QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids

Article abstract of DOI:10.1016/j.ejmech.2010.08.062

Naphthylisoquinoline alkaloids have attracted considerable interest because of their intriguing structure, their unique biosynthetic origin, and their biological activities against several pathogens causing tropical diseases. Their promising pharmacologic

Full text of DOI:10.1016/j.ejmech.2010.08.062

European Journal of Medicinal Chemistry 45 (2010) 5370e5383
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
QSAR guided synthesis of simplified antiplasmodial analogs of
naphthylisoquinoline alkaloids
,
a
a
a,
Gerhard Bringmann a , Sebastian K. Bischof , Steffen Müller , Tanja Gulder 1, Christian Winter a,
*
August Stich b, Heidrun Moll c, Marcel Kaiser d e, Reto Brun d e, Jan Dreher f, Knut Baumann f
,
,
a Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
b Medical Mission Institute Würzburg, Department of Tropical Medicine, Salvatorstr.7, D-97074 Würzburg, Germany
c Institute for Molecular Infection Biology, University of Würzburg, Josef-Scheider-Str. 2/D15, D-97080 Würzburg, Germany
d Swiss Tropical and Public Health Institute, Socinstr. 57, CH-4002 Basel, Switzerland
e University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland
f Institute of Pharmaceutical Chemistry, University of Technology Braunschweig, Beethovenstr. 55, D-38106 Braunschweig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Naphthylisoquinoline alkaloids have attracted considerable interest because of their intriguing structure,
their unique biosynthetic origin, and their biological activities against several pathogens causing tropical
diseases. Their promising pharmacologic properties make them suitable lead structures for new agents,
in particular against malaria. Since these natural products are not easy to isolate in sufficient quantities or
to synthesize stereoselectively, quantitative structureeactivity relationship studies were accomplished to
find new antiplasmodial analogs that are structurally related to the naturally occurring naph-
thylisoquinoline alkaloids, but more easily accessible, more active against Plasmodium falciparum, and,
last but not least, less toxic. We report on the synthesis of several simplified compounds by a Suzuki
coupling between the naphthalene and the isoquinoline moieties and on their activities against different
pathogens causing infectious diseases. Some structures were found to exhibit excellent e and selective e
activities against P. falciparum in vitro.
Received 13 July 2010
Received in revised form
25 August 2010
Accepted 26 August 2010
Available online 17 September 2010
Dedicated to Prof. Karlheinz Drauz on the
occasion of his 60th birthday.
Keywords:
Naphthylisoquinoline alkaloids
Arylisoquinolines
Dioncophylline C analogs
Antiplasmodial activity
QSAR
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
Promising new lead structures for the design potent novel
substances originate from tropical Dioncophyllaceae and Ancis-
In spite of all recent efforts to find new potential drugs, infec-
tious diseases are still the number one reason for mortality
worldwide [1]. During the past years many vector-borne diseases
like leishmaniasis, dengue fever, and malaria emerged in new areas
or re-emerged in areas affected previously [1]. With a number of
over 300 million infected people and about one million of lethal
cases per year malaria is still the most fatal tropical disease [2]. The
increasing resistance of P. falciparum against traditional antima-
larial drugs like chloroquine or the antifolates makes the devel-
opment of new, highly efficient, and easily available agents an
urgent task.
trocladaceae plants, which are the only known producers of the
naphthylisoquinoline alkaloids [3,4]. These secondary metabolites
differ from all other isoquinoline alkaloids by their acetogenic
origin [5,6], and they feature manifold pharmacological properties
[7e10]. Some of these biaryl alkaloids exhibit excellent activities
against pathogens causing different tropical infectious diseases.
The N,C-coupled representatives of the naphthylisoquinoline
alkaloids, like, e.g. ancistrocladinium A (1), as recently isolated by
our group [11], and their synthetic derivatives have proven to be
highly active against the pathogens causing leishmaniasis,
trypanosomiasis or malaria (see Fig. 1) [12e15]. Some C,C-linked
naphthylisoquinolines, among them e.g. dioncophylline C (2,
0.01 mM) and dioncopeltine A (3, 0.02 mM), show interesting in vitro
and even in vivo activities against P. falciparum [7,16,17]. These and
other promising bioactivities make the naphthylisoquinoline
alkaloids suitable pharmaceutical lead structures for the synthesis
of new potent agents [18,19].
* Corresponding author.
E-mail address: bringman@chemie.univ-wuerzburg.de (G. Bringmann).
Present address: Institute of Organic Chemistry, RWTH Aachen University,
1
Landoltweg 1, D-52074 Aachen, Germany.
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.062

G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
5371
subunit, since that should reduce the antiplasmodial activity [42],
and, on the other hand, possess no methyl substituent at C-1
resulting in a better accessibility of the nitrogen to improve
hydrogen bonding, and, thus, permit stronger interactions with the
biological targets.
OH
OMe
Me
MeO
S
Me
1’
5’
+
P
N
8'
For reasons of simplicity, the target structures of type I possess
no stereogenic centers. The biaryl axis, a characteristic feature of
the naphthylisoquinoline alkaloids, should be configurationally
semistable [41], because of the lack of a substituent at C-6 of the
isoquinoline moiety (in nature mostly OH or OMe) and the missing
methyl group at C-20 of the naphthalene part, which is present in all
natural naphthylisoquinolines [3,16]. The conformational flexibility
of the biaryl axis should favor flexible interactions between the
target molecules and a potential protozoan target and, in addition,
avoid the need for a directed, atropo-enantioselective synthesis.
Furthermore, a couple of chiral analogs (type II, III) were
synthesized, with an R-configuration at C-3 and a free hydroxy
group at C-8. Like the structures of type I, these compounds are also
derived from dioncophylline C (2), but possess a dihydroisoquino-
line subunit. The respective building block was coupled with
several naphthyl- and arylboronic acids, thus permitting to inves-
tigate the influence of the northern part on the biological activity.
Me
M
R
MeO
Me
N
R
OMe
H
Me
OMe
OH Me
ancistrocladinium A (1)
dioncophylline C (2)
Me
R
HO
7
M
N
1’
R
H
OH Me
MeO
HO
dioncopeltine A (3)
Fig. 1. Ancistrocladinium
A (1), dioncophylline C (2), and dioncopeltine A (3),
naphthylisoquinoline alkaloids with remarkable biological activities.
2. Results and discussion
Naphthylisoquinoline alkaloid-producing plants are rare and
difficult to cultivate [20] and the stereoselective synthesis of the
active compounds is quite complex. Although elegant pathways to
obtain this class of compounds have already been developed
[21e38] the synthesis of structurally simplified derivatives with
further improved antiplasmodial activities and a better accessibility
was worthwhile. Therefore, extensive (Q)SAR studies based on the
data of over 40 naphthylisoquinoline alkaloids were accomplished
[39,40].
We have recently published the synthesis of simplified deriva-
tives that show significant antiprotozoal activities, especially
against the pathogens of malaria and trypanosomiasis [41]. In this
paper we report on the synthesis of structurally modified naphthyl-
and phenylisoquinolines with systematically altered functional
groups that can provide exact information about the pharmaco-
logically essential structural parameters and an improved activity
against P. falciparum in comparison to derivatives of anti-infective
naphthylisoquinolines alkaloids previously synthesized [41]. The
target molecules of type I (see Fig. 2), which are derived from
dioncophylline C (2), were chosen with respect to (Q)SAR studies.
These investigations suggested that the structures should, on the
one hand, have no oxygen substituent at C-6 of the isoquinoline
2.1. Chemistry
2.1.1. A general route to the achiral isoquinoline building blocks 15
and 16
The isoquinoline building blocks were synthesized via a route
first described by Hoye et al. and recently improved in our group
[43,44]. The key step in this synthesis is the reaction of the cuprate
of 3-bromoanisole (4) with N-activated aziridines, here 5 and 6,
which are available from 2-aminoethanol and 2-amino-2-methyl-
propan-1-ol by functionalization of the nitrogen and aziridine
formation with tosyl chloride under basic conditions [45]. Although
3,3-dimethylisoquinolines can be prepared by Ritter reaction [41],
this approach should not be applicable to the isoquinoline building
block 16 bearing two hydrogen atoms at C-3. These strained
heterocycles were then opened (regioselectively in the case of 5) by
the cuprate derived from 3-bromoanisol (4). The resulting carba-
mates 7 and 8 were regioselectively brominated at C-4, followed by
removal of the N-Boc group in a one-pot reaction. N-formylation of
the resulting amines 9 and 10 with ethyl formate, and Bisch-
lereNapieralski cyclization gave both isoquinolines 13 and 14 in
good overall yields. The introduced bromo substituent did not only
deliver the halogen atom for the later coupling with the naphtha-
lene building blocks, but also served as a directing group for the
regioselective cyclization into the C-2 position. Final deprotection
of 13 and 14 using aluminum trichloride at elevated temperature
gave the achiral 8-hydroxyisoquinolines 15 and 16 (see Scheme 1).
1
OH
R
X
X
2
3
R
Y
2'
R
1'
R
4
1
5
5
Me
Me
2.1.2. Synthesis of the boronic acid 17 and the boronic acid ester 21
The naphthylboronic acid 17 was obtained from 1-methox-
ynaphthalene by para-selective bromination [46], and conversion
to the desired product with nBuLi and B(OMe)3 [47].
The naphthylboronic acid ester 21, as required for the investi-
gation of the influence of a second oxygen substituent on the
biological activity, was obtained from commercially available 1,8-
naphthosultone. Following a protocol by Erdmann [48], the diol 18
was obtained in satisfying yield. Mono-O-isopropylation and acyl-
ation of the remaining phenolic group under standard conditions
gave naphthalene 19, which was regioselectively brominated to
afford 20 in quantitative yield after ester saponification (see
Scheme 2). O-Methylation yielded the respective ether, which was
6
7
R
3
R
R
2
N
N
N
H
8
HO
HO
1
Me
HO
Me
I
II
III
a: R = H,
a: X = H, Me, OMe,
X = H, OMe
R = H, Me
2
3
2
R /R = benzo
CF , Cl
3
1
b: R /R = benzo
Y = H
b: X = H
Y = Cl
3
R = H
Fig. 2. Simplified achiral target compounds with systematically altered functional
groups (type I) and some chiral derivatives (type II, III) of dioncophylline C (2).

5372
G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
OMe
1. Mg, THF
R
Br
.
R
2. CuBr SMe
2
N
H
OMe
3.
Boc
N
Boc
OMe
17
OMe
Pd(PPh ) , Na CO ,
B(OH)
R
R
2
3 4
2
3
toluene/H O
2
+
R
4
5: R = Me
6: R = H
7: R = Me 52%
8: R = H 77%
R
Br
R
N
Br , CH Cl ,
then TFA
R
2
2
2
N
OMe
Br
Br
EtO
O
H
R
R
R
22: R = Me 88%
23: R = H 83%
OMe
R
13: R = Me
14: R = H
NH
2
N
H
H
BBr , CH Cl
3
2
2
O
OMe
OMe
9: R = Me 78%
10: R = H 93%
11: R = Me 93%
12: R = H 99%
OH
OH
PPA
NaBH , MeOH
Br
4
Br
R
R
H
R
R
R
R
R
R
AlCl , C H Cl
3
3
3
3
6 5
N
N
N
N
HO
OMe
HO
OH
26: R = Me 83 %
27: R = H 36 %
24: R = Me 79 %
25: R = H 54 %
13: R = Me 56%
14: R = H 52%
15: R = Me 83%
16: R = H 97%
Scheme 3. Synthesis of the naphthyltetrahydroisoquinolines 26 and 27.
Scheme 1. Synthetic route to 5-bromo-8-hydroxyisoquinolines 15 and 16.
converted into the boronic acid ester 21 by Miyaura borylation [49].
The reaction sequence from 1,8-naphthosultone to 21 in six steps
was attained in an excellent overall yield of 40%.
By using a slightly different route, the target compounds 32
and 33 were obtained: to circumvent regioselectivity problems in
the required selective deprotection step of the oxygen function at
C-40 in the naphthalene subunit, the isoquinoline portions were
used in a free, hydroxylated form (15 and 16) as the coupling
partners in the Suzuki reaction with the pinacol ester 21 (see
Scheme 4). In this case the reaction in DMF with potassium
phosphate gave better results than the conditions used before.
Cleavage of the isopropyl ether with boron trichloride and
reduction of the naphthyldihydroisoquinolines gave the desired
target compounds 32 and 33.
2.1.3. Synthesis of naphthyltetrahydroisoquinolines of type I
The biaryl coupling of the 8-methoxyisoquinoline 13 and the
boronic acid 17 was attained with Pd(PPh3)4 and Na2CO3 in
a toluene/water-mixture. Deprotection of the biaryl 22 with boron
tribromide and reduction with sodium borohydride gave the
naphthyldihydroisoquinoline 26. Starting from isoquinoline 14 the
same reaction sequence was successfully applied to the synthesis of
the 3-unsubstituted analog 27 (see Scheme 3).
2.1.4. Synthesis of aryl- and naphthyldihydroisoquinolines of type II
and III
OAc
OH OH
iPrO
1. iPrI, K CO ,
2
3
The isoquinoline building block 38 bearing an R-configuration at
C-3, as in the lead structure dioncophylline C (2), was also
synthesized via the aziridine route mentioned before, here only
requiring seven steps. Ring opening of the aziridine 34 with the
cuprate of 4 gave the carbamate 35, which was regioselectively
brominated, followed by cleavage of the N-Boc group (see Scheme
5). Acylation and BischlereNapieralski reaction yielded the desired
isoquinoline 38. This building block was submitted to a Suzu-
kieMiyaura coupling with several commercially available aryl- and
naphthylboronic acids mostly possessing diverse electron-donating
or -withdrawing substituents. In the last step of the synthesis the
biaryl compounds were O-deprotected with boron tribromide, to
give the corresponding structures 39be46b with a free hydroxy
function at C-8.
acetone
2. Ac O, K CO
2
2
3
89%
19
18
Br , NaOAc, CH Cl ,
2
2
2
97%
OH
then NaOH, MeOH
OMe
iPrO
iPrO
1. Me SO , NaH,
2
4
DMF
2. (Bpin) , Pd(PPh ) ,
2
3 4
2
KOAc, toluene/H O
B
Br
62%
O
O
20
Me
Me
Me
Me
2.2. Biology and QSAR studies
21
The target structures and their synthetic precursors were tested
at the Swiss Tropical and Public Health Institute in Basel, and within
Scheme 2. Synthesis of the naphthylboronic acid ester 21 from 1,8-naphthosultone
(18).

