1 H,
ind 6-H), 7.06 (m; 1 H, tol 4-H), 7.14 (m; 1 H, tol 5-H), 7.19
(d; Jo = 7.5 Hz, 1 H, tol 3-H), 7.27 (d; 7.9 Hz, 1 H, ind 7-H),
7.36 (d; Jo = 7.7 Hz, 1 H, tol 6-H), 7.39 (d; Jo = 7.0 Hz, 1 H,
ind 4-H), 9.24 (s; 1 H, NH), 10.89 (s; 1 H, NH); IR(KBr) ν:
3363, 3276, 3052–2861, 1663, 1501; 752 cm–1. Anal.
(C20H22N2O) C, H, N.
6.2.4.8. 2-(3-Methoxyphenyl)-1H-indole (3h). Yield: 0.60 g
(2.7 mmol; 18% from methyl-3-methoxybenzoate); Rf 0.83
(CH2Cl2); m.p. 136 °C; 1H-NMR δ 3.83 (s; 3 H, OCH3),
6.85–6.90 (m; 1 H, ind 5-H), 7.09 (m; 1 H, ind 6-H), 7.35–
7.45 (m; 4 H, ph 2-H, ph 4-H, ph 5-H, ind 7-H), 7.52 (d;
Jo = 7.5 Hz, 1 H, ind 4-H), 12.51 (s; 1 H, NH); IR (KBr) ν:
3396, 1601, 1482, 1464, 1454, 1435, 1350, 1304, 1263, 1235,
1219, 1177, 1165, 1036, 852, 785, 758, 677 cm−1. Anal.
(C17H13NO) Calc. 80.69 C, H 5.87, N 6.27. Found C 80.08,
H 5.59, N 6.09.
6.2.5. Formation of the indole-amides from the dicarboxylic
acid methyl ester amides (6a–6f)
6.2.5.4. 7-(1H-2-Indolyl)-N-(o-methylphenyl)hexanoylamide
(6d). Yield: 1.1 g (3.43 mmol; 24% from 5d); m.p. 93 °C; Rf
0.41 (CH2Cl2/ethyl acetate 9:1); 1H-NMR δ 1.39 (m; 2 H), 1.68
(m; 4 H), 1.68 (m; 4 H), 2.15 (s; 3 H, CH3), 2.32 (t; J = 7.3 Hz,
2 H), 2.71 (t; J = 7.3 Hz, 2 H), 6.11 (s; 1 H, ind. 3-H), 6.89 (m;
1 H, ind 5-H), 6.97 (m; 1 H, ind 6-H), 7.05 (m; 1 H, tol 4-H),
7.12 (m; 1 H, tol 5-H), 7.17 (d; J = 7.9 Hz, 1 H, tol 3-H), 7.24
(d; J = 7.9 Hz, 1 H, ind 7-H), 7.32 (d; J = 7.5 Hz, 1 H, tol 6-H),
7.37 (d; J = 7.5 Hz, 1 H, ind 4-H), 9.20 (s; 1 H, NH), 10.86 (s;
1 H, NH); IR (KBr) ν: 3405, 3307, 2934, 2863, 1653, 1588,
1528, 783, 748 cm−1. Anal. (C21H24N2O) C, H, N.
In one flask, TMSOT (0.014 mol) was lithiated according to
the procedure described above for 3a–h. In a second flask, a
solution of dicarboxylic acid mono esteramide (0.014 mol) in
dry THF (50 ml) was cooled under N2 to –80 °C, then n-butyl-
lithium (0.014 mol, 1.6 M solution in hexane) was added
slowly, so that the temperature in the solution did not rise above
–70 °C. Then the Li2TMSOT suspension was added in the same
way. The mixture was stirred overnight while slowly warming
up to RT. Then it was poured onto ice (200 g) and stirred until
most of the ice was molten. The mixture was extracted with
ethyl acetate (4 × 100 ml), the extract was dried over Na2SO4
and concentrated in vacuo yielding a dark oil. The raw material
was purified by CC (CH2Cl2/ethyl acetate mixtures, which are
cited below following the Rf values of the compounds). The
products precipitate as colorless crystals after removing most
of the solvent under reduced pressure and adding pentane to
promote precipitation.
6.2.5.5. 7-(1H-2-Indolyl)-N-(o-methylphenyl)heptanoylamide
(6e). Yield: 0.45 g (1.35 mmol; 12% from 5e); m.p. 123–125 °
1
C; Rf 0.22 (CH2Cl2/ethyl acetate 9:1); H-NMR δ 1.38 (m; 4
H), 1.61 (m; 2 H), 1.70 (m; 2 H), 2.17 (s; 3 H, CH3), 2.35 (t,
J = 7.0 Hz, 2 H), 2.71 (t, J = 7.5 Hz, 2 H), 6.11 (s, 1 H, ind 3-
H), 6.90 (m; 1 H, ind 5-H), 6.97 (m; 1 H, ind 6-H), 7.05 (m; 1
H, tol 4-H), 7.14 (m; 1 H, tol 5-H), 7.19 (d, Jo = 7.5 Hz, 1 H, tol
3-H), 7.26 (d, Jo = 8.3 Hz, 1 H, ind 7-H), 7.35 (d, Jo = 8.7 Hz, 1
H, tol 6-H), 7.38 (d, Jo = 8.3 Hz, 1 H, ind 4-H) 9.20 (s; 1 H,
NH), 10.87 (s, 1H, NH); IR (KBr) ν: 3425, 3253, 2927–2861,
1649, 1607, 1584, 1541, 764, 748 cm−1. Anal. (C22H26N2O) C,
H, N.
6.2.5.1. 3-(1H-2-Indolyl)-N-(o-methylphenyl)propionylamide
(6a). Yield: 0.36 g (1.29 mmol; 9% from 5a [24]); m.p. 173 °C;
1
Rf 0.47 (CH2Cl2/ethyl acetate 6:1); H-NMR δ 2.15 (s; 3 H,
CH3); 2.78 (t; J = 7.5 Hz, 2 H), 3.05 (t; J = 7.5 Hz, 2 H), 6.19
(s; 1 H, ind 3-H), 6.91 (m; 1 H, ind 5-H), 6.99 (m; 1 H, ind 6-
H), 7.05 (m; 1 H, tol 4-H), 7.14 (m; 1 H, tol 5-H), 7.19 (d;
Jo = 7.1 Hz, 1 H, tol 3-H), 7.28 (d; Jo = 7.9 Hz, 1 H, ind 7-
H), 7.38 (d; Jo = 7.0 Hz, 1 H, tol 6-H), 7.41 (d; Jo = 7.5 Hz, 1
H, ind 4-H), 9.34 (s; 1 H, NH), 10.92 (s; 1 H, NH); IR (KBr) ν:
6.2.5.6. 8-(1H-2-Indolyl)-N-(o-methylphenyl)octanoylamide
(6f). Yield: 0.85 g (2.44 mmol; 17% from 5f); m.p. 95 °C; Rf
1
0.7 (CH2Cl2/ethyl acetate 9:1); H-NMR δ 1.35 (m; 6 H), 1.66
(m; 4 H), 2.17 (s; 3 H, CH3), 2.32 (t; J = 7.3 Hz, 2 H), 2.70 (t;
J = 7.5 Hz, 2 H), 6.11 (s; 1 H, ind 3-H), 6.90 (m; 1 H, ind 5-H),
6.97 (m; 1 H, ind 6-H), 7.06 (m; 1 H, tol 4-H), 7.13 (m; 1 H, tol
5-H), 7.18 (d; Jo = 7.5 Hz, 1 H, tol 3-H), 7.25 (d; Jo = 7.9 Hz, 1
H, ind 7-H), 7.34 (d; Jo = 9.1 Hz, 1 H, tol 6-H), 7.38 (d;
Jo = 8.7 Hz, 1 H, ind 4-H), 9.21 (s; 1 H, NH), 10.86 (s; 1 H,
NH); IR (KBr) ν: 3394, 3052–2853, 1651, 1586, 1530, 1485;
748 cm−1. Anal. (C23H28N2O) C, H, N.
3355, 3291, 2950–2700, 1663, 1501, 754, 741 cm−1 Anal.
.
(C18H18N2O) C, H, N.
6.2.5.2. 4-(1H-2-Indolyl)-N-(o-methylphenyl)butanoylamide
(6b). Yield: 1.13 g (3.86 mmol; 27% from 5b); m.p. 107 °C; Rf
0.51 (CH2Cl2/ethyl acetate 6:1); 1H-NMR δ 2.04 (m; 2 H), 2.18
(s; 3 H, CH3), 2.40 (t; Jo = 7.5 Hz, 2 H), 2.78 (t; Jo = 7.5 Hz, 2
H), 6.16 (s; 1 H, ind 3-H), 6.92 (m; 1 H, ind 5-H), 6.99 (m; 1 H,
ind 6-H), 7.07 (m; 1 H, tol 4-H), 7.13 (m; 1 H, tol 5-H), 7.19
(d; Jo = 7.5 Hz, 1 H, tol 3-H), 7.27 (d; Jo = 8.3 Hz, 1 H, ind
7-H), 7.36 (d; Jo = 7.5 Hz, 1 H, tol 6-H), 7.41 (d; Jo = 7.5 Hz,
1 H, ind 4-H), 9.26 (s; 1 H, NH), 10.93 (s; 1 H, NH); IR ν:
6.2.6. Condensation of 8 or 9 with indole derivatives—general
procedure A
The indole derivative (2 mmol) was dissolved in dry THF
(10 ml) and cooled under N2 to –20 °C. Then 4 ml of LiHMDS

186
S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
(1 M in THF) were slowly added. After stirring the solution for
45 min, 2 mmol of TBS-dibromomaleinimide (8) or N-methyl-
dibromomaleinimide (9) in 10 ml of THF were added within 3 h.
The solution was stirred for 15 min, poured into sat. aq. NH4Cl
(100 ml), extracted with ethyl acetate (4 × 50 ml), dried over
Na2SO4, concentrated in vacuo and purified by CC (CH2Cl2/
ethyl acetate; mixtures cited below following every Rf value).
6.2.6.6. 1-Methyl-3-bromo-4-(2-pentyl-1H-3-indolyl)-2,5-dihy-
dro-1H-2,5-pyrrole-dione (10f). Yield: 0.41 g (1.09 mmol;
55% from 3d and 9); m.p. 80 °C; Rf 0.72 (CH2Cl2); 1H-
NMR δ 0.83 (t; J = 6.6 Hz, 3 H, CH3), 1.23 (m; 4 H, CH2),
1.67 (m; 2 H, CH2), 2.72 (t; J = 7.8 Hz, 2 H, CH2), 3.00 (s; 3
H, NCH3), 7.01 (m; 1 H, 5-H), 7.10 (m; 1 H, 6-H), 7.33 (d;
Jo = 8.3 Hz, 1 H, 7-H), 7.36 (d; Jo = 7.5 Hz, 1 H, 4-H), 11.69
(s; 1 H, NH); IR (KBr) ν: 3361, 2954, 2930, 1173, 1707,
1626, 1613, 1460, 1439, 1338, 737 cm−1. Anal.
(C18H19BrN2O2) C, H, N.
6.2.6.1. 1-Methyl-3-bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione (10a) [13]. Yield: 0.46 g (1.5 mmol; 75%
from indole and 9); m.p. 145 °C (dec.) (Lit. 145 °C [13]); Rf
1
6.2.6.7. 1-Methyl-3-bromo-4-(2-hexyl-1H-3-indolyl)-2,5-dihy-
0.22 (CH2Cl2); H-NMR δ 3.01 (s; 3 H, CH3), 7.18–7.72 (m;
dro-1H-2,5-pyrrole-dione (10g). Yield: 0.32 g (0.82 mmol;
5 H, aromat.), 12.33 (s; 1 H, NH); IR (KBr) ν: 3270, 3115–
1
2985, 1760, 1710, 1595, 1495, 1460, 1430 cm−1.
56% from 3e and 9); m.p. 100 °C; Rf 0.74 (CH2Cl2); H-
NMR (CDCl3) δ 0.87 (t; J = 6.6 Hz, 3 H, CH3), 1.30 (m; 6
H, CH2), 1.70 (m; 2 H, CH2), 2.82 (t; J = 7.4 Hz, 2 H, CH2),
3.18 (s; 3 H, NCH3), 7.16 (m, 1 H, 5-H), 7.21 (m; 1 H, 6-H),
7.36 (m; 1 H, 7-H), 7.43 (m; 1 H, 4-H), 8.38 (s; 1 H, NH); IR
(KBr) ν: 3351, 1773, 1707, 1460, 1437, 1385, 989, 739 cm−1.
Anal. (C19H21BrN2O2) C, H, N.
6.2.6.2. 1-Methyl-3-bromo-4-(2-methyl-1H-3-indolyl)-2,5-di-
hydro-1H-2,5-pyrrole-dione (10b). Yield: 0.38 g (1.19 mmol;
59% from 2-methyl indole and 9); m.p. 160 °C (dec.); Rf 0.33;
1H-NMR δ 2.40 (s; 3 H, CH3), 3.00 (s; 3 H, NCH3), 7.01 (m;
1 H, 5-H), 7.10 (m; 1 H, 6-H), 7.35 (d; Jo = 7.1 Hz, 1 H, 7-H),
7.37 (d; Jo = 7.1 Hz, 1 H, 4-H), 11.75 (s; 1 H, NH); IR (KBr)
ν: 3361, 2925, 1771, 1705, 1624, 1613, 1422, 1379, 752,
735 cm−1. Anal. (C14H11BrN2O2) C, H, N.