G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
1. Mg, THF
5373
iPrO
OMe
Me
Br
.
2. CuBr SMe
2
R
iPrO
4'
OMe
N
3.
Boc
H
Boc
21
, 83%
N
OMe
OMe
R
Pd(PPh ) , K PO ,
Bpin
3 4
3
4
Me
DMF
+
R
4
34
35
R
Br
Br , CH Cl ,
then TFA
R
2
2
2
N
76%
R
OH
N
Br
Cl
Me
, NEt
Br
Me
Me
3
Me
2
28: R = Me 66%
29: R = H 38%
OH
O
R
R
N
NH
36
15: R = Me
16: R = H
99%
H
BCl , CH Cl
3
2
2
O
OMe
68%
Br
OMe
37
POCl , MeCN
OH OMe
OH OMe
3
1. Pd(PPh ) , Na CO ,
Ar
3 4
2
3
toluene/H O,
2
Me
Me
NaBH , MeOH
4
ArB(OH)
2
3
3
R
R
R
R
N
N
R
R
2. BBr , CH Cl
2
3
3
2
N
N
H
OMe
OR
39-46 (a = Me, b = H)
Me
Me
HO
HO
38
32: R = Me 44%
33: R = H 74%
30: R = Me 68%
31: R = H 82%
OH
Me
Cl
CF
3
Scheme 4. Synthesis of the naphthyltetrahydroisoquinolines 32 and 33.
the Z1 project of the SFB 630 network in Würzburg for their
bioactivities against Leishmania donovani, Leishmania major, Try-
panosoma brucei brucei, T. brucei rhodesiensis, Trypanosoma cruzi,
and P. falciparum.
39
40
41
42
43
Ar =
Cl
The most potent compounds with respect to their activity
against P. falciparum were the naphthyldihydroisoquinolines 28
(IC50 ¼ 0.138
droisoquinolines 32 (IC50 ¼ 0.223
and e surprisingly e the naphthalene-devoid dihydroisoquinoline
15 (IC50 ¼ 0.708 M) (see Table 1). Their activities were in the range
of the value of chloroquine (IC50 ¼ 0.259 M), the reference drug
m
M) and 29 (IC50 ¼ 0.119
m
M), the naphthyltetrahy-
45
46
44
m
M) and 33 (IC50 ¼ 0.264
mM),
Scheme 5. Synthesis of target structures of types II and III.
m
m
against P. falciparum, but inferior relating cytotoxicity. The activity
values of the C,C-coupled molecules were found to be higher than
those of other structurally simplified naphthylisoquinolines we
reported recently, by one order of magnitude [41], and, in partic-
ular, the selectivity indices of these five structures e i.e., the ratio of
the cytotoxicities divided by the IC50 values of the anti-infective
activities e were very high (between >141 and >725). Due to their
simultaneous lack of activity against other protozoan pathogens
causing infectious diseases(T. brucei rhodesiense, T. cruzi, L. major,
and L. donovani) or L6 cells, all the molecules showed promising
selectivities against the pathogen that causes malaria, a good
precondition for potential anti-infective agents. It is noteworthy
that all compounds exhibiting good antiplasmodial activities
possess a free phenolic hydroxy function at C-8 of the isoquinoline
moiety. Similar molecules with a methyl ether group at C-8 had
previously shown a reduced antiplasmodial activity [41]. Appar-
ently the antimalarial potency of the biaryl structures of type I
profits from the presence of a two-fold oxygenated naphthalene
portion. Both target structures 26 and 27 with only one O-function
in the naphthalene subunit and also the corresponding precursors
were not active against P. falciparum in the single-concentration
tests and so no IC50 values were determined. A free hydroxy group
at C-40 of the northern portion, however, decreases the anti-
plasmodial activity.
The positive influence of a free hydroxy group at C-8 of the
isoquinoline portion was also seen for the antiplasmodial activity of
the aryl- and naphthylisoquinolines 39be46b (see Table 2). All of
the precursors with an O-methylated hydroxy function (39ae46a)
at this position show a drastically reduced activity against P. falci-
parum. Here, as seen for the molecules of type I (see above), a free
hydroxy group at C-40 of the northern portion has also a negative
influence on the antimalarial activity. Furthermore, no unambig-
uous effect of the electron-donating or -withdrawing substituents
of the aryl part was found.
A 3D-QSAR analysis using GRID/PLS [50] was carried out in
order to quantify the influence of the structural changes. The
resulting QSAR model showed sufficient predictivity with an R2
Test
of 0.69 (RMSEPTest: 0.32). The computation of the statistical figures
as well as the details of the analysis can be found in Methods
section. The analysis immediately revealed the paramount influ-
ence of the substitution pattern at the 8-position of the isoquino-
line ring. Moreover, it can be seen that the presence of an
sp3-hybridized nitrogen in the isoquinoline ring is advantageous.
The same is true for a lipophilic substituent on the 40-position (i.e.,

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G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
Table 1
In vitro activities of compounds of the type I series against P. falciparum, T. cruzi, T. brucei rhodesiense, T. brucei brucei, L. major, L. donovani, and L6 cells
Compound
IC50 (mM)
T. cruzi
T. brucei rhodesiense
T. brucei brucei
L. donovani
L. major
P. falciparum
Cytotoxicity (L6 cells)
Selectivity index
15
16
22
23
25
28
29
30
inah
ina
ina
10.90
ina
ina
ina
ina
ina
ina
ina
ina
ina
ina
ina
ina
ina
ina
>100
ina
30.40
26.30
ina
ina
ina
34.14
ina
ina
ina
ina
1.954
ina
ina
ina
ina
ina
ina
>100
ina
37.25
46.30
ina
ina
ina
>100
ina
ina
0.708
1.239
2.399
1.701
3.490
0.138
0.119
1.701
1.988
0.223
0.264
0.259f
>100
>100
43.79
34.34
94.18
>100
27.00
>100
98.20
37.51
40.23
0.017g
>141
>725
227
31
32
33
ina
2.919
2.483
0.007b
ina
168
152
ina
ina
ina
ina
Standard drugs
1.979a
0.003c
0.351d
2.51e
a
Benznidazole.
Melarsoprol.
Pentamidin.
Miltefosine.
Amphotericine B.
Chloroquine.
Podophyllotoxin.
b
c
d
e
f
g
h
ina ¼ inactive in the medium-throughput assay and therefore not screened for IC50 value.
the free phenolic group is disadvantageous). In Fig. 3 these findings
are shown as the back-projection (PLS regression coefficients times
standard deviation of the respective grid point) of the O probe
(H-bond acceptor). Apart from the aforementioned effect, no
pronounced influence of the variations of the molecules in the
northern ring was found.
Fig. 4 shows the residual plot for the computed model based on
the predicted ensemble averages. Few less active molecules are
predicted with large deviations while the more active molecules
are predicted quite precisely. Those molecules that are flagged
show residuals larger than 0.5 pIC50 units. The naphthalene-devoid
isoquinoline 38 is predicted to be more active since the detrimental
influence of the methylation in position 8 is underestimated by the
model. Phenylisoquinolines 41a and 41b are predicted incorrectly
since the O-methylation of position 8 has no influence on the
biological data here while the model does not account for this
special case (both molecules show the disadvantageous free
phenolic group in the northern part of the molecule).
The values of the most promising candidates 40b, 42b, 43b, and
44b were e like those of the compounds of type I e still in the range
of that of chloroquine (IC50 ¼ 0.259
m
M), and the activities (IC50
values between 0.437 M and 0.532
m
mM) and therapeutic indices
(152 to >229) were comparable to those of simplified naph-
thylisoquinolines synthesized previously [41]. Furthermore, the
compounds were not active against any other pathogen or L6 cells
and, thus, had a good selectivity for P. falciparum.
Table 2
In vitro activities of types II and III compounds against P. falciparum, T. cruzi, T. brucei rhodesiense, T. brucei brucei, L. major, L. donovani, and L6 cells.
Compound
IC50 (mM)
T. cruzi
T. brucei rhodesiense
T. brucei brucei
L. donovani
L. major
P. falciparum
Cytotoxicity (L6 cells)
Selectivity index
38
39a
39b
40a
40b
41a
41b
42a
42b
43a
43b
44a
44b
45a
45b
46a
>100
46.67
57.12
19.29
39.34
25.52
>100
15.04
ina
>100
19.19
13.98
13.87
15.88
15.79
20.85
16.73
1.979a
>100
6.484
4.737
5.83
7.123
4.773
53.49
7.805
ina
7.379
14.81
1.179
7.631
3.963
11.05
4.436
1.011
0.007b
inah
>100
74.87
>100
35.54
52.00
21.36
>100
15.94
ina
18.30
35.07
13.00
24.72
14.39
27.11
21.21
38.21
0.351d
ina
>18.87
1.877
0.820
2.491
0.437
10.83
9.91
6.437
0.532
2.997
0.460
7.957
0.856
6.911
0.763
1.181
0.476
0.259f
>100
58.84
52.22
>100
>100
>100
>100
56.70
>100
>100
96.76
38.36
50.76
34.87
57.07
71.98
72.54
0.017g
14.84
13.42
20.20
32.00
ina
ina
ina
>40
10.40
15.92
ina
27.07
ina
2.74
10.10
25.40
0.003c
>100
>100
>83
>86
ina
>229
ina
ina
>100
>100
>100
ina
52.35
ina
13.4
28.10
34.70
2.51e
>188
210
46b
Standard drugs
152
a
Benznidazole.
Melarsoprol.
Pentamidin.
Miltefosine.
Amphotericine B.
Chloroquine.
Podophyllotoxin.
b
c
d
e
f
g
h
ina ¼ inactive in the medium-throughput assay and therefore not screened for IC50 value.

G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
5375
were synthesized, by ring opening of protected aziridines as the
key step. SuzukieMiyaura coupling of the isoquinolines with the
boronic acids or boronic esters of the aryl building blocks gave
new biaryl structures, some of which showed excellent activity
against P. falciparum. Furthermore, these compounds have good
selectivity indices and a high selectivity for the pathogen that
causes malaria, due to their significantly lower toxicity and
activity against pathogens causing other infectious diseases.
Remarkably all of the most active compounds have in common
a phenolic OH function at C-8 of the isoquinoline moiety and, in
the case of the type I series, benefit from a two-fold oxygenated
naphthalene moiety in the northern subunit. Moreover, for all
compounds the presence of an sp3-hybridized nitrogen in the
isoquinoline ring was beneficial, whereas a free phenolic group at
C-40 appeared to be disadvantageous. Apart from this, no
pronounced influence of the variations of the molecules in the
northern ring was found. The most promising compounds were
almost as active as their natural precedents, but much more easily
available, since most of them have no stereocenters and lack the
phenomenon of axial chirality. Furthermore, the obtained bio-
logical data complement the existing SAR dataset and will thus
contribute to the design of new (Q)SAR-derived target structures,
as a more rational alternative to the mostly difficult total synthesis
or isolation of the natural products. Studies on the in vivo anti-
malarial activities of the most active compounds and on the
synthesis of further improved structures are currently in progress.
Fig. 3. Compound 32 with back-projection of the O probe (H-bond acceptor). Repul-
sive forces are displayed in yellow and attractive forces are shown in blue. Attractive
areas clearly indicate that H-bond donors are advantageous at the nitrogen and at the
8-position of the isoquinoline scaffold while an H-bond donor in the C-40 position of
the northern part are disadvantageous. (For interpretation of the references to color in
this figure legend, the reader is referred to the web version of this article).
4. Experimental
Due to their excellent in vitro activities and their promising
selectivity indices five compounds of type I, namely 15, 28, 29, 32,
33, and in addition, four structures of type II, 40b, 42b, 43b, 44b
appear potent enough for in vivo studies. Of these, compound 44b
was already tested in vivo in Plasmodium berghei-infected mice,
showing a reduction of the parasitemia by 44% (4 day intraperito-
neal application of 50 mg/kg/day). This first preliminary in vivo
result seems quite promising since the majority of the suggested
structures have even better in vitro activities than 44b, so that
higher activities may be expected.
4.1. Instrumentations and chemicals
Melting points were measured with a Kofler melting point
apparatus and are uncorrected. IR spectra were recorded with
a Jasco FT/IR-410 spectrometer and are reported in wave numbers
(cmꢀ1). NMR spectra were taken either with a Bruker AC 250,
a Bruker AV 400 or a Bruker DMX 600 at ambient temperature. The
chemical shifts d are given on the ppm scale while taking the signals
of the deuterated solvents as internal reference for 1H and 13C NMR
spectroscopy; the coupling constants J are given in Hertz (Hz).
Elemental analyses were performed on an Elementar vario MICRO
cube elemental analyzer at the Institute of Inorganic Chemistry of
the University of Würzburg. Mass spectra were taken on a Finnigan
MAT 8200 mass spectrometer at 70 eV for EI and on a Bruker
Daltonics micrOTOF-focus for ESI. All reactions with air and/or
moisture sensitive material were carried out in flame dried glass-
ware using the Schlenk tube technique under an inert nitrogen
atmosphere. Preparative HPLC was performed on a SymmetryPrep-
C18-column (Waters; 19 ꢁ 300 mm) using the following gradient:
H2O þ 0.05% TFA (A), MeCN þ 0.05% TFA (B); 10 mL/min; 0 min 25%
B; 20 min 45% B; 20.5 min 100% B; 24 min 100% B; 24.5 min 25% B;
28 min 25% B.
3. Conclusion
A general route to simplified analogs of naphthylisoquinoline
alkaloids with remarkable in vitro antiplasmodial activities was
elaborated. New chiral and achiral isoquinoline building blocks
4.2. Chemistry
4.2.1. tert-Butyl-1-(3-methoxyphenyl)-2-methylpropan-2-
ylcarbamate (7)
A Grignard reagent, freshly prepared from 3-bromoanisol (4)
(11.8 g, 63.1 mmol) and magnesium (11.1 g, 456 mmol) in THF
(45 mL) was cooled to ꢀ30 ꢂC. CuBr$SMe2 (720 mg, 3.50 mmol) was
added in four portions and the mixture was stirred at this
temperature for 30 min. After cooling to ꢀ78 ꢂC a solution of 5
(6.00 g, 35.0 mmol) in THF (40 mL) was added over a period of
30 min and the mixture was allowed to warm up to room
temperature over night. The insoluble components were filtered off
and washed with H2O, Et2O and CH2Cl2. The organic solvents were
Fig. 4. Residual plot for the predictions (pIC50 values). It can be seen that the
predictions for the more active molecules are precise while few less active molecules
are flagged as unusual objects (residual > 0.5 pIC50). For the discussion, see text.

5376
G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
evaporated and the remaining aqueous phase extracted with
CH2Cl2. The combined organic layers were dried over MgSO4,
concentrated in vacuo and the residue purified by flash chroma-
tography (petroleum ether/ethyl acetate 25:1) giving 7 (5.07 g,
crystallized from CH2Cl2/petroleum ether to give 11 as colorless
cubes (1.94 g, 6.76 mmol, 93%). Mp 84e85 ꢂC (CH2Cl2/petroleum
ether). IR (KBr, cmꢀ1
)
n
3313, 3038, 2986, 2969, 2938, 2871, 2830,
1681, 1656, 1592, 1577, 1524, 1472, 1388, 1309, 1293, 1253, 1237,
1170, 1106, 861, 800, 604. 1H NMR (CDCl3) Z-isomer:
8.09 (d,
18.1 mmol, 52%) as a colorless oil; IR (neat, cmꢀ1
)
n
3416, 2948,
2932, 1716, 1602, 1584, 1500, 1263, 1168, 1076. 1H NMR (CDCl3)
7.19 (dd, J ¼ 7.9 Hz, J ¼ 7.9 Hz, 1H, Ar-H), 6.70e6.80 (m, 3H, Ar-H),
4.30 (s,1H, NH), 3.79 (s, 3H, OeCH3), 2.95 (s, 2H, CeCH2), 1.47 (s, 9H,
Ce(CH3)3), 1.27 (s, 6H, CeCH3). 13C NMR (CDCl3)
159.3, 154.6,
d
J ¼ 1.9 Hz, 1H, CHO) 7.42 (d, J ¼ 8.7 Hz, 1H, Ar-H), 6.79 (d, J ¼ 3.0 Hz,
1H, Ar-H), 6.66 (dd, J ¼ 8.7 Hz, J ¼ 3.0 Hz, 1H, Ar-H), 5.40 (br s, 1H,
NH), 3.75 (s, 3H, OeCH3), 3.22 (s, 2H, CH2), 1.41 (s, 6H, CH3). E-
d
d
isomer:
d
8.00 (d, J ¼ 12.1 Hz, 1H, CHO) 7.44 (d, J ¼ 8.7 Hz, 1H, Ar-H),
139.7, 128.7, 123.1, 116.4, 111.6, 78.8, 55.1, 52.8, 45.1, 27.6, 28.5. EI-MS
(70 eV) m/z (%): 206 (2), 178 (2), 158 (33), 121 (16), 102 (54), 57
(100). MS (ESI) exact mass calcd for C16H25NO3: 302.17266
[M þ H]þ; found: 302.17266 [M þ H]þ.
6.73 (d, J ¼ 3.0 Hz, 1H, Ar-H), 6.68 (dd, J ¼ 8.7 Hz, J ¼ 3.0 Hz, 1H, Ar-
H), 6.05 (br d, J ¼ 12.1 Hz, 1H, NH), 3.76 (s, 3H, OeCH3), 2.97 (s, 2H,
CH2), 1.39 (s, 6H, CH3). 13C NMR (CDCl3) Z-isomer:
d 160.8, 158.5,
136.8, 133.4, 117.9, 116.4, 114.1, 55.4, 54.0, 43.7, 27.4. E-isomer:
162.8, 158.5, 138.3, 133.8, 117.9, 116.4, 114.6, 55.4, 55.3, 48.3, 28.5.
d
4.2.2. tert-Butyl 3-methoxyphenethylcarbamate (8)
EI-MS (70 eV) m/z (%):206 (2), 188 (100), 145 (17), 127 (16), 115 (43),
86 (12), 44 (15). MS (ESI) exact mass calcd for C12H16BrNO2:
308.02566 [M þ Na]þ; found: 308.02567 [M þ Na]þ.
The compound was prepared as described for 7, using aziridine
6. Purification by flash chromatography on deactivated silica gel
(petroleum ether/ethyl acetate 25:1) gave 8 as a colorless oil (2.74 g,
10.9 mmol, 78%). IR (KBr, cmꢀ1
)
n
3384, 2976, 2934, 1696, 1603,
4.2.6. N-(2-Bromo-5-methoxyphenethyl)formamide (12)
The compound was synthesized as described for 11. Compound
12 was obtained as colorless needles (1.11 g, 4.30 mmol, 99%). Mp
1585, 1518, 1491, 1455, 1366, 1259, 1168, 1042. 1H NMR (CDCl3)
d
7.22 (dd, J ¼ 7.8 Hz, J ¼ 7.8 Hz, Ar-H) 6.76e6.79 (m, 2H, Ar-H), 6.74
(m, 1H, Ar-H), 4.56 (br s, 1H, NH), 3.80 (s, 3H, OeCH3), 3.37 (m, 2H,
NeCH2), 2.77 (t, J ¼ 7.0 Hz, 2H, CeCH2),1.44 (s, 9H, CeCH3). 13C NMR
66e67 ꢂC (CH2Cl2/petroleum ether). IR (KBr, cmꢀ1
)
n
3288, 3047,
2918, 1653, 1572, 1543, 1473, 1387, 1258, 1235, 1166, 1061, 1014. 1H
NMR (CDCl3) Z-isomer:
(CDCl3)
d
160.0156.1, 140.8, 129.8, 121.3, 114.7, 112.0, 55.4, 41.9, 36.4,
d
8.17 (s, 1H, CHO), 7.43 (d, J ¼ 8.7 Hz,1H, Ar-
28.6. EI-MS (70 eV) m/z (%):251 (13) [M]þ, 195 (53), 134 (100), 122
(24), 91 (10), 57 (88). Anal. calcd for C14H21NO3 (251.32): C, 66.91; H,
8.42; N, 5.57; found: C, 66.40; H, 8.29; N, 6.17.
H), 6.79 (d, J ¼ 3.0 Hz, 1H, Ar-H), 6.68 (dd, J ¼ 8.7 Hz, J ¼ 3.0 Hz, 1H,
Ar-H), 5.61 (br s, 1H, NH), 3.78 (s, 3H, OeCH3), 3.59 (dt, J ¼ 7.0 Hz,
J ¼ 6.4 Hz, 2H, NeCH2), 2.96 (t, J ¼ 7.0 Hz, 2H, CeCH2). E-isomer:
d
7.96 (br d, J ¼ 11.5 Hz, 1H, CHO), 7.44 (d, J ¼ 8.7 Hz, 1H, Ar-H), 6.74
4.2.3. 1-(2-Bromo-5-methoxyphenyl)-2-methylpropan-2-amine (9)
To a solution of 7 (1.32 g, 4.74 mmol) in CH2Cl2 (25 mL) a solu-
tion of Br2 (833 mg, 5.21 mmol) in CH2Cl2 (5 mL) was added
dropwise within 30 min at 0 ꢂC. After complete addition the
mixture was stirred for 3 h at ambient temperature. TFA (0.5 mL)
was added and after stirring over night the solvent was removed
under reduced pressure. The residue was taken up in H2O, acidified
with diluted HCl and was washed with ethyl acetate twice. The
aqueous layer was basified with NaOH pellets and extracted with
CH2Cl2. The combined organic layers were dried over MgSO4.
Evaporation of the solvent gave 9 as yellowish oil (952 mg,
(d, J ¼ 3.0 Hz, 1H, Ar-H), 6.69 (dd, J ¼ 8.7 Hz, J ¼ 3.0 Hz, 1H, Ar-H),
5.61 (br s, 1H, NH), 3.78 (s, 3H, OeCH3), 3.50 (dt, J ¼ 6.8 Hz,
J ¼ 6.5 Hz, 2H, NeCH2), 2.92 (t, J ¼ 6.8 Hz, 2H, CeCH2). 13C NMR
(CDCl3) Z-isomer:
d 161.2, 159.1, 138.8, 133.5, 116.6, 114.8, 114.1, 55.5,
37.8, 35.9. E-isomer:
d
164.4, 159.1, 137.8, 133.7, 117.0, 114.7, 114.1,
55.5, 41.3, 38.3. EI-MS (70 eV) m/z (%): 259/257 (12/13) [M]þ, 214/
212 (100/100), 201/199 (10/12), 178 (64), 89 (11), 77 (11), 58 (41).
Anal. calcd for C10H12BrNO2 (258.11): C, 46.53; H, 4.69; N, 5.43;
found: C, 45.57; H, 4.38; N, 5.28.
4.2.7. 5-Bromo-8-methoxy-3,3-dimethyl-3,4-dihydroisoquinoline
3.69 mmol, 78%). IR (KBr, cmꢀ1
1280, 1166, 1015. 1H NMR (CDCl3)
)
n
3356, 2962, 1595, 1437, 1239,
(13)
d
7.44 (d, J ¼ 8.9 Hz, 1H, Ar-H),
The formamide 11 (53.5 mg, 187 m
mol) was heated to 140 ꢂC in
6.83 (d, J ¼ 3.1 Hz, 1H, Ar-H), 6.66 (dd, J ¼ 8.9 Hz, J ¼ 3.1 Hz, 1H, Ar-
H), 3.77 (s, 3H, OeCH3), 2.86 (s, 2H, CH2), 1.18 (s, 6H, CeCH3), 1.34
polyphosphoric acid (1 g) for 4 h. After cooling to room tempera-
ture the mixture was basified with aqueous 2 N NaOH and
extracted with CH2Cl2. The organic layer was dried over MgSO4 and
concentrated in vacuo. Flash chromatography on deactivated silica
(7.5% NH3, petroleum ether/ethyl acetate 4:1) gave 13 as yellow
(br s, 2H, NH2). 13C NMR (CDCl3)
d 158.5, 139.2, 133.6, 118.0, 116.7,
113.7, 55.5, 51.5, 49.4, 30.6. EI-MS (70 eV) m/z (%): 244 (2), 201 (2),
77 (6), 63 (3), 58 (100), 42 (8). MS (ESI) exact mass calcd for
C11H16BrNO: 258.04862; found: 258.04880.
solid (28.3 mg, 106
cmꢀ1
2965, 2838, 1617, 1572, 1469, 1440, 1362, 1273, 1173, 1083,
800. 1H NMR (CDCl3)
8.54 (s, 1H, CH), 7.50 (d, J ¼ 8.9 Hz, 1H, Ar-H),
6.71 (d, J ¼ 8.9 Hz, 1H, Ar-H), 3.86 (s, 3H, OeCH3), 2.72 (s, 2H, CH2),
1.25 (s, 6H, CH3). 13C NMR (CDCl3)
156.5, 152.1, 137.0, 135.5, 118.4,
m
mol, 56%). Mp 58e59 ꢂC (CH2Cl2). IR (KBr,
)
n
4.2.4. 2-(2-Bromo-5-methoxyphenyl)ethanamine (10)
d
Following the procedure described for 9, 10 was obtained as
a colorless oil (1.10 g, 4.78 mmol, 93%). IR (KBr, cmꢀ1
)
n
3365, 2936,
d
2836,1594, 1573,1474, 1308, 1279, 1242, 1164, 1015. 1H NMR (CDCl3)
115.1, 111.2, 56.0, 54.4, 37.9, 28.4. EI-MS (70 eV) m/z (%): 269/267
(98/100) [M]þ, 254/252 (56/56), 239/237 (14/14), 211 (12), 173 (45),
132 (46), 89 (9), 41 (10). MS (ESI) exact mass calcd for C12H15BrNO:
268.03315 [M þ H]þ; found: 268.03315 [M þ H]þ.
d
7.41 (d, J ¼ 8.7 Hz, 1H, Ar-H) 6.78 (d, J ¼ 3.0 Hz, 1H, Ar-H), 6.64 (dd,
J ¼ 8.7 Hz, J ¼ 3.0 Hz, 1H, Ar-H), 3.77 (s, 3H, OeCH3), 2.96 (t,
J ¼ 7.1 Hz, 2H, NeCH2), 2.84 (t, J ¼ 7.1 Hz, 2H, CeCH2), 1.40 (br s, 2H,
NH2). 13C NMR (CDCl3)
d 158.9, 140.0, 133.3, 116.6, 115.1, 113.4, 55.4,
42.0, 40.4. MS (ESI) exact mass calcd for C9H12BrNO: 230.01750
[M þ H]þ; found: 230.01758 [M þ H]þ. Anal. calcd for C9H12BrNO
(230.10): C, 46.98; H, 5.26; N, 6.09; found: C, 46.40; H, 4.93; N, 6.50.
4.2.8. 5-Bromo-8-methoxy-3,4-dihydroisoquinoline (14)
Following the procedure described for 13, the isoquinoline 14
was obtained after chromatography on deactivated silica (7.5% NH3,
petroleum ether/ethyl acetate 6:1) as pale brown soliꢀd1 (8.57 mg,
4.2.5. N-(1-(2-Bromo-5-methoxyphenyl)-2-methylpropan-2-yl)
formamide (11)
35.7
m
mol, 52%). Mp 58e60 ꢂC (CH2Cl2). IR (KBr, cm
) n 3005,
22940, 2848, 1616, 1584, 1572, 1469, 1276, 1186, 1140, 1091, 805. 1H
Amine 9 (1.88 g, 7.28 mmol) was refluxed in ethyl formate
(50 mL) for 48 h. After complete consumption of the starting
material the solvent was removed in vacuo and the residue was
NMR (CDCl3)
d
8.64 (d, J ¼ 2.0 Hz, 1H, CeH), 7.48 (d, J ¼ 8.9 Hz, 1H,
Ar-H), 6.71 (d, J ¼ 8.9 Hz, 1H, Ar-H), 3.85 (s, 3H, OeCH3), 3.72 (td,
J ¼ 8.0 Hz, J ¼ 2.0 Hz, 2H, NeCH2), 2.72 (t, J ¼ 8.0 Hz, 2H, CeCH2). 13
C