6.2.6.8. 1-Methyl-3-bromo-4-(2-heptyl-1H-3-indolyl)-2,5-dihy-
dro-1H-2,5-pyrrole-dione (10h). Yield: 0.28 g (0.69 mmol;
46% from 3f and 9); m.p. 75 °C; Rf 0.77 (CH2Cl2); 1H-
NMR δ 0.82 (t; J = 6.4 Hz, 3 H, CH3), 1.21 (m; 6 H, CH2),
1.66 (m; 2 H, CH2), 2.72 (t; J = 7.3 Hz, 2 H, CH2), 3.00 (s; 3
H, NCH3), 7.01 (m, 1 H, 5-H), 7.10 (m; 1 H, 6-H), 7.33 (d;
Jo = 7.9 Hz, 1 H, 7-H), 7.36 (d; Jo = 7.9 Hz, 1 H, 4-H), 11.68
(s; 1 H, NH); IR (KBr) ν: 3361, 2929, 1773, 1705, 1613,
1460, 1439, 1383, 987, 808, 737 cm−1. Anal. (C20H13BrN2O2)
C, H, N.
6.2.6.3. 1-Methyl-3-bromo-4-(2-ethyl-1H-3-indolyl)-2,5-dihy-
dro-1H-2,5-pyrrole-dione (10c). Yield: 0.23 g (0.69 mmol;
34% from 3a and 9); m.p. 140 °C (dec.); Rf 0.53 (CH2Cl2);
1H-NMR δ 1.28 (t; J = 7.5 Hz, 3 H, CH3), 2.73 (q;
Jo = 7.5 Hz, 2 H, CH2), 3.00 (s; 3 H, CH3), 7.02 (m; 1 H, 5-
H), 7.11 (m; 1 H, 6-H), 7.34 (d; Jo = 7.5 Hz, 1 H, 7-H), 7.37
(d; Jo = 7.15 Hz, 1 H, 4-H), 11.71 (s; 1 H, NH); IR (KBr) ν:
3378, 2979, 1771, 1705, 1626, 1433, 1385, 1140, 1001, 748,
735 cm−1. Anal. (C15H13BrN2O2) C, H, N.
6.2.6.9. 1-Methyl-3-bromo-4-(2-phenyl-1H-3-indolyl)-2,5-di-
hydro-1H-2,5-pyrrole-dione (10i). Yield: 0.65 g (1.7 mmol;
56% from 2-phenylindole and 9); m.p. 225 °C; Rf 0.59
1
(CH2Cl2); H-NMR (CDCl3) δ 3.11 (s; 3 H, CH3), 7.22 (m;
6.2.6.4. 1-Methyl-3-bromo-4-(2-propyl-1H-3-indolyl)-2,5-di-
hydro-1H-2,5-pyrrole-dione (10d). Yield: 0.33 g (0.95 mmol;
47% from 3b and 9), m.p. 155 °C; Rf 0.65 (CH2Cl2); 1H-NMR
δ 0.86 (t; J = 7.25 Hz, 3 H, CH3), 1.73 (m; 2 H, CH2), 2.70 (t;
J = 7.3 Hz, 2 H, CH2), 3.00 (s; 3 H, CH3), 7.02 (m; 1 H, 5-H),
7.10 (m; 1 H, 6-H), 7.33 (d; Jo = 7.5 Hz, 1 H, 7-H), 7.36 (d;
Jo = 7.5 Hz, 1 H, 4-H), 11.68 (s; 1 H, NH); IR (KBr) ν: 3378,
2965, 1771, 1707, 1624, 1431, 1383, 749 cm−1. Anal.
(C16H15BrN2O2) C, H, N.
1 H, ind 5-H), 7.29 (m; 1H, ind 6-H), 7.41 (m; 1 H, ph 4-H),
7.42–7.50 (m; 4 H, ind 4-H, ind 7-H, ph 3-H, ph 5-H), 7.58 (d;
Jo = 7.15 Hz, 2 H, ph 2-H, ph 6-H), 8.68 (s; 1 H, NH); IR
(KBr) ν: 3444, 2925, 1771, 1705, 1624, 1451; 752, 737,
696 cm−1. Anal. (C19H13BrN2O2) C, H, N.
6.2.6.10. 1-Methyl-3-bromo-4-(2-(2-methoxyphenyl)-1H-3-in-
dolyl)-2,5-dihydro-1H-2,5-pyrroledione (10j). Yield: 0.56 g
(1.36 mmol; 68% from 3g and 9); m. p. 185 °C; Rf 0.36
1
(CH2Cl2); H-NMR δ 2.95 (s; 3 H, NCH3), 3.68 (s, 3 H,
6.2.6.5. 1-Methyl-3-bromo-4-(2-butyl-1H-3-indolyl)-2,5-dihy-
NCH3), 7.00–7.11 (m; 3 H, ind 5-H, ph 4-H, ph 5-H), 7.18
(m; 1 H, ind 6-H), 7.34–7.41 (m; 2 H, ph 3-H, ph 6-H), 7.46
(d; Jo = 6.7 Hz, 1 H, ind 7-H), 7.48 (d; Jo = 6.3 Hz, 1 H, ind 4-
H), 11. 91 (s; 1 H, NH); IR (KBr) ν: 3351, 3062–2834, 1775,
1709, 1620, 1466, 1439, 1379, 1298, 1250, 1180, 1155, 1101,
980, 850, 741, 733 cm−1. Anal. (C20H15BrN2O3) C, H, N.
dro-1H-2,5-pyrrole-dione (10e). Yield: 0.48 g (1.3 mmol; 66%
1
from 3c and 9), m.p. 115 °C; Rf 0.6 (CH2Cl2); H-NMR δ
10.16 (t; J = 7.3 Hz, 3 H, CH3), 1.27 (m; 2 H, CH2), 1.66
(m; 2 H, CH2), 2.73 (t; J = 7.3 Hz, 2 H, CH2), 3.00 (s; 3 H,
CH3), 7.01 (m; 1 H, 5-H), 7.10 (m; 1 H, 6-H), 7.33 (d;
Jo = 7.5 Hz, 1 H, 4-H), 7.36 (d; J = 7.9 Hz, 1 H, 4-H), 11.68
(s; 1 H, NH); IR (KBr) ν: 3373, 2964, 1773, 1709, 1624,
1460, 1439, 1385, 1192, 1138, 995, 735 cm−1. Anal.
(C17H17BrN2O2) C, H, N.
6.2.6.11. 1-Methyl-3-bromo-4-(2-(3-methoxyphenyl)-1H-3-in-
dolyl)-2,5-dihydro-1H-2,5-pyrroledione (10k). Yield: 0.515 g

S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
187
(1.25 mmol; 63% from 3h and 9); m.p. 162 °C; Rf 0.33
(CH2Cl2); H-NMR δ 2.97 (s; 3 H, NCH3), 3.80 (s; 3 H,
7.09 (m; 1 H, ind 6-H), 7.13 (m; 1 H, tol 5-H), 7.18 (d;
Jo = 7.5 Hz, 1 H, tol 3-H), 7.32 (d; Jo = 8.7 Hz, 1 H, tol 6-
H), 7.35 (d; Jo = 8.7 Hz, 1 H, ind 7-H), 7.39 (d; Jo = 7.5 Hz,
1 H, ind 4-H), 9.25 (s; 1 H, NH), 11.38 (s; 1 H, NH), 11.76 (s;
1 H, NH); IR (KBr) ν: 3345, 3235, 3060–2500, 1771, 1757,
1725, 1642, 1530, 743 cm−1. Anal. (C23H20BrN3O3) Calc. C,
H, N.
1
OCH3), 6.95 (m; 1 H, ph 6-H), 7.07–7.17 (m: 3 H, ind 5-H,
ph 2-H, ph 4-H); 7.22 (m; 1 H, ind 6-H), 7.34 (m; 1 H, ph 5-
H), 7.47 (d; Jo = 7.9 Hz, 1 H, ind 7-H), 7.49 (d; Jo = 7.9 Hz, 1
H, ind 4-H), 12.14 (s; 1 H, NH); IR (KBr) ν: 3378, 2954,
1775, 1711, 1626, 1611, 1491, 1437, 1379, 1229, 1204, 987,
789, 737 cm−1. Anal. (C20H15BrN2O3) C, H, N.
6.2.7.3. 5-(3-(4-Bromo-2,5-dihydro-1H-2,5-pyrroledione-3-
6.2.6.12. 1-Methyl-3-bromo-4-(2-(4-methoxyphenyl)-1H-3-in-
dolyl)-2,5-dihydro-1H-2,5-pyrroledione (10l). Yield: 0.63 g
(1.5 mmol; 51% from 2-(4-methoxyphenyl)-1H-indole [31]
yl)-1H-2-indolyl)-N-(2-methylphenyl)pentanoylamide
(11c).
Yield: 0.16 g (0.33 mmol; 16% from 2 mmol 6c and 8); m.
p. 185 °C (dec.); Rf 0.12 (CH2Cl2/ethyl acetate 9:1). 1H-NMR
δ 1.61 (m; 2 H), 1.74 (m; 2 H), 2.15 (s; 3 H, CH3), 2.33 (t;
J = 7.1 Hz, 2 H), 2.77 (t; Jo = 6.7 Hz, 2 H), 7.03 (m; 1 H, ind
5-H), 7.05 (m; 1 H, tol 4-H), 7.12 (m; 1 H, ind 6-H), 7.13 (m;
1 H, tol 5-H), 7.18 (d; Jo = 7.1 Hz, 1 H, tol 3-H), 7.34 (d;
Jo = 8.3 Hz, 2 H, tol 6-H, ind 7-H), 7.37 (d; Jo = 7.9 Hz, 1
H, ind 4-H), 9.21 (s; 1 H, NH), 11.37 (s; 1 H, NH), 11.712
(s; 1 H, NH); IR (KBr) ν: 3390, 3300; 3054–2857, 1734,
1701, 1665, 1524, 748 cm−1. Anal. (C24H22BrN3O3) C, H, N.
1
and 9); m.p. 227 °C; Rf 0.64 (CH2Cl2); H-NMR δ 2.98 (s;
3 H, NCH3), 3.80 (s; 3 H, OCH3), 7.02 (d; Jo = 8.7 Hz, 2 H,
ph 3-H, ph 5-H), 7.08 (m; 1 H, ind H-5), 7.19 (m; 1 H, ind 6-
H), 7.44 (d; Jo = 3.6 Hz, 1 H, ind H-7), 7.47 (d; Jo = 4.0 Hz, 1
H, ind H-4), 7.53 (d, Jo = 8.7 Hz, 2 H, ph 2-H, ph 6-H), 12.04
(s, 1H, ind NH); IR (KBr) ν: 3397, 1767, 1707, 1622, 1495,
1441, 914, 746 cm−1. Anal. (C20H15BrN2O3) C, H, N.
6.2.7. Removal of the silyl-protecting group [14]—general
procedure B
6.2.7.4. 6-(3-(4-Bromo-2,5-dihydro-1H-2,5-pyrroledione-3-
yl)-1H-2-indolyl)-N-(2-methylphenyl)hexanoylamide
Yield: 0.08 g (0.16 mmol; 16% from 1 mmol 6d and 8); m.
p. 186–188 °C (dec.); Rf 0.11 (CH2Cl2/ethyl acetate 9:1); H-
(11d).
The raw silyl-protected indole-maleinimide (1 mmol), ob-
tained from the procedure described in general Procedure A,
was dissolved in THF (100 ml) under N2, tetrabutylammo-
nium fluoride trihydrate (1.2 mmol) was added, and the mix-
ture was stirred for 2 h, poured on to ice, mixed with saturated
NH4Cl solution (200 ml) and extracted with ethyl acetate
(2 × 100 ml). The extract was dried over Na2SO4, the solvent
was removed in vacuo and the remaining oil was purified by
CC (CH2Cl2/ethyl acetate, mixtures are cited below, following
the Rf value of the compounds). The solution was concen-
trated in vacuo in order to obtain a nearly saturated solution
of the product in ethyl acetate. A small amount of CH2Cl2 was
added, and the product precipitated in small red crystals.
1
NMR δ 1.31 (m; 2H), 1.60 (m; 2 H), 1.72 (m; 2 H), 2.14 (s; 3
H, CH3), 2.29 (t; J = 7.1 Hz, 2 H), 2.74 (t; J = 7.0 Hz, 2 H),
7.02 (m; 1 H, ind 5-H), 7.05 (m; 1 H, tol 4-H), 7.11 (m, 1 H,
ind 6-H), 7.12 (m; 1 H, tol 5-H), 7.20 (d; Jo = 7.5 Hz, 1 H, tol
3-H), 7.33 (d, Jo = 8.3 Hz, 2 H, tol 6-H, ind 7-H), 7.36 (d,
Jo = 7.9 Hz, 1 H, ind 4-H), 9.18 (s; 1 H, NH), 11.36 (s; 1 H,
NH), 11.68 (s, 1 H, NH); IR (KBr) ν: 3370, 2932–2363, 1773,
1725, 1653, 1624, 1522, 1458; 740 cm−1. Anal.
(C25H24BrN3O3) C, H, N.
6.2.7.5. 7-(3-(4-Bromo-2,5-dihydro-1H-2,5-pyrroledione-3-
yl)-1H-2-indolyl)-N-(2-methylphenyl)heptanoylamide
(11e).
6.2.7.1. 3-(3-(4-Bromo-2,5-dihydro-1H-2,5-pyrroledione-3-
Yield: 0.077 g (0.15 mmol; 10% from 1.5 mmol 6e and 8);
m.p. 178 °C; Rf 0.06 (CH2Cl2/ethyl acetate 9:1); H-NMR δ
yl)-1H-2-indolyl)-N-(2-methylphenyl)propionylamide
(11a).
1
Yield: 0.09 g (0.2 mmol; 10% from 2 mmol 6a and 8); m.p.
1
1.31 (m; 4 H), 1.58 (t; J = 6.0 Hz, 2 H), 1.70 (t; J = 6.3 Hz, 2
H), 2.19 (s; 3 H, CH3), 2.96 (t; J = 7.5 Hz, 2 H), 2.74 (t;
J = 7.5 Hz, 2 H), 7.03 (m; 1 H, ind 5-H), 7.07 (m; 1 H, tol
4-H), 7.11 (m; 1 H, ind 6-H), 7.15 (m; 1 H, tol 5-H), 7.18 (d;
Jo = 7.1 Hz, 1 H, tol 3-H), 7.34 (m; 2H, ind 7-H, tol 6-H), 7.37
(d; Jo = 7.5 Hz, 1 H, ind 4-H), 9.19 (s; 1 H, NH), 11.37 (s; 1
H, NH), 11.68 (s; 1 H NH); IR (KBr) ν: 3340, 3210, 2963–
2855, 1771, 1717, 1653, 1624, 1530; 741 cm−1. Anal.