G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
5377
NMR (CDCl3)
d
156.5,155.1,137.8,135.4,119.3,114.2,111.2, 56.0, 46.8,
yellowish solid (1.45 g, 5.92 mmol, 93%). Mp 56e58 ꢂC (CH2Cl2). IR
(KBr, cmꢀ1
3057, 2981, 2932, 1758, 1576, 1381, 1366, 1268, 1212,
1117, 1053, 1027. 1H NMR (CDCl3)
25.2. EI-MS (70 eV) m/z (%):241/239 (97/100) [M]þ, 226/224 (40/
45), 145 (12), 132 (19), 89 (18), 63 (11). Anal. calcd for C10H10BrNO
(240.10): C, 50.02; H, 4.20; N, 5.83; found: C, 50.27; H, 4.32; N, 5.76.
) n
d
7.68 (dd, J ¼ 8.1 Hz, J ¼ 1.2 Hz,1H,
Ar-H), 7.32e7.43 (m, 3H, Ar-H), 7.02 (dd, J ¼ 7.3 Hz, J ¼ 1.2 Hz,1H, Ar-
H), 6.87 (dd, J ¼ 7.3 Hz, J ¼ 0.9 Hz,1H, Ar-H), 4.74 (sept, J ¼ 6.1 Hz,1H,
CH), 2.38 (s, 3H, CH3), 1.42 (d, J ¼ 6.1 Hz, 6H, CH3). 13C NMR (CDCl3)
4.2.9. 5-Bromo-3,3-dimethyl-3,4-dihydroisoquinolin-8-ol (15)
A solution of 13 (133 mg, 494
mmol) in chlorobenzene (7 mL)
d 170.1, 153.7, 146.9, 137.4, 126.8, 126.6, 126.0, 120.7, 120.4, 119.5,
was treated with AlCl3 (198 mg, 1.48 mmol) and heated to 130 ꢂC
for 90 min. After cooling to room temperature saturated NaHCO3
solution was added and the mixture extracted with ethyl acetate.
After drying over MgSO4 the ethyl acetate was removed under
reduced pressure whereupon the product crystallized from the
remaining chlorobenzene at ꢀ20 ꢂC as orange-colored cubes
108.3, 70.4, 22.2, 21.8. EI-MS (70 eV) m/z (%): 244 (12) [M]þ, 202 (10),
160 (100), 131 (5), 114 (5), 77 (2). MS (ESI) exact mass calcd for
C15H16O: 267.09917 [M þ Na]þ; found: 267.09916 [M þ Na]þ.
4.2.13. 5-Bromo-8-isopropoxy-naphthalen-1-ol (20)
A solution of Br2 (945 mg, 5.91 mmol) in CH2Cl2 (10 mL) was
added to a mixture of 19 (61.6 mg, 252 mmol) and NaOAc (103 mg,
(104 mg, 409
3433, 3165, 3093, 2975, 2958, 2925, 1613, 1587, 1472, 1439, 1360,
1295, 1274, 1162, 1130. 1H NMR (MeOD)
8.44 (s, 1H, CH), 6.58 (d,
J ¼ 9.1 Hz, 1H, Ar-H), 6.40 (d, J ¼ 9.1 Hz, 1H, Ar-H), 2.80 (s, 2H, CH2),
1.30 (s, 6H, CH3). 13C NMR (MeOD)
165.4, 157.2, 141.4, 137.2, 129.6,
120.7,111.5, 56.2, 40.1, 27.3. EI-MS (70 eV) m/z (%): 255/253 (99/100)
[M]þ, 240/238 (52/55), 227/225 (11/11), 212 (12), 173 (18), 159 (48),
132 (14), 89 (11). Anal. calcd for C11H12BrNO (254.12): C, 51.99; H,
4.76; N, 5.51; found: C, 52.49; H, 4.79; N, 5.44.
m
mol, 83%). Mp 214e216 ꢂC (C6H5Cl). IR (KBr, cmꢀ1
)
n
1.26 mmol) in CH2Cl2 (10 mL) at ꢀ20 ꢂC over a period of 30 min.
After warming up to ambient temperature and stirring for 4 h, the
reaction was quenched with aqueous Na2S2O3 solution. The organic
phase was washed with water, dried over MgSO4 and concentrated
to dryness. The residue was dissolved in MeOH (10 mL) and treated
with 2 N NaOH (2 mL) at 80 ꢂC for 4 h. After cooling to room
temperature the mixture was acidified with diluted HCl and
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, concentrated and subjected to column chromatog-
raphy (petroleum ether/ethyl acetate 25:1) to afford the product as
an orange-colored solid (68.8 mg, 245 mol, 97%) mp 74e75 ꢂC
d
d
4.2.10. 5-Bromo-3,4-dihydroisoquinolin-8-ol (16)
According to the procedure described above, 16 (25.5 mg,
113
113
m
m
mol, 53%) was obtained as orange-colored crystals (25.5 mg,
mol, 53%). Evaporating the mother liquor to dryness gave
(CH2Cl2/petroleum ether). IR (KBr, cmꢀ1
1601, 1388, 1376, 1240, 1110, 1051, 804. 1H NMR (CDCl3)
)
n
3337, 2984, 2937, 1622,
9.87 (s, 1H,
d
additional product as a yellow oil (21.0 mg, 92.9
only small impurities. Yield: 97%. Mp 181e183 ꢂC (C6H5Cl). IR (KBr,
cmꢀ1
3434, 2954, 2914, 2855, 1626, 1577, 1451, 1349, 1329, 1299,
1176, 1055, 1011, 805. 1H NMR (MeOD)
8.58 (s, 1H, CH), 7.42 (d,
m
mol, 44%) with
OH), 7.68 (dd, J ¼ 8.5 Hz, J ¼ 1.1 Hz, 1H, Ar-H), 7.61 (d, J ¼ 8.4 Hz, 1H,
Ar-H), 7.46 (dd, J ¼ 8.5 Hz, J ¼ 7.63 Hz, 1H, Ar-H), 6.93 (dd, J ¼ 7.6 Hz,
J ¼ 1.1 Hz, 1H, Ar-H), 6.67 (d, J ¼ 8.4 Hz, 1H, Ar-H), 4.84 (sept,
J ¼ 6.1 Hz, 1H, CH), 1.51 (d, J ¼ 6.1 Hz, 6H, CH3). 13C NMR (CDCl3)
)
n
d
J ¼ 9.1 Hz, 1H, Ar-H), 6.62 (d, J ¼ 9.1 Hz, 1H, Ar-H), 3.69 (td,
d 155.1, 154.0, 134.6, 129.4, 129.0, 118.4, 116.8, 114.8, 111.4, 106.9,
J ¼ 7.8 Hz, J ¼ 1.3 Hz, 2H, NeCH2), 2.83 (t, J ¼ 7.8 Hz, 2H, CeCH2). 13
C
73.3, 21.9. EI-MS (70 eV) m/z (%): 282/280 (21/20) [M]þ, 240/238
(96/100), 194 (10), 159 (8), 102 (23), 59 (74), 43 (35). Anal. calcd for
C13H13BrO2 (281.15): C, 55.54; H, 4.66; found: C, 55.01; H, 4.64.
NMR (MeOD)
d
¼ 158.8, 140.3, 137.9, 127.7, 120.1, 117.5, 110.6, 44.8,
26.5. EI-MS (70 eV) m/z (%): 227/225 (99/100) [M]þ, 200/198 (9/11),
145 (23), 118 (14), 112 (11), 91 (22), 59 (15), 44 (14). MS (ESI) exact
mass calcd for C9H8BrNO: 225.98629 [M þ H]þ; found: 225.98634
[M þ H]þ. Anal. calcd for C9H8BrNO (226.07): C, 47.82; H, 3.57; N,
6.20; found: C, 46.45; H, 3.64; N, 5.80.
4.2.14. 1-Bromo-5-isopropoxy-4-methoxynaphthalene
A solution of 20 (1.37 g, 4.86 mmol) in DMF was treated with
NaH (175 mg, 7.28 mmol) and stirred at ambient temperature until
gas evolution had ceased. Dimethylsulfate (918 mg, 7.28 mmol) was
added and the mixture was stirred for 2 h. The reaction was
quenched by careful addition of water and the aqueous layer
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, concentrated to dryness and the residue crystallized
from CH2Cl2/petroleum ether to afford the desired compound as an
orange-colored solid (1.42 g, 4.82 mmol, 99%). Mp 63e65 ꢂC
4.2.11. 8-Isopropoxynaphthalen-1-ol
A mixture of 18 (940 mg, 5.87 mmol) and K2CO3 (891 mg,
6.45 mmol) in acetone (30 mL) was treated with 2-iodopropane
(1.50 g, 8.82 mmol). After stirring at ambient temperature for 16 h
and heating up to 56 ꢂC for 4 h, the mixture was diluted with water
(20 mL) and extracted with Et2O. The organic layer was washed
with water and sat. K2CO3 solution, dried over MgSO4, and
concentrated in vacuo to give the desired product as brownish oil
(CH2Cl2/petroleum ether). IR (KBr, cmꢀ1
)
n
3107, 2983, 2929, 1586,
7.83 (dd, J ¼ 8.5 Hz,
1374, 1276, 1092, 813, 753. 1H NMR (CDCl3)
d
(1.10 g, 5.42 mmol, 92%). 1H NMR (CDCl3)
d
9.77 (s,1H, OH), 7.40 (dd,
J ¼ 0.9 Hz, 1H, Ar-H), 7.65 (d, J ¼ 8.3 Hz, 1H, Ar-H), 7.46 (dd,
J ¼ 8.5 Hz, J ¼ 7.3 Hz, 1H, Ar-H), 6.90 (d, J ¼ 7.3 Hz, 1H, Ar-H), 6.79 (d,
J ¼ 8.3 Hz, 1H, Ar-H), 4.53 (sept, J ¼ 6.1 Hz, 1H, CH), 3.95 (s, 3H,
J ¼ 8.2 Hz, J ¼ 0.9 Hz, 1H, Ar-H), 7.29e7.37 (m, 3H, Ar-H), 6.85 (dd,
J ¼ 7.2 Hz, J ¼ 1.7 Hz, 1H, Ar-H), 6.80 (d, J ¼ 7.6 Hz, 1H, Ar-H), 4.86
(sept, J ¼ 6.1 Hz, 1H, CH), 1.51 (d, J ¼ 6.1 Hz, 6H, CH3). 13C NMR
OeCH3), 1.40 (d, J ¼ 6.1 Hz, 6H, CH3). 13C NMR (CDCl3)
d 157.3, 155.0,
(CDCl3)
d
154.9, 154.2, 137.0, 127.6, 125.7, 121.6, 118.9, 116.0, 110.2,
135.1, 130.3, 127.5, 120.7, 120.2, 114.3, 112.9, 107.4, 73.2, 56.5, 22.0.
EI-MS (70 eV) m/z (%): 294 [M]þ (33), 252 (100), 237 (57), 209 (29),
173 (5), 102 (24), 75 (10), 43 (8). Anal. calcd for C14H15BrO2 (295.17):
C, 56.97; H, 5.12; found: C, 57.09; H, 5.08.
106.5, 72.7, 22.0. EI-MS (70 eV) m/z (%): 202 (20) [M]þ, 160 (100),
131 (7), 114 (20), 77 (6), 51 (9). MS (ESI) exact mass calcd for
C13H14O2: 225.08860 [M þ Na]þ; found: 225.08858 [M þ Na]þ.
4.2.12. 8-Isopropoxynaphthalen-1-yl acetate (19)
4.2.15. 2-(4-Isopropoxy-5-methoxynaphthalen-1-yl)-4,4,5,5-
To a solution of 8-isopropoxynaphthalen-1-ol in Ac2O (20 mL)
K2CO3 (1.06 g, 7.64 mmol) was added and the mixture was heated to
60 ꢂC for 6 h. The cold mixturewas poured onto ice water and stirred
for 2 h. The precipitate was filtered off, the aqueous phase extracted
with CH2Cl2, dried over MgSO4 and concentrated in vacuo. The
residue was combined with the precipitate and purified by flash
chromatography (petroleum ether/ethyl acetate 20:1) to give 19 as
tetramethyl-1,3,2-dioxaborolane (21)
1-Bromo-5-isopropoxy-4-methoxynaphthalene
382 mol), KOAc (375 mg, 3.82 mmol), bispinacolatodiborane
(292 mg, 1.15 mmol) and Pd(dppf)Cl2 (31.2 mg, 38.2 mol) were
(113 mg,
m
m
solved in a toluene/water-mixture (7 mL, 5:2), degassed and
afterwards heated to 90 ꢂC for 6 h. After cooling to room temper-
ature water (10 mL) was added and the aqueous layer extracted