(C26H26BrN3O3) Calc. C 61.42, H 5.15, N 8.26. Found C
60.85, H 5.11, N 8.12.
195 °C (dec.); Rf 0.17 (CH2Cl2/ethyl acetate 9:1); H-NMR δ
2.12 (s; 3 H, CH3), 2.78 (t; J = 7.5 Hz, 2 H), 3.09 (m; 2 H),
7.04 (m; 1 H, ind 5-H), 7.05 (m; 1 H, tol 4-H), 7.07 (m; 1 H,
ind 6-H), 7.13 (m; 1 H, tol 5-H), 7.17 (d; Jo = 7.1 Hz, 1 H, tol
3-H), 7.34 (d; Jo = 6.3 Hz, 1 H, tol 6-H), 7.36 (d; Jo = 7.2 Hz,
1 H, ind 7-H), 7.39 (d; Jo = 7.5 Hz, ind 4-H), 9.27 (s; 1 H,
NH), 11.37 (s; 1 H, NH), 11.74 (s; 1 H, NH); IR (KBr) ν:
3338, 3228, 3060–2650, 1771, 1755, 1719, 1707, 1672,
1640, 1539, 740 cm−1. Anal. (C22H18BrN3O3) Calc. C 58.42,
H 4.01, N 9.29. Found C 58.96, H 4.40, N 8.75.
6.2.7.2. 4-(3-(4-Bromo-2,5-dihydro-1H-2,5-pyrroledione-3-
6.2.7.6. 8-(3-(4-Bromo2,5-dihydro-1H-2,5-pyrroledione-3-yl)-
1H-2-indolyl)-N-(2-methylphenyl)octanoylamide (11f). Yield:
0.21 g (0.4 mmol; 20% from 2 mmol 6f and 8); m.p. 145–
150 °C (THF/pentane); Rf 0.17 (CH2Cl2/ethyl acetate 9:1);
1H-NMR δ 1.19 (m; 6 H), 1.56 (m; 2 H), 1.68 (m; 2 H),
2.16 (s; 3 H, CH3), 2.29 (t; J = 7.0 Hz, 2 H), 2.74 (t;
yl)-1H-2-indolyl)-N-(2-methylphenyl)butanoylamide
(11b).
Yield: 0.15 g (0.32 mmol; 16% from 2 mmol 6b and 8); m.
p. 135 °C (dec.); Rf 0.13 (CH2Cl2/ethyl acetate 6:1); 1H-NMR
δ 2.03 (m; 2 H), 2.15 (s; 3 H, CH3), 2.33 (t; J = 7.2 Hz, 2 H),
2.83 (m; 2 H), 7.03 (m; 1 H, ind 5-H), 7.07 (m; 1 H, tol 4-H),

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S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
J = 7.5 Hz, 2 H), 7.02 (m; 1 H, ind 5-H), 7.05 (m; 1 H, tol 4-
H), 7.08 (m; 1 H, ind 6-H), 7.14 (m; 1 H, tol 5-H), 7.18 (d;
Jo = 7.5 Hz, 1 H, tol 3-H), 7.34 (m; 2 H, tol 7-H, ind 7-H),
7.37 (d; Jo = 7.5 Hz, 1 H, ind 4-H), 9.19 (s; 1 H, NH), 11.38
(s; 1 H, NH), 11.68 (s; 1 H, NH); IR (KBr) ν: 3345, 3216,
2927–2855, 1771, 1719, 1647, 743 cm−1. Anal.
(C27H28BrN3O3) C, H, N.
6.2.7.12. 3-Bromo-4-(2-pentyl-1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione (12f). Yield: 0.281 g (0.78 mmol; 38% from
1
2 mmol 3d and 8); m.p. 150 °C (dec.); Rf 0.3 (CH2Cl2); H-
NMR δ 0.83 (t; J = 6.7 Hz, 3 H, CH3), 1.30 (m; 4 H), 1.70 (m;
2 H), 2.73 (t; J = 7.0 Hz, 2 H), 7.02 (m; 1 H, 5-H), 7.11 (m; 1
H, 6-H), 7.34 (d; J = 8.8 Hz, 1 H, 7-H), 7.37 (d; J = 7.5 Hz, 1
H, 4-H), 11.36 (s; 1 H, NH), 11.67 (s; 1 H, NH). IR (KBr) ν:
3345, 3222, 2957–2869, 1771, 1753, 1717, 1624, 1607, 1493,
743 cm−1. Anal. (C17H17BrN2O2) C, H, N.
6.2.7.7. 3-Bromo-4-(1H-3-indolyl)-2,5-dihydro-1H-2,5-pyrro-
ledione (12a) [32]. Yield: 0.1 g (0.34 mmol; 17% from
2 mmol indole and 8); m.p. 195 °C (Lit. 196 °C [32]); H-
NMR δ 7.12–7.26 (m; 2 H, 5-H, 6-H), 7.51 (d; Jo = 7.7 Hz,
1 H), 7.90 (d; Jo = 7.7 Hz, 1 H), 8.04 (d; Jm = 3 Hz, 1 H, 2-H),
11.35 (s; 1 H, NH), 12.10 (s; 1 H, NH); IR (KBr) ν: = 3340,
3270, 3140–3035, 1760, 1700, 1620, 1610, 1490, 1460 cm−1.
1
6.2.7.13. 3-Bromo-4-(2-hexyl-1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione (12g). Yield: 0.325 g (0.87 mmol; 43% from
1
2 mmol 3e and 8); m.p. 135 °C (dec.); Rf 0.22 (CH2Cl2); H-
NMR δ: 0.82 (t; J = 6.3 Hz, 3 H, CH3); 1.23 (m; 6 H), 1.67
(m; 2 H), 2.73 (t; J = 7.1 Hz, 2 H), 7.03 (m; 1 H, 5-H), 7.11
(m; 1 H, 6-H), 7.33 (d; Jo = 8.3 Hz, 1 H, 7-H), 7.36 (d;
Jo = 7.9 Hz, 1 H, 4-H), 11.37 (s; 1 H, NH), 11.67 (s; 1 H,
NH). IR (KBr) ν: 3342, 3226, 2929, 1771, 1721, 1707,
1607, 1535, 743 cm−1. Anal. (C18H19BrN2O2) C, H, N.
6.2.7.8. 3-Bromo-4-(2-methyl-1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione (12b). Yield: 0.23 g (0.74 mmol; 37% from
2 mmol 2-methylindole and 8); m.p. 185 °C (dec.); Rf 0.36
1
(CH2Cl2); H-NMR δ 2.41 (s; 3 H, CH3), 7.02 (m; 1 H, 5-
6.2.7.14. 3-Bromo-4-(2-heptyl-1H-3-indolyl)-2,5-dihydro-1H-
H), 7.10 (m; 1 H, 6-H), 7.35 (d, Jo = 7.6 Hz, 1 H, 7-H), 7.36
(d; Jo = 7.5 Hz, 1 H, 4-H), 11.32 (s; 1 H, NH), 11.72 (s; 1 H,
NH). IR (KBr) ν: 3349, 3220, 3062–2695, 1771, 1753, 1626,
1613, 1541; 739 cm−1. Anal. (C13H9BrN2O2) C, H, N.
2,5-pyrroledione (12h). Yield: 0.314 g (0.8 mmol; 40% from
1
2 mmol 3f and 8); m.p. 153 °C (dec.); Rf 0.36 (CH2Cl2); H-
NMR δ 0.83 (t; J = 6.7 Hz, 3 H, CH3), 1.22 (m; 8 H); 1.66 (m;
2 H), 2.73 (t; J = 7.5 Hz, 2 H), 7.03 (m; 1 H, 5-H), 7.11 (m; 1
H, 6-H), 7.33 (d; J = 8.3 Hz, 1 H, 7-H), 7.37 (d; J = 8.0 Hz, 1
H, 4-H), 11.37 (s; 1 H, NH), 11.67 (s; 1 H, NH); IR (KBr) ν:
3341, 3216, 3062–2689, 1771, 1755, 1719, 1624, 1493,
742 cm−1. Anal. (C19H19BrN2O2) C, H, N.
6.2.7.9. 3-Bromo-4-(2-ethyl-1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione (12c). Yield: 0.365 g (1.14 mmol; 57% from
2 mmol 3a and 8); m.p. 160 °C (dec.); Rf 0.6 (CH2Cl2/ethyl
1
acetate 9:1); H-NMR δ 1.28 (t; Jo = 7.5 Hz, 3 H, CH3), 2.74
(m; 2 H), 7.03 (m; 1 H, 5-H), 7.11 (m; 1 H, 6-H), 7.34 (d;
Jo = 8.2 Hz, 1 H, 7-H) 7.37 (d; Jo = 7.7 Hz, 1 H, 4-H) 10.69 (s;
1 H, NH), 11.70 (s; 1 H, NH). IR (KBr) ν: 3347, 3214, 3058–
2689, 1771, 1753 1715, 1624, 1607 1493, 740 cm−1. Anal.
(C14H11BrN2O2) C, H, N.
6.2.7.15. 3-Bromo-4-(2-phenyl-1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione (12i). Yield: 0.247 g (0.67 mmol; 33% from
1
2 mmol 2-phenylindole); m.p. 270 °C; Rf 0.11 (CH2Cl2); H-
NMR δ 7.11 (m; 1 H, ind 5-H), 7.22 (m; 1 H, ind 6-H), 7.38
(m; 1 H, ph 4-H), 7.46 (d; Jo = 6.5 Hz, 1 H, ind 7-H), 7.47 (m;
2 H, ph 3-H, ph 5-H), 7.49 (d; Jo = 8.3 Hz, 1 H, ind 4-H), 7.57
(m; 2 H, ph 2-H, ph 6-H), 11.12 (s; 1 H, NH), 12.14 (s; 1 H,
NH); IR (KBr) ν: 3363, 3183, 1769, 1709, 1620, 1580, 1481,
770, 750, cm−1. Anal. (C18H11BrN2O2) C, H, N.
6.2.7.10. 3-Bromo-4-(2-propyl-1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione (12d). Yield: 0.42 g (1.26 mmol; 63% from
2 mmol 3d and 8); m.p. 150 °C; Rf 0.7 (CH2Cl2/ethyl acetate
1
1:9); H-NMR δ 0.87 (t; Jo = 7.5 Hz, 3 H, CH3), 1.70 (m; 2
H), 2.71 (t; J = 7.7 Hz, 2 H), 7.03 (m; 1 H, 5-H), 7.11 (m; 1 H,
6-H), 7.34 (d; Jo = 7.9 Hz, 1 H, 7-H), 7.37 (d; Jo = 7.9 Hz, 1H,
4-H), 11.37 (s; 1 H, NH), 11.672 (s; 1 H, NH). IR (KBr) ν:
3378, 3222, 3066–2871, 1775, 1757, 1719, 1624, 1609 1489,
741 cm−1. Anal. (C15H13BrN2O2) C, H, N.
6.2.7.16. 3-Bromo-4-(2-(2-methoxyphenyl)-1H-3-indolyl)-2,5-
dihydro-1H-2,5-pyrroledione (12j). Yield: 0.17 g (0.45 mmol;
1
22% from 2 mmol 3g); m.p. 205 °C; Rf 0.18 (CH2Cl2); H-
NMR δ 3.69 (s; 3 H, OCH3), 7.01–7.11 (m; 3 H, ind 5-H, ph
4-H, ph 5-H), 7.18 (m; 1 H, ind 6-H), 7.34–7.41 (m; 2 H, ph
3-H, ph 6-H), 7.46 (d; Jo = 7.9 Hz, 1 H, ind 7-H), 7.47 (d;
Jo = 7.9 Hz, 1 H, ind 4-H), 11.22 (s; 1 H, NH), 11.89 (s; 1
H, NH); IR (KBr) ν: 3353, 2834–2280, 1775, 1717, 1616,
1601, 1489, 1466, 1452, 1441, 1327, 1298, 1277, 1248,
1204, 1028, 739 cm−1. Anal. (C19H13BrN2O3) C, H, N.
6.2.7.11. 3-Bromo-4-(2-butyl-1H-3-indolyl)-2,5-dihydro-1H-
2,5-pyrroledione (12e). Yield: 0.272 g (0.78 mmol; 39% from
2 mmol 3c and 8); m.p. 155 °C; Rf 0.18 (CH2Cl2); 1H-NMR δ
0.85 (t; J = 7.1 Hz, 3 H, CH3), 1.26 (m; 2 H), 1.65 (m; 2 H),
2.72 (t; J = 7.5 Hz, 2 H), 7.01 (m; 1 H, 5-H), 7.10 (m; 1 H, 6-
H), 7.32 (d; Jo = 8.7 Hz, 1 H, 7-H), 7.36 (d; Jo = 7.5 Hz, 4-H),
11.35 (s; 1 H, NH), 11.66 (s; 1 H, NH); IR (KBr) ν: 3416,
3224, 2947–2854, 1773, 1766, 1716, 1616, 1538, 1488;
741 cm−1. Anal. (C16H15BrN2O2) C, H, N.