5378
G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
with CH2Cl2. The combined organic layers were dried over MgSO4,
concentrated and the residue purified by flash chromatography
(petroleum ether/ethyl acetate 35:1) to afford the desired product
Pd(PPh3)4 (12.8 mg,11.1 m
mol) was added. After heating up to 90 ꢂC for
5 h, the reaction mixture was diluted with water (10 mL) and the
aqueous phase extracted with CH2Cl2. The combined organic layers
were dried over MgSO4, concentrated and purified via column chro-
matography on deactivated silica gel (7.5% NH3, CH2Cl2/MeOH 12:1) to
as a yellowish solid (82.0 mg, 240
acetate). IR (KBr, cmꢀ1
2979, 2930, 2827, 1612, 1584, 1324, 1285,
1268, 1146, 1117. 1H NMR (CDCl3)
m
mol, 63%). Mp 86e88 ꢂC (ethyl
)
n
d
8.39 (dd, J ¼ 8.5 Hz, J ¼ 0.9 Hz,
give 28 as a yellow oil (21.8 mg, 56.0
m
mol, 66%). IR (KBr, cmꢀ1
8.76 (s, 1H,
) n 3426,
1H, Ar-H), 7.98 (d, J ¼ 7.8 Hz, 1H, Ar-H), 7.39 (dd, J ¼ 8.5 Hz,
J ¼ 8.0 Hz, 1H, Ar-H), 6.89 (d, J ¼ 8.0 Hz, 1H, Ar-H), 6.85 (d, J ¼ 7.8 Hz,
1H, Ar-H), 4.65 (sept, J ¼ 6.1 Hz, 6H, CH), 1.40 (s, 12H, CH3), 3.92 (s,
2972, 2929, 1603, 1406, 1381, 1269, 1117. 1H NMR (MeOD)
d
CH), 7.28 (dd, J ¼ 8.2 Hz, J ¼ 8.0 Hz,1H, Ar-H), 7.27 (d, J ¼ 8.9 Hz,1H, Ar-
H), 7.16 (d, J ¼ 7.9 Hz, 1H, Ar-H), 7.01 (d, J ¼ 7.9 Hz, 1H, Ar-H), 6.99 (dd,
J ¼ 8.5 Hz, J ¼ 0.7 Hz, 1H, Ar-H), 6.94 (d, J ¼ 7.6 Hz, 1H, Ar-H), 6.81 (d,
J ¼ 8.7 Hz,1H, Ar-H), 4.62 (sept, J ¼ 6.1 Hz,1H, CH), 3.94 (s, 3H, OeCH3),
2.50 (d, J ¼ 16.8 Hz, 1H, CH2), 2.36 (d, J ¼ 16.8 Hz, 1H, CH2), 1.42 (d,
J ¼ 6.1 Hz, 6H, CH3),1.23 (s, 3H, CH3),1.18 (s, 3H, CH3).13C NMR (MeOD)
3H, OeCH3), 1.42 (d, J ¼ 6.1 Hz, 6H, CH3). 13C NMR (CDCl3)
d 158.0,
157.4, 141.4, 137.0, 126.5, 121.4, 119.1, 110.4, 107.0, 83.4, 72.0, 56.6,
24.9, 22.0. EI-MS (70 eV) m/z (%):342 (36) [M]þ, 300 (100), 227 (18),
200 (19), 157 (10), 127 (6). Anal. calcd for C20H27BO4 (342.24): C,
70.19; H, 7.95; found: C, 69.61; H, 7.81.
d
165.8, 158.8, 158.3, 155.9, 141.6, 137.5, 136.7, 131.3, 130.6, 129.1, 127.7,
120.7, 119.8, 118.3, 114.0, 113.2, 108.1, 74.2, 56.9, 55.2, 37.7, 27.0, 26.4,
22.4, 22.4. EI-MS (70 eV) m/z(%):389(100) [M]þ, 347 (54), 332(41), 290
(24), 258 (49), 189 (11). MS (ESI) exact mass calcd for C25H27NO3:
390.20637 [M þ H]þ; found: 390.20698 [M þ H]þ.
4.2.16. 8-Methoxy-5-(40-methoxynaphthalen-10-yl)-3,3-dimethyl-
3,4-dihydroisoquinoline (22)
Pd(PPh3)4 (15.1 mg, 13.1
of 13 (35.0 mg, 131 mol), 4-methoxynaphthylboronic acid (17)
(36.9 mg, 183 mol) and 2 M Na2CO3 solution (1 mL) in toluene
mmol) was added to a degassed mixture
m
m
4.2.19. 5-(40-Isopropoxy-50-methoxynaphthalen-10-yl)-3,4-
(5 mL). After heating up to 80 ꢂC over night, water (10 mL) was
added to the reaction mixture and the aqueous phase was extracted
with CH2Cl2. The combined organic layers were dried over MgSO4,
concentrated and purified via column chromatography on deacti-
vated silica gel (7.5% NH3, petroleum ether/ethyl acetate 6:1) to give
dihydroisoquinolin-8-ol (29)
Treating 16 (36.7 mg, 162 mmol) and 21 (66.7 mg, 195 mmol) as
described in Section 4.2.18 gave after column chromatography on
deactivated silica gel (7.5% NH3, CH2Cl2/MeOH 15:1) the desired
product as a yellow oil (22.6 mg, 62.4
2963, 2923, 2855,1612,1582,1459,1406,1380,1266,1096,1051, 807.1H
NMR (MeOD)
m ) n 3431,
mol, 38%). IR (KBr, cmꢀ1
28 as a brown oil (39.4 mg, 115 mmol, 88%), that was crystallized
from CH2Cl2/petroleum ether as a colorless solid. Mp 130e132 ꢂC
d
8.73 (s, 1H, CH), 7.27 (dd, J ¼ 8.4 Hz, J ¼ 8.0 Hz, 1H, Ar-
(CH2Cl2/petroleum ether). IR (KBr, cmꢀ1
1460, 1390, 1277, 1083. 1H NMR (CDCl3)
)
d
n
2931, 1735, 1638, 1584,
H), 7.2 (d, J ¼ 8.1 Hz, 2H, Ar-H), 7.01 (dd, J ¼ 8.4 Hz, J ¼ 0.7 Hz,1H, Ar-H),
7.00 (d, J ¼ 8.0 Hz, 1H, Ar-H), 6.92 (d, J ¼ 7.6 Hz, 1H, Ar-H), 6.76 (d,
J ¼ 8.7 Hz,1H, Ar-H), 4.60 (sept, J ¼ 6.1 Hz,1H, CH), 3.93 (s, 3H, OeCH3),
3.44e3.52 (m, 2H, NeCH2), 2.24e2.41 (m, 2H, CeCH2), 1.40 (d,
8.74 (s, 1H, CH), 8.35 (d,
1H, J ¼ 8.3 Hz, Ar-H), 7.50e7.46 (m, 1H, Ar-H), 7.43e7.38 (m, 2H, Ar-
H), 7.28 (d, J ¼ 8.6 Hz, 1H, Ar-H), 6.89 (d, J ¼ 7.3 Hz, 1H, Ar-H), 6.87
(d, J ¼ 7.6 Hz, 1H, Ar-H), 4.06 (s, 3H, OeCH3), 3.94 (s, 3H, OeCH3),
2.32 (d, J ¼ 16.6 Hz, 1H, CH2), 2.24 (d, J ¼ 16.6 Hz, 1H, CH2), 1.12 (s,
J ¼ 6.1 Hz, 6H, CH3). 13C NMR (MeOD)
d 159.3, 158.7, 155.6, 139.4, 137.5,
137.3,132.1,129.3,129.0,127.6,120.8,119.8,118.1,116.0,113.5,108.1, 74.3,
56.9, 24.6, 24.6, 22.4. EI-MS (70 eV) m/z (%): 361 (65) [M]þ, 319 (100),
304(36), 286 (10), 231 (5), 202 (7),189 (8). MS (ESI) exact masscalcd for
C23H23NO3: 362.17507 [M þ H]þ; found: 362.17489 [M þ H]þ.
3H, CH3), 1.07 (s, 3H, CH3). 13C NMR (CDCl3)
d 156.4, 155.0, 152.9,
136.7, 134.5, 133.3, 131.8, 129.8, 127.1, 126.5, 125.7, 125.5, 125.2,
122.2, 116.0, 108.7, 103.3, 55.6, 55.5, 53.9, 35.7, 28.2, 27.3. EI-MS
(70 eV) m/z (%):345 (100) [M]þ, 330 (23), 298 (17), 257 (6), 165 (7).
Anal. calcd for C23H23NO2 (345.43): C, 79.97; H, 6.71; N, 4.05;
found: C, 79.21; H, 6.60; N, 3.98.
4.2.20. 5-(40-Hydroxynaphthalen-10-yl)-3,3-dimethyl-3,4-
dihydroisoquinolin-8-ol (24)
A solution of 22 (11.1 mg, 32.1 mmol) in CH2Cl2 (5 mL) was treated
4.2.17. 8-Methoxy-5-(40-methoxynaphthalen-10-yl)-3,4-
dihydroisoquinoline (23)
with BBr3 (0.1 mL, 1 M solution in n-hexane) at ꢀ20 ꢂC. The reaction
mixture was allowed to warm up to room temperature over night
before a second portion of BBr3 (0.1 mL, 1 M solution in hexanes) was
added. After 3 h of vigorous stirring MeOH (5 mL) was added, the
mixture concentrated to dryness and purified by column chroma-
tography on deactivated silica (7.5% NH3, CH2Cl2/MeOH 20:1) to give
The naphthylisoquinoline 23 was obtained by reaction of 14
(29.7 mg, 124
(35.0 mg, 172
m
mol) and 4-methxonaphthylboronic acid (17)
mmol) as described for 22. The rude product was
purified by column chromatography on deactivated silica (7.5%
NH3, petroleum ether/ethyl acetate 4:1). After crystallisation from
ethyl acetate/petroleum ether 29 was obtained as a colorless solid
24 as a yellow oil (8.00 mg, 25.2
3180, 2967, 2925, 1602, 1580, 1468, 1444, 1369, 1293, 1266, 1177, 1157.
1H NMR (MeOD)
m ) n 3414,
mol, 79%). IR (KBr, cmꢀ1
(32.6 mg, 103
ether). IR (KBr, cmꢀ1
1270, 1241, 1083, 808, 768. 1H NMR (CDCl3)
m
mol, 83%). Mp 196e198 ꢂC (ethyl acetate/petroleum
d
8.72 (s, 1H, CH), 8.27 (d, J ¼ 8.3 Hz, 1H, Ar-H),
)
n
2938, 2839, 1618, 1584, 1463, 1389, 1372,
8.86 (s, 1H, CH), 8.34
7.41e7.43 (m, 1H, Ar-H), 7.37e7.38 (m, 2H, Ar-H), 7.27 (d, J ¼ 8.6 Hz,
1H, Ar-H), 7.07 (d, J ¼ 7.6 Hz, 1H, Ar-H), 6.87 (d, J ¼ 7.6 Hz, 1H, Ar-H),
6.79 (d, J ¼ 8.6 Hz, 1H, Ar-H), 2.49 (d, J ¼ 16.8 Hz, 1H, CH2), 2.37 (d,
J ¼ 16.8 Hz, 1H, CH2), 1.21 (s, 3H, CH3), 1.16 (s, 3H, CH3). 13C NMR
d
(d, J ¼ 8.3 Hz, 1H, 50-H), 7.46e7.50 (m, 1H, Ar-H), 7.41 (m, 2H, Ar-H),
2.32 (m, 2H, CeCH2), 7.32 (d, J ¼ 8.5 Hz,1H, Ar-H), 7.22 (d, J ¼ 7.8 Hz,
1H, Ar-H), 6.91 (d, J ¼ 8.5 Hz, 1H, Ar-H), 6.86 (d, J ¼ 7.8 Hz, 1H, Ar-H),
(MeOD)
d 165.8, 158.3, 154.5, 141.9, 136.9, 134.7, 130.3, 129.0, 128.8,
4.05 (s, 3H, OeCH3), 3.95 (s, 3H, OeCH3), 3.56 (m, 2H, NeCH2). 13
C
127.4, 126.5, 126.4, 125.6, 123.8, 118.2, 114.0, 108.3, 55.3, 37.8, 26.9,
26.4. EI-MS (70 eV) m/z (%):317 (100) [M]þ, 302 (22), 260 (59), 231
(26), 202 (12), 150 (6), 101 (10), 58 (17). MS (ESI) exact mass calcd for
C21H19NO2: 318.14886 [M þ H]þ; found: 318.14893 [M þ H]þ.
NMR (CDCl3)
d 156.5, 156.1, 155.1, 137.5, 134.6, 133.1, 131.0, 129.7,
127.1, 126.6, 125.5, 125.5, 125.1, 122.3, 108.9, 103.2, 55.6, 55.5, 46.8,
23.3. EI-MS (70 eV) m/z (%): 317 (100) [M]þ, 302 (17), 286 (17), 202
(6), 151 (9), 101 (7). Anal. calcd for C21H19NO2 (317.38): C, 79.47; H,
6.03; N, 4.41; found: C, 78.90; H, 5.98; N, 4.41.
4.2.21. 5-(40-Hydroxynaphthalen-10-yl)-3,4-dihydroisoquinolin-8-
ol (25)
4.2.18. 5-(40-Isopropoxy-50-methoxynaphthalen-10-yl)-3,3-
dimethyl-3,4-dihydroisoquinolin-8-ol (28)
BBr3 (0.25 mL,1 M solution in n-hexane) was added to a solution
of 23 (27.4 mg, 86.2 m
mol) in CH2Cl2 (6 mL) at 0 ꢂC. After stirring at
To a degassed mixture of 15 (37.9 mg, 111
mmol), boronic acid ester
0 ꢂC for 5 h the mixtures was warmed to room temperature and
stirred for additional 24 h. Then MeOH (5 mL) was added and the
21 (49.4 mg, 144 mol), and K3PO4 (118 mg, 555
m
mmol) in DMF (5 mL)

G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
5379
solvent removed under reduced pressure. The residue was
submitted to column chromatography on deactivated silica (7.5%
NH3, CH2Cl2/MeOH 15:1 to 10:1). The obtained product still con-
tained small impurities, which were removed by preparative HPLC
with NaBH4 (3 equiv.). After being stirred at this temperature for
2 h water was added and the mixture concentrated to dryness. The
residue was taken up in CH2Cl2/MeOH (20:1), the insoluble parts
were filtered off and the filtrate concentrated and purified by
preparative HPLC.
to afford 25 as a yellow oil (13.5 mg, 46.5
3421, 2950, 2919, 1677, 1587, 1509, 1448, 1351, 1305, 1197, 1137,
1053, 836, 800, 770, 723. 1H NMR (MeOD)
9.23 (s, 1H, CH), 8.30 (d,
m )
mol, 54%). IR (KBr, cmꢀ1
n
d
4.3.1. 5-(40-Hydroxynaphthalen-10-yl)-3,3-dimethyl-1,2,3,4-
J ¼ 8.0 Hz, 1H, Ar-H), 7.59 (d, J ¼ 8.6 Hz, 1H, Ar-H), 7.41e7.46 (m, 2H,
Ar-H), 7.35 (d, J ¼ 7.8 Hz, 1H, Ar-H), 7.15 (d, J ¼ 7.7 Hz, 1H, Ar-H), 7.04
(d, J ¼ 8.6 Hz, 1H, Ar-H), 6.89 (d, J ¼ 7.7 Hz, 1H, Ar-H), 3.71e3.80 (m,
2H, NeCH2), 2.75e2.80 (m, 1H, CeCH2), 2.66e2.75 (m, 1H, CeCH2).
tetrahydroisoquinolin-8-ol (26)
Colorless oil (7.70 mg, 24.1
m ) n 3434,
mol, 83%). IR (KBr, cmꢀ1
2925, 2852, 1680, 1433, 1385, 1324, 1207, 1139. 1H NMR (MeOD)
d
8.27 (dd, J ¼ 8.4 Hz, J ¼ 0.5 Hz, 1H, Ar-H), 7.41e7.44 (m, 1H, Ar-H),
13C NMR (MeOD)
d
163.6, 162.5, 155.0, 144.5, 138.2, 134.3, 132.4,
7.34e7.37 (m, 1H, Ar-H), 7.26 (d, J ¼ 8.4 Hz, 1H, Ar-H), 7.08 (d,
J ¼ 8.1 Hz, 1H, Ar-H), 7.07 (d, J ¼ 7.6 Hz, 1H, Ar-H), 6.87 (d, J ¼ 7.6 Hz,
1H, Ar-H), 6.86 (d, J ¼ 8.1 Hz, 1H, Ar-H), 4.33 (s, 2H, CH2), 2.53 (d,
J ¼ 17.5 Hz, 1H, CH2), 2.39 (d, J ¼ 17.5 Hz, 1H, CH2), 1.28 (s, 3H, CH3),
128.9, 127.8, 127.7, 126.5, 125.8, 124.0, 116.1, 113.5, 108.3, 42.3, 24.1.
EI-MS (70 eV) m/z (%): 289 (100) [M]þ, 272 (21), 261 (11), 231 (12),
202 (15), 135 (11). MS (ESI) exact mass calcd for C19H15NO2:
290.11756 [M þ H]þ; found: 290.11756 [M þ H]þ.
1.27 (s, 3H, CH3). 13C NMR (MeOD)
d 154.7, 154.4, 134.7, 133.1, 132.4,
132.2,130.0,128.6,127.4,126.4,126.2,125.6,123.8,114.9,113.4,108.4,
54.3, 39.3, 37.9, 24.6, 24.3. EI-MS (70 eV) m/z (%): 319 (75) [M]þ, 304
(100), 262 (59), 247 (26), 152 (18). MS (ESI) exact mass calcd for
C21H21NO2: 320.16451 [M þ H]þ; found: 320.16450 [M þ H]þ.
4.2.22. 5-(40-Hydroxy-50-methoxynaphthalen-10-yl)-3,3-dimethyl-
3,4-dihydroisoquinolin-8-ol (30)
A solution of 28 (31.0 mg, 79.7 mmol) in CH2Cl2 (10 mL) was
treated with BCl3 (0.4 mL, 1 M solution in n-hexane) at 0 ꢂC. After
being stirred at this temperature for 2 h, MeOH (2 mL) was added
and the mixture concentrated to dryness. The residue was
submitted to column chromatography on deactivated silica (7.5%
NH3, CH2Cl2/MeOH 15:1 to 10:1) to afford the desired product along
with small impurities which were removed by preparative HPLC to
4.3.2. 5-(40-Hydroxy-50-methoxynaphthalen-10-yl)-3,3-dimethyl-
1,2,3,4-tetrahydroisoquinolin-8-ol (32)
Colorless oil(4.46 mg,12.8
m
mol, 44%). IR(KBr, cmꢀ1
)
n
3413, 2981,
7.26
2923, 2851, 1677, 1611, 1409, 1268,1203,1137. 1H NMR (MeOD)
d
(dd, J ¼ 7.9 Hz, J ¼ 8.4 Hz, 1H, Ar-H), 7.13 (d, J ¼ 7.8 Hz, 1H, Ar-H), 7.05
(d, J ¼ 8.2 Hz, 1H, Ar-H), 6.96 (d, J ¼ 7.5 Hz, 1H, Ar-H), 6.90 (dd,
J ¼ 8.6 Hz, J ¼ 0.7 Hz, 1H, Ar-H), 6.85 (d, J ¼ 7.8 Hz, 2H, Ar-H), 4.32 (s,
2H, CH2), 4.11 (s, 3H, OeCH3), 2.50 (d, J ¼ 17.5 Hz, 2H, CH2), 2.36 (d,
J ¼ 17.5 Hz, 1H, CH2), 1.28 (s, 3H, CH3), 1.27 (s, 3H, CH3). 13C NMR
give pure 30 as a yellow oil (18.7 mg, 53.9 m )
mol, 68%). IR (KBr, cmꢀ1
n
3411, 2979, 2925, 1673, 1637, 1588, 1459, 1410, 1307, 1271, 1181,
1133, 1086, 1039. 1H NMR (MeOD)
d 9.10 (s, 1H, CH), 7.54 (d,
J ¼ 8.6 Hz, 1H, Ar-H), 7.32 (dd, J ¼ 8.5 Hz, J ¼ 8.0 Hz, 1H, Ar-H), 7.17
(d, J ¼ 7.8 Hz, 1H, Ar-H), 7.04 (d, J ¼ 8.6 Hz, 1H, Ar-H), 6.99 (d,
J ¼ 7.8 Hz, 1H, Ar-H), 6.95 (d, J ¼ 8.5 Hz, 1H, Ar-H), 6.88 (d, J ¼ 8.0 Hz,
1H, Ar-H), 4.11 (s, 3H, OeCH3), 2.74 (d, J ¼ 17.1 Hz, 1H, CH2), 2.58 (d,
J ¼ 17.1 Hz, 1H, CH2), 1.36 (s, 3H, CH3), 1.31 (s, 3H, CH3). 13C NMR
(MeOD)
d 158.1, 155.6, 154.8, 136.6, 132.3, 133.2, 132.2, 130.1, 129.8,
127.4,120.3,116.2,115.0,113.5,110.8,105.5, 56.9, 54.3, 39.2, 37.8, 24.7,
24.3. EI-MS (70 eV) m/z (%): 349 (91) [M]þ, 334 (100), 318 (17), 292
(79), 277 (24), 260 (33), 167 (24), 159 (15). MS (ESI) exact mass calcd
for C22H23NO3: 350.17507 [M þ H]þ; found: 350.17546 [M þ H]þ.
(MeOD)
d 162.8, 161.6, 158.2, 156.3, 144.7, 137.7, 136.3, 133.2, 130.4,
127.9, 127.3, 120.0, 116.4, 112.5, 110.9, 105.8, 57.0, 56.3, 37.6, 26.0,
25.6. EI-MS (70 eV) m/z (%): 347 (88) [M]þ, 332 (33), 315 (14), 290
(24), 258 (43), 120 (17), 44 (100). MS (ESI) exact mass calcd for
C22H21NO3: 348.15942 [M þ H]þ; found: 348.15961 [M þ H]þ.
4.3.3. 5-(40-Hydroxynaphthalen-10-yl)-1,2,3,4-
tetrahydroisoquinolin-8-ol (27)
Colorless oil (5.33 mg, 18.3
2927, 2851,1679,1588,1430,1343,1206, 1138, 840, 803, 769, 724. 1H
NMR (MeOD)
m ) n 3422,
mol, 36%). IR (KBr, cmꢀ1
4.2.23. 5-(40-Hydroxy-50-methoxynaphthalen-10-yl)-3,4-
dihydroisoquinolin-8-ol (31)
d
8.26 (d, J ¼ 8.2 Hz, 1H, Ar-H), 7.42 (ddd, J ¼ 8.2 Hz,
J ¼ 8.0 Hz, J ¼ 1.3 Hz, 1H, Ar-H), 7.36 (ddd, J ¼ 8.1 Hz, J ¼ 8.0 Hz,
J ¼ 1.3 Hz, 1H, Ar-H), 7.32 (d, J ¼ 8.1 Hz, 1H, Ar-H), 7.09 (d, J ¼ 7.6 Hz,
1H, Ar-H), 7.07 (d, J ¼ 8.2 Hz, 1H, Ar-H), 6.87 (d, J ¼ 7.6 Hz, 1H, Ar-H),
6.84 (d, J ¼ 8.2 Hz, 1H, Ar-H), 4.36 (d, J ¼ 16.3 Hz, 1H, CH2), 4.30 (d,
J ¼ 16.3 Hz, 1H, CH2), 3.27e3.33 (m, 2H, CH2), 2.61e2.66 (m, 1H,
To a solution of 29 (8.92 mg, 24.7 mmol) in CH2Cl2 (7 mL) BCl3
(0.1 mL, 1 M solution in n-hexane) was added at ꢀ20 ꢂC. After 2 h of
vigorous stirring the reaction was quenched by addition of MeOH
(2 mL) and the solvent removed in vacuo. Gel chromatography on
Sephadex LH-20 (100% MeOH) followed by final purification by
preparative HPLC gave the desired product as a yellow oil (6.45 mg,
CH2), 2.51e2.56 (m, 1H, CH2). 13C NMR (MeOD)
d 154.8, 154.4, 134.7,
133.0, 132.8, 132.2, 130.0, 128.5, 127.4, 126.4, 126.3, 125.5, 123.7,
116.3, 113.4, 108.4, 42.5, 42.3, 24.9. EI-MS (70 eV) m/z (%): 291 (100)
[M]þ, 262 (27), 247 (11), 231 (8), 215 (9), 145 (10), 126 (20). MS (ESI)
exact mass calcd for C19H17NO2: 292.13321 [M þ H]þ; found:
292.13321 [M þ H]þ.
20.2
m
mol, 82%). IR (KBr, cmꢀ1
)
n
3395, 2958, 2922, 2851,1677, 1459,
9.21 (s, 1H, CH), 7.55 (d,
1410, 1263, 1193, 1132. 1H NMR (MeOD)
d
J ¼ 8.6 Hz,1H, Ar-H), 7.32 (dd, J ¼ 8.3 Hz, J ¼ 8.0 Hz,1H, Ar-H), 7.20 (d,
J ¼ 7.8 Hz, 1H, Ar-H), 7.03 (d, J ¼ 8.7 Hz, 1H, Ar-H), 6.99 (d, J ¼ 6.4 Hz,
1H, Ar-H), 6.97 (d, J ¼ 8.7 Hz, 1H, Ar-H), 6.88 (d, J ¼ 7.8 Hz, 1H, Ar-H),
4.11 (s, 3H, OeCH3), 3.69e3.82 (m, 2H, NeCH2), 2.61e2.80 (m, 2H,
4.3.4. 5-(40-Hydroxy-50-methoxynaphthalen-10-yl)-1,2,3,4-
tetrahydroisoquinolin-8-ol (33)
CeCH2). 13C NMR (MeOD)
d
163.6, 162.6, 158.2, 156.3, 144.4, 138.2,
136.3, 132.5, 130.4, 127.9, 127.5, 119.9, 116.3, 116.2, 113.6, 110.8, 105.8,
56.9, 42.2, 24.0. EI-MS (70 eV) m/z (%):319 (100) [M]þ, 304 (28), 275
(14), 247 (7), 189 (9). MS (ESI) exact mass calcd for C20H17NO3:
320.12812 [M þ H]þ; found: 320.12864 [M þ H]þ.
Colorless solid (9.21 mg, 28.7
IR (KBr, cmꢀ1
3382, 3222, 3030, 2932, 1685, 1611, 1589, 1460,
1425, 1410, 1266, 1200, 1153, 840, 766, 726. 1H NMR (MeOD)
7.26
m
mol, 74%). Mp >200 ꢂC decomp.
)
n
d
(dd, J ¼ 8.7 Hz, J ¼ 7.5 Hz, 1H, Ar-H), 7.14 (d, J ¼ 7.8 Hz, 1H, Ar-H),
7.03 (d, J ¼ 8.2 Hz, 1H, Ar-H), 6.95 (d, J ¼ 8.7 Hz, 1H, Ar-H), 6.95 (d,
J ¼ 7.5 Hz, 1H, Ar-H), 6.85 (d, J ¼ 7.8 Hz, 1H, Ar-H), 6.84 (d, J ¼ 8.2 Hz,
1H, Ar-H), 4.35 (d, J ¼ 16.3 Hz, 1H, CH2), 4.30 (d, J ¼ 16.3 Hz, 1H,
CH2), 4.10 (s, 3H, OeCH3), 3.27e3.31 (m, 2H, CH2), 2.58e2.66 (m,
4.3. General procedure for the reduction of
naphthyldihydroisoquinolines
A solution of the corresponding naphthyldihydroisoquinoline in
an appropriate amount of MeOH was cooled to 0 ꢂC and treated
1H, CH2), 2.46e2.54 (m, 1H, CH2). 13C NMR (MeOD)
d
158.0, 155.6,
154.9,136.6,132.9,132.9,131.9,130.1,129.9,127.3,120.4,116.4,116.3,