6.2.7.17. 3-Bromo-4-(2-(3-methoxyphenyl)-1H-3-indolyl)-2,5-
dihydro-1H-2,5-pyrroledione (12k). Yield: 0.082
g
(0.21 mmol; 10% from 2 mmol 3h); m.p. 225 °C; Rf 0.1
1
(CH2Cl2); H-NMR δ 3.79 (s; 3H, OCH3), 6.95 (m; 1 H, ph

S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
189
6-H), 7.07–7.13 (m; 3 H, ind 5-H, ph 4-H, ph 2-H), 7.21 (m; 1
H, ind 6-H), 7.36 (m; 1 H ph 5-H) 7.46 (d; Jo = 6.7 Hz, 1 H,
ind 7-H), 7.48 (d; Jo = 7.1 Hz, 1 H, ind 4-H), 11.37 (s; 1 H,
NH), 12.13 (s; 1 H, NH); IR (KBr) ν: 3064, 1773, 1707, 1613,
1578, 1533, 1485, 1445, 1335, 1288, 1261, 1223, 1205, 1180,
1146, 1119, 1031, 910, 885, 783, 752, 694 cm−1. Anal.
(C19H13BrN2O3) C, H, N.
6.2.8.3. 3-Bromo-4-(1-methyl-2-hexyl-1H-3-indolyl)-2,5-dihy-
dro-1H-2,5-pyrrole-dione (13c). Yield: 0.27 g (0.69 mmol;
35% from 2 mmol silyl-protected 12g); m.p. 120 °C; Rf 0.26
1
(CH2Cl2); H-NMR δ 0.80 (t; J = 6.4 Hz, 3 H, CH3), 1.19 (m;
6 H), 1.55 (m; 2 H), 2.80 (t; J = 7.4 Hz, 2 H), 3.77 (s; 3 H,
NCH3), 7.04 (m; 1 H, 5-H), 7.18 (m; 1 H, 6-H), 7.32 (d;
Jo = 7.15 Hz, 1 H, 7-H), 7.49 (d; Jo = 7.9 Hz, 1 H, 4-H), 11.41
(s; 1 H, NH). IR (KBr) ν: 3204, 2961–2859, 1775, 1763 1725,
1622, 1472; 740 cm−1. Anal. (C19H21BrN2O2) C, H, N.
6.2.7.18. 3-Bromo-4-(2-(4-methoxyphenyl)-1H-3-indolyl)-2,5-
dihydro-1H-2,5-pyrroledione (12l). Yield: 0.320 g (0.8 mmol;
40% from 2 mmol 2-(4-Methoxyphenyl)-1H-indole [31]); m.p.
6.2.8.4. 3-Bromo-4-(1-methyl-2-phenyl-1H-3-indolyl)-2,5-di-
hydro-1H-2,5-pyrrole-dione (13d). Yield: 0.027 g (0.07 mmol;
3.5% from 2 mmol silyl-protected 12i); m.p. 245 °C; Rf = 0.41
(CH2Cl2); 1H-NMR δ: 3.77 (s; 3 H, CH3), 7.26 (m; 1 H, 5-H),
7.35 (m; 1 H, 6-H), 7.38–7.51 (m; 6 H, arom.), 7.59 (m; 2 H,
ph 2-H, ph 6-H); IR (KBr) ν: 3193, 1771, 1715, 1616, 1472,
743 cm−1. Anal. (C19H13BrN2O2) C, H, N.
1
262 °C; Rf 0.15 (CH2Cl2); H-NMR δ 3.80 (s; 3 H, OCH3),
7.04 (d; Jo = 9.1 Hz, 2 H, ph 3-H, ph 5-H), 7.09 (m; 1 H, ind
5-H), 7.19 (m; 1 H, ind 6-H), 7.43 (d; Jo = 7.1 Hz, 1 H, ind 7-
H), 7.46 (d; Jo = 9.1 Hz, 1 H, ind 4-H), 7.50 (d; Jo = 8.7 Hz, 2
H, ph 2-H, ph 6-H), 11.26 (s; 1 H, NH), 12.03 (s; 1 H, NH).
IR (KBr) ν: 3376, 1771, 1721, 1609, 1580, 1495, 837,
746 cm−1. Anal. (C19H13BrN2O3) C, H, N.
6.2.8.5. 3-Bromo-4-(1-methyl-2-(4-methoxyphenyl)-1H-3-in-
dolyl)-2,5-dihydro-1H-2,5-pyrroledione (13e). Yield: 0.400 g
(9.7 mmol; 10% from 10 mmol of silyl-protected 12l); m.p.
6.2.8. Methylation of the silyl-protected indolyl-maleinimide
derivatives
1
225 °C; Rf: 0.15 (CH2Cl2); H-NMR (CDCl3) δ: 3.75 (s; 1
A solution of the silyl-protected products (1 mmol) from
indole derivative and 8, produced by the procedure described
in general procedure A, in THF (10 ml) was cooled to –78 °C
under N2. Then n-BuLi (1.1 mmol 1.6 M solution in hexane)
was added slowly, and the mixture was stirred for 1 h. Then
DMS (0.6 mmol) was added, and the solution was stirred
overnight while slowly warming to RT. Then it was poured
into a saturated solution of NH4Cl (100 ml), extracted with
ethyl acetate, dried over Na2SO4, concentrated in vacuo and
purified by CC (CH2Cl2). The products were collected as
crude oils and were directly used for the procedure described
in general procedure B to remove the silyl protection group.
H, NCH3); 3.87 (s; 1 H, OCH3); 6.99 (d; Jo = 6.7 Hz; 2 H,
ph 3-H); 7.22–7.44 (m; 5 H, arom.); 7.57 (d; Jo = 7.9 Hz; 1
H, ind 5-H); IR (KBr) ν: 3222, 2934–2836, 1775, 1717, 1611,
1535, 1483, 843, 752 cm−1. Anal. (C20H15BrN2O3) C, H, N.
6.2.9. Preparation of 3-(1H-3-indolyl)-2,5-pyrrolidinedione
(14) [33]
0.7 mmol 12a were stirred together with 0.2 g Pd/C (5%) in
5 ml of methanol under low H2 pressure. Then the catalyst
was removed by filtration through Celite. The filtrate was eva-
porated under reduced pressure, and the residue was crystal-
lized from methanol.
Yield: 0.11 g (0.51 mmol; 75%); m.p. 195 °C (Lit. 196 °C
[33]); 1H-NMR δ 2.76 (m; 1 H), 3.18 (m; 1 H), 4.33 (m; 1 H),
6.96–7.43 (m; 5 H, aromat.), 11.02 (s; 1 H, NH), 11.30 (s; 1
H, NH). IR (KBr) ν: 3405, 3040–2990, 1490, 1460 cm−1.
6.2.8.1. 3-Bromo-4-(1,2-dimethyl-1H-3-indolyl)-2,5-dihydro-
1H-2,5-pyrroledione (13a). Yield: 0.25 g (0.78 mmol; 39%
from 2 mmol silyl-protected 12b); m.p. 195 °C; Rf 0.29
1
(CH2Cl2); H-NMR δ 2.39 (s; 3 H, NCH3), 3.75 (s, 3 H,
OCH3), 7.06 (m; 1 H, 5-H), 7.17 (m; 1 H, 6-H), 7.37 (d;
Jo = 7.52 Hz, 7-H), 7.49 (d; Jo = 7.9 Hz, 1 H, 4-H), 11.35 (s;
1 H, NH); IR (KBr) ν: 3212, 3062, 2927, 1767, 1713, 1611,
1597, 1412, 1323, 999, 746, 486 cm−1. Anal. (C14H11BrN2O2)
C, H, N.