5380
G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
113.5, 110.8, 105.5, 56.9, 42.5, 42.2, 24.8. EI-MS (70 eV) m/z (%): 321
(100) [M]þ, 304 (23), 292 (23), 277 (17), 260 (18), 160 (10), 101 (7).
MS (ESI) exact mass calcd for C20H19NO3: 322.14377 [M þ H]þ;
found: 322.14320 [M þ H]þ.
239
m
mol, 68%); mp 75e76 ꢂC (CH2Cl2).
½
a 2D5
ꢃ
¼ ꢀ76:1ꢂ
(c ¼ 0.13 mol/l, MeOH). IR (KBr, cmꢀ1
) n 2973, 2927, 2843, 1612,
1577, 1564, 1454, 1424, 1364, 1345, 1313, 1281, 1250, 1203, 1114,
1088, 1060, 1019, 951, 871, 797, 688, 647, 634, 612. 1H NMR (CDCl3)
d
7.49 (d, 3J ¼ 8.8 Hz, 1H, Ar-H), 6.76 (d, 3J ¼ 8.8 Hz, 1H, Ar-H), 3.85
4.3.5. (R)-3-(N-tert-Butoxycarbonyl-propyl-20-amino)-anisole (35)
A Grignard reagent, freshly prepared from 3-bromoanisole (4)
(9.95 g, 53.2 mmol) and magnesium (9.10 g, 374 mmol) in THF
(45 mL) was cooled to ꢀ30 ꢂC. CuBr$SMe2 (620 mg, 3.02 mmol) was
added in four portions and the mixture was stirred at this temper-
ature for 30 min. After cooling to ꢀ78 ꢂC a solution of 34 (4.56 g,
29.0 mmol) in THF (30 mL) was added over a period of 30 min and
the mixture was allowed to warm up to room temperature over
night. The insoluble components were filtered off and washed with
H2O, Et2O and CH2Cl2. The organic solvents were evaporated and the
remaining aqueous phase extracted with CH2Cl2. The combined
organiclayersweredriedover MgSO4, concentratedinvacuoand the
residue was ingested in n-hexane/2-propanol (100:1) and the
desired product was obtained as beige crystals. The mother liquor
was concentrated and remains of the desired product were purified
by flash chromatography (petroleum ether/ethyl acetate 9:1)
a 25
(s, 3H, OeCH3), 3.31 (m, 1H, CH), 2.91 (dd, 2J ¼ 16.4 Hz, 3J ¼ 4.6 Hz,
1H, CH2), 2.44 (s, 3H, CNCH3), 2.22 (dd, 2J ¼ 16.4 Hz, 3J ¼ 13.1 Hz, 1H,
CH2), 1.40 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (CDCl3)
d 165.7, 158.8,
141.7, 136.8, 123.1, 116.0, 113.7, 57.6, 52.9, 36.1, 28.7, 23.3. EI-MS
(70 eV) m/z (%): 269 (69), 268 [M]þ (55), 267 (100), 266 (47), 254
(68), 252 (61), 239 (20), 237 (19), 224 (23), 173 (26), 132 (17), 115
(29), 103 (20), 102 (22), 44 (16). MS (ESI) exact mass calcd for
C12H15BrNO: 268.03315 [M þ H]þ; found: 268.03314 [M þ H]þ.
4.4. General procedure of the SuzukieMiyaura coupling between
38 and the boronic acids
Pd(PPh3)4 (10 mol%) was added to a degassed mixture of 38
(100 mg), boronic acid (2 equiv.) and 2 M Na2CO3 solution (5 mL) in
toluene (40 mL). After heating up to 80 ꢂC over night, water (15 mL)
was added to the reaction mixture and the aqueous phase was
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, concentrated and purified via column chromatog-
raphy on deactivated silica gel (7.5% NH3, petroleum ether/ethyl
acetate 5:1) giving the biaryl compounds.
(6.36 g, 24.0 mmol, 83%); mp 70e72 (n-hexane/2-propanol). ½ ꢃD
¼
ꢀ93:4ꢂ (c ¼ 0.11 mol/l, MeOH). IR (KBr, cmꢀ1
) n 3384, 3008, 2981,
2968, 2936, 2873, 2841, 1682, 1602, 1514, 1446, 1391, 1366, 1259,
1168, 1057, 1036, 882, 841, 791, 754, 739, 699, 553, 466, 410. 1H NMR
(CDCl3)
d
7.20 (t, 3J ¼ 7.7 Hz, 1H, Ar-H), 6.77 (d, 3J ¼ 8.1 Hz, 1H, Ar-H),
6.76 (d, 3J ¼ 8.1 Hz,1H, Ar-H), 6.72 (dd, 4J ¼ 2.0 Hz, 4J ¼ 1.6 Hz,1H, Ar-
H), 4.37 (s, 1H, NH), 3.92 (m, 1H, CH), 3.80 (s, 3H, OeCH3), 2.82 (dd,
2J ¼ 13.3 Hz, 3J ¼ 5.5 Hz, 1H, CH2), 2.62 (dd, 2J ¼ 13.3 Hz, 3J ¼ 7.4 Hz,
1H, CH2),1.43 (s, 9H, C(CH3)3), 1.08 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13C NMR
4.4.1. (R)-8-Methoxy-1,3-dimethyl-5-phenyl-3,4-
dihydroisoquinoline (39a)
Yellowish oil (60 mg, 0.23 mmol, 77%); ½a D25
ꢃ
¼ ꢀ112ꢂ (0.1 mol/
l). IR (KBr, cmꢀ1
) n 3732, 3628, 3032, 2926, 2852, 1616, 1583, 1474,
(CDCl3)
d
159.6, 155.2, 139.8, 129.2, 121.9, 115.0, 111.8, 79.1, 55.1, 47.3,
1440, 1406, 1368, 1268, 1199, 1153, 1105, 1088, 1064, 1025, 814, 770,
43.0, 28.4, 20.2. EI-MS (70 eV) m/z (%): 265 [M]þ (1),144 (11), 57 (65),
44 (100). Anal. calcd for C15H23NO3 (265.35): C, 67.90; H, 8.74; N,
5.28; found: C, 67.77; H, 8.78; N, 5.52.
738, 702, 668, 649, 638, 623, 614, 605. 1H NMR (CDCl3)
d 7.41e7.25
(m, 6H, Ar-H), 6.91 (d, 3J ¼ 8.5 Hz,1H, Ar-H), 3.89 (s, 3H, OeCH3), 3.16
(m, 1H, CH), 2.56 (dd, 2J ¼ 16.0 Hz, 3J ¼ 4.2 Hz, 1H, CH2), 2.51 (s, 3H,
CNCH3), 2.25 (dd, 2J ¼ 13.3 Hz, 3J ¼ 2.6 Hz, 1H, CH2), 1.30 (d,
4.3.6. (R)-4-Bromo-3-(20-acetamidoprop-10-yl)-anisole (37)
3J ¼ 6.8 Hz, 3H, CH3). 13C NMR (CDCl3)
d 157.0, 140.5, 138.5, 133.1,
A solution of 36 (400 mg, 1.64 mmol) in CH2Cl2 (10 mL) was
cooled to 0 ꢂC. Successively NEt3 (199 mg, 1.96 mmol) and dest.
acetylchloride (142 mg, 1.80 mmol) was added. The reaction
mixture was allowed to warm up to room temperature and stirred
for 1 h. After addition of water (10 mL) the mixture was extracted
with CH2Cl2 and the organic layer dried over Na2SO4. Purification
by column chromatography (CH2Cl2/MeOH 30:1) gave the desired
product as yellow solid (370 mg, 1.29 mmol, 79%); mp. 138e139 ꢂC
132.9,129.6,128.4,127.2,119.9,110.1, 55.7, 52.0, 32.9, 27.7, 22.1. EI-MS
(70 eV) m/z (%): 266 (20), 265 [M]þ (100), 264 (47), 250 (40), 236 (9),
235 (9), 222 (9), 178 (12), 165 (11), 57 (9). MS (ESI) exact mass calcd
for C18H20NO: 266.15394 [M þ H]þ; found: 266.15394 [M þ H]þ.
4.4.2. (R)-8-Methoxy-1,3-dimethyl-5-p-tolyl-3,4-
dihydroisoquinoline (40a)
Yellow oil (98 mg, 0.35 mmol, 78%);
½
a 2D5
ꢃ
¼ ꢀ59:5ꢂ
(CH2Cl2/MeOH). ½a D25
ꢃ
¼ ꢀ5:35ꢂ (c ¼ 0.10 mol/l, MeOH). IR (KBr,
(c ¼ 0.02 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n 2962, 2926,1616,1581,1477,
cmꢀ1
)
n
3429, 3071, 2966, 2837, 1638, 1542, 1458, 1378, 1243, 1167,
1439, 1373, 1346, 1270, 1250, 1198, 1153, 1104, 1087, 1063, 1021, 954,
1127, 1081, 1019, 970, 858, 810, 701, 601, 463, 412. 1H NMR (CDCl3)
875, 808, 724, 689, 632, 620.1H NMR (CDCl3)
d
7.29 (d, 3J ¼ 8.6 Hz,1H,
d
7.38 (d, 3J ¼ 8.8 Hz, 1H, Ar-H), 6.78 (d, 4J ¼ 3.1 Hz, 1H, Ar-H), 6.62
Ar-H), 7.21 (d, 3J ¼ 7.9 Hz,2H,Ar-H), 7.15(d, 3J ¼ 8.1 Hz,2H,Ar-H), 6.88
(d, 3J ¼ 8.6, 1H, Ar-H), 3.13 (m, 1H, CH), 2.57 (dd, 2J ¼ 16.0 Hz,
3J ¼ 4.24 Hz, 1H, CH2), 2.50 (d, 5J ¼ 1.69 Hz, 3H, CNCH3), 2.23 (dd,
(dd, 3J ¼ 8.8 Hz, 4J ¼ 3.1 Hz, 1H, Ar-H), 5.71 (s, 1H, NH), 4.29 (m, 1H,
CH), 3.74 (s, 3H, OeCH3), 2.91 (dd, 2J ¼ 13.2 Hz, 3J ¼ 7.6 Hz, 1H, CH2)
2.82 (dd, 2J ¼ 13.2 Hz, 3J ¼ 7.6 Hz, 1H, CH2), 1.89 (s, 3H, COCH3), 1.17
2J ¼ 13.1 Hz, 3J ¼ 2.7 Hz, 1H, CH2), 1.29 (d, 3J ¼ 6.8 Hz, 3H, CH3). 13
C
(d, 3H, 3J ¼ 6.7 Hz, CH3). 13C NMR (CDCl3)
d
171.3, 160.9, 140.8, 135.2,
NMR (CDCl3) d 164.9, 157.0, 138.4, 137.5, 136.9, 133.0, 129.5, 129.1,
118.5, 117.3, 116.0, 57.4, 48.2, 44.0, 25.4, 22.5. EI-MS (70 eV) m/z (%):
206 (4), 86 (16), 44 (100). Anal. calcd for C12H16BrNO2 (286.16): C,
50.37; H, 5.64; N, 4.89; found: C, 50.16; H, 5.50; N, 4.71.
119.8, 115.6, 110.1, 55.7, 51.9, 32.9, 27.6, 22.0, 21.4. EI-MS (70 eV) m/z
(%): 280 (22), 279 [M]þ (100), 278 (47), 265 (10), 264 (47), 250 (10),
249 (10), 236 (10), 222 (8), 178 (10). MS (ESI) exact mass calcd for
C19H22NO: 280.16959 [M þ H]þ; found: 280.16959 [M þ H]þ.
4.3.7. (R)-5-Bromo-8-methoxy-1,3-dimethyl-3,4-
dihydroisoquinoline (38)
4.4.3. (R)-8-Methoxy-5-(40-methoxyphenyl)-1,3-dimethyl-3,4-
POCl3 (2.51 g, 5.79 mmol) was added to a solution of 37 (100 mg,
dihydroisoquinoline (41a)
349
m
mol) in abs. MeCN (10 mL) and the reaction mixture refluxed
Yellowish oil (29.3 mg, 99.0
m
mol, 87%);
½
a 2D5
ꢃ
¼ ꢀ163ꢂ
for 1.5 h. First water and then 20% NaOH-solution was added.
Afterwards the solvent was removed under reduced pressure and
the residue extracted with CH2Cl2. The crude product was purified
by column chromatography on deactivated silica (7.5% NH3, CH2Cl2)
and the desired compound was obtained as yellow solid (64 mg,
(c ¼ 1.00 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n 2925, 2852, 1615, 1478,
1030. 1H NMR (CDCl3)
d
7.30 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 7.20 (d,
3J ¼ 8.8 Hz, 2H, Ar-H), 6.95 (d, 3J ¼ 8.8 Hz, 2H, Ar-H), 6.90 (d,
3J ¼ 8.6 Hz, 1H, Ar-H), 3.90 (s, 3H, OeCH3), 3.85 (s, 3H, OeCH3), 3.16
(m, 1H, CH), 2.58 (dd, 2J ¼ 16.0 Hz, 3J ¼ 4.2 Hz, 1H, CH2), 2.52 (d,