6.2.10. Preparation of 3-(1H-3-indolyl)-2,5-dihydro-1H-2,5-
pyrroledione (15)
The pyrrolidinedione 14 (0.5 g, 2.33 mmol) was dissolved
in benzene (200 ml), and DDQ (0.58 g, 2.57 mmol) and p-
toluenesulfonic acid (0.05 g, 0.26 mmol) were added. After
stirring for 30 min at RT. the solvent was removed; the residue
was dissolved in ethyl acetate (200 ml) and washed with satu-
rated NaHSO3 solution (100 ml) and brine (100 ml). The or-
ganic phase was separated and dried over Na2SO4, the solvent
was removed in vacuo and the residue was purified by CC
(CH2Cl2/ethyl acetate 7:3).
6.2.8.2. 3-Bromo-4-(1-methyl-2-butyl-1H-3-indolyl)-2,5-dihy-
dro-1H-2,5-pyrrole-dione (13b). Yield: 0.216 g (0.61 mmol;
31% from 2 mmol silyl-protected 12e); m.p. 165 °C; Rf 0.34
(CH2Cl2); 1H-NMR δ 0.83 (t; J = 7.1 Hz, 3 H, CH3), 1.27 (m;
2 H, CH2), 1.54 (m; 2 H, CH2), 2.79 (t; J = 7.5 Hz, 2 H, CH2);
3.77 (s; 3 H, NCH3), 7.07 (m; 1 H, 5-H), 7.18 (m; 1 H, 6-H),
7.32 (d; Jo = 7.5 Hz, 1 H, 7-H), 7.49 (d; Jo = /.49, 1 H, 4-H),
11.40 (s; 1 H, NH); IR (KBr) ν: 3233, 2959, 2871, 1759,
1713, 1622, 1472, 1329, 1016, 740 cm−1. Anal.
(C17H17BrN2O2) C, H, N.
1
Yield: 0.23 g (1.08 mmol; 47%); m.p. 201 °C; H-NMR δ
6.79 (s; 1 H), 7.17–7.98 (m; 4 H, arom.), 8.36 (d; J = 3.0 Hz, 1
H, 2-H), 10.75 (s; 1 H, NH); IR (KBr) ν: 3395, 3080–3010,
1755, 1690, 1605, 1500, 1460 cm−1. Anal. (C12H8N2O2) C, H,
N.

190
S. Mahboobi et al. / European Journal of Medicinal Chemistry 41 (2006) 176–191
Appendix A. Additional information: compound number combustion elemental analysis
Analysis
3g
3h
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
Calc.
C 80.69
C 80.69
C 66.38
C 67.47
C 68.44
C 69.31
C 70.10
C 77.69
C 78.05
C 78.43
C 78.75
C 79.01
C 79.31
C 52.69
C 54.07
C 55.35
C 56.52
C 57.61
C 58.62
C 59.56
C 59.86
C 58.41
C 58.41
C 58.41
C 51.14
C 52.66
C 54.05
C 55.33
C 56.51
C 57.61
C 58.61
C 58.88
C 57.45
C 57.45
C 57.45
C 50.17
C 58.42
C 59.24
C 60.01
C 60.74
C 61.42
C 62.07
C 52.69
C 56.52
C 58.62
C 59.86
C 58.41
C 67.92
H 5.87
H 5.87
H 7.23
H 7.63
H 7.98
H 8.30
H 8.59
H 6.47
H 6.89
H 7.18
H 7.50
H 7.84
H 8.05
H 3.47
H 3.93
H 4.35
H 4.74
H 5.10
H 5.44
H 5.75
H 3.44
H 3.67
H 3.67
H 3.67
H 2.92
H 3.45
H 3.90
H 4.32
H 4.71
H 5.10
H 5.39
H 3.02
H 3.20
H 3.30
H 3.30
H 3.31
H 4.01
H 4.32
H 4.62
H 4.89
H 5.15
H 5.40
H 3.47
H 4.74
H 5.44
H 3.44
H 3.68
H 3.80
N 6.27
N 6.27
N 5.96
N 5.62
N 5.32
N 5.05
N 4.81
N 10.07
N 9.58
N 9.15
N.8.75
N 8.38
N 8.05
N 8.78
N 8.41
N 8.07
N 7.75
N 7.47
N 7.20
N 6.95
N 7.35
N 6.81
N 6.81
N 6.81
N 9.18
N 8.78
N 8.41
N 8.07
N 7.76
N 7.47
N 7.20
N 7.63
N 7.05
N 7.05
N 7.05
N 8.36
N 9.29
N 9.01
N 8.75
N 8.50
N 8.26
N 8.04
N 8.78
N 7.75
N 7.20
N 7.35
N 6.81
N 13.20
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
Found
C 80.48
C 80.08
C 66.43
C 67.57
C 68.35
C 69.22
C 70.04
C 77.60
C 77.70
C 78.18
C 78.63
C 78.65
C 78.95
C 52.67
C 54.14
C 55.31
C 56.38
C 57.74
C 58.69
C 59.32
C 60.01
C 58.42
C 58.44
C 58.26
C 50.93
C 52.65
C 53.96
C 55.04
C 56.26
C 57.59
C 58.60
C 58.68
C 57.55
C 57.20
C 57.55
C 50.61
C 58.96
C 59.01
C 60.01
C 60.65
C 60.85
C 61.73
C 52.87
C 56.60
C 58.88
C 59.60
C 58.80
C 68.33
H 5.54
H 5.59
H 7.32
H 7.78
H 8.06
H 8.46
H 8.72
H 6.62
H 7.05
H 7.25
H 7.65
H 7.87
H 8.22
H 3.56
H 4.09
H 4.22
H 4.69
H 5.14
H 5.44
H 5.72
H 3.70
H 4.04
H 3.85
H 3.75
H 3.18
H 3.57
H 4.00
H 4.49
H 4.77
H 5.22
H 5.40
H 3.43
H 3.59
H 3.49
H 3.59
H d.77
H 4.40
H 4.46
H 4.84
H 5.03
H 5.11
H 5.48
H 3.86
H 4.85
H 5.39
H 3.80
H 3.82
H 4.12
N 6.19
N 6.09
N 5.91
N 5.88
N 5.41
N 5.00
N 4.88
N 9.99
N 9.24
N 9.10
N 8.71
N 8.14
N 7.79
N 8.67
N 8.21
N 7.95
N 7.70
N 7.08
N 7.20
N 6.89
N 7.21
N 6.59
N 6.62
N 6.64
N 8.89
N 8.60
N 8.12
N 7.92
N 7.51
N 7.20
N 7.20
N 7.29
N 6.87
N 6.74
N 6.87
N 7.98
N 8.75
N 8.87
N 8.16
N 8.25
N 8.12
N 7.75
N 8.48
N 7.56
N 7.30
N 7.21
N 6.72
N 12.00
6f
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12 m
11a
11b
11c
11d
11e
11f
13a
13b
13c
13d
13e
15

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