G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
5381
5J ¼ 1.9 Hz, 3H, CNCH3), 2.24 (dd, 2J ¼ 16.0 Hz, 3J ¼ 13.3 Hz, 1H, CH2),
3J ¼ 6.8 Hz, 3H, CH3). 13C NMR (CDCl3)
d
164.0, 156.9, 139.7, 138.4,
1.31 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (CDCl3)
d
173.4, 164.5, 158.7,
133.7, 133.4, 132.4, 131.2, 128.4, 127.8, 127.6, 127.0, 126.2, 125.9,
125.4, 119.4, 55.5, 51.6, 32.3, 27.7, 21.8. EI-MS (70 eV) m/z (%): 317
(39), 316 (31), 315 [M]þ (78), 314 (58), 313 (100), 304 (36), 303 (46),
302 (30), 300 (41), 288 (36), 286 (29), 257 (30), 215 (32), 202 (32),
189 (18) 57 (31). MS (ESI) exact mass calcd for C19H22NO: 316.16959
[M þ H]þ; found: 316.16961 [M þ H]þ.
156.6, 138.3, 132.4, 132.7, 130.4, 119.7, 113.6, 109.8, 55.5, 55.3, 51.8,
32.7, 27.4, 21.9. EI-MS (70 eV) m/z (%): 296 (26), 295 [M]þ (100), 294
(58), 293 (73), 282 (15), 281 (16), 280 (46), 279 (14), 237 (21), 165
(20), 152 (13), 97 (14), 83 (16), 69 (18). MS (ESI) exact mass calcd for
C22H22NO: 296.16451 [M þ H]þ; found: 296.16454 [M þ H]þ.
4.4.4. (R)-5-(40-Chlorophenyl)-8-methoxy-1,3-dimethyl-3,4-
4.4.8. (R)-8-Methoxy-1,3-dimethyl-5-(naphthalen-2-yl)-3,4-
dihydroisoquinoline (42a)
dihydroisoquinoline (46a)
White solid (29.0 mg, 96.7
m
mol, 83%); mp 114 ꢂC (CH2Cl2/
Bright yellow solid (25.8 mg, 82.0 m
mol, 72%); mp 119 ꢂC (ethyl
MeOH). ½a 2D5
ꢃ
¼ ꢀ123ꢂ (c ¼ 1.00 mol/l, CH2Cl2). IR (KBr, cmꢀ1
)
n
acetate). ½a 2D5
ꢃ
¼ ꢀ129ꢂ (c ¼ 1.00 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n
2925, 2852, 1620, 1475. 1H NMR (CDCl3)
d
7.39 (d, 3J ¼ 8.6 Hz, 2H,
2924, 2852, 1620, 1028, 938, 865. 1H NMR (CDCl3)
d 7.90e7.85 (m,
Ar-H), 7.29 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 7.21 (d, 3J ¼ 8.6 Hz, 2H, Ar-H),
6.92 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 3.91 (s, 3H, OeCH3), 3.19 (m, 1H, CH),
2.53 (d, 5J ¼ 1.9 Hz, 3H, CNCH3), 2.52 (dd, 2J ¼ 15.8 Hz, 3J ¼ 4.2 Hz,
1H, CH2), 2.23 (dd, 2J ¼ 15.8 Hz, 3J ¼ 13.1 Hz, 1H, CH2), 1.32 (d,
3H, Ar-H), 7.74 (s, 1H, Ar-H), 7.52 (m, 2H, Ar-H), 7.43 (m, 2H, Ar-H),
6.96 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 3.93 (s, 3H, OeCH3), 3.18 (m, 1H, CH),
2.62 (dd, 2J ¼ 16.0 Hz, 3J ¼ 4.2 Hz, 1H, CH2), 2.55 (d, 5J ¼ 1.9 Hz, 3H,
CH3), 2.31 (dd, 2J ¼ 16.0 Hz, 3J ¼ 13.3 Hz, 1H, CH2), 1.30 (d,
3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (CDCl3)
d
157.7, 139.3, 138.8, 133.7,
3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (CDCl3)
d 164.3, 156.8, 138.5, 137.8,
133.3, 132.2, 131.4, 129.1, 110.6, 56.2, 52.3, 33.3, 28.1, 22.5. EI-MS
(70 eV) m/z (%): 301 (35), 300 (38), 299 [M]þ (100), 298 (49), 286
(18), 285 (13), 284 (52), 270 (14), 269 (14), 256 (13), 178 (18), 165
(13). MS (ESI) exact mass calcd for C17H18NO: 300.11497 [M þ H]þ;
found: 300.11408 [M þ H]þ.
133.2, 132.8, 132.7, 132.2, 128.0, 127.9, 127.7, 126.3, 126.0, 119.7,
109.8, 55.5, 51.7, 32.7, 27.5, 21.9. EI-MS (70 eV) m/z (%): 315 [M]þ (4),
314 (27), 313 (100), 270 (7), 257 (22), 239 (7), 229 (13), 228 (17), 226
(8), 156 (4), 113 (4). MS (ESI) exact mass calcd for C22H22NO:
316.16959 [M þ H]þ; found: 316.16972 [M þ H]þ.
4.4.5. (R)-8-Methoxy-1,3-dimethyl-5-(40-(trifluoromethyl)phenyl)-
3,4-dihydroisoquinoline (43a)
White solid (105 mg, 0.31 mmol, 84%); mp 123 ꢂC (CH2Cl2/
4.5. General procedure of O-demethylation of 39ae46a using BBr3
MeOH). ½a 2D5
ꢃ
¼ ꢀ127ꢂ (c ¼ 0.01 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n
2952, 2896, 2845, 1735, 1616, 1585, 1565, 1523, 1478, 1442, 1420,
1399, 1368, 1323, 1286, 1270, 1196, 1170, 1153, 1113, 1095, 1068,
1043,1017, 964, 942, 924, 905, 876, 857, 812, 766, 748, 710, 683, 664,
BBr3 (0.25 mL, 1 M solution in n-hexane, 5 equiv.) was added to
a solution of the isoquinoline in CH2Cl2 (6 mL) at 0 ꢂC. After stirring
at 0 ꢂC for 5 h the mixtures were warmed to room temperature and
stirred for additional 24 h. Then MeOH (5 mL) was added and the
solvent removed under reduced pressure. The residue was
submitted to column chromatography on deactivated silica (7.5%
NH3, CH2Cl2/MeOH 15:1 to 12:1).
621. 1H NMR (CDCl3)
d
7.66 (d, 3J ¼ 8.0 Hz, 2H, Ar-H), 7.38 (d, 3J ¼ 7.9,
2H, Ar-H), 7.28 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 6.92 (d, 3J ¼ 8.6 Hz, 1H, Ar-
H), 3.90 (s, 3H, OeCH3), 3.13 (m, 1H, CH), 2.49 (d, 5J ¼ 2.0 Hz, 3H,
CNCH3), 2.49 (dd, 2J ¼ 15.9 Hz, 3J ¼ 4.2, 1H, CH2), 2.22 (dd,
2J ¼ 13.2 Hz, 3J ¼ 2.7 Hz, 1H, CH2), 1.29 (d, 3J ¼ 6.8 Hz, 3H, CH3). 13
C
NMR (CDCl3)
d
157.4, 144.2, 138.5, 132.6, 131.6, 129.9, 129.5, 129.2,
4.5.1. (R)-1,3-Dimethyl-5-phenyl-3,4-dihydroisoquinolin-8-ol
125.4, 120.1, 110.2, 55.7, 51.9, 32.8, 27.7, 22.2. EI-MS (70 eV) m/z (%):
334 (23), 333 [M]þ (100), 332 (41), 331 (12), 320 (33), 319 (14), 318
(70), 304 (14), 303 (11), 290 (15), 275 (10). MS (ESI) exact mass calcd
for C19H19F3NO: 334.14133 [M þ H]þ; found: 334.14118 [M þ H]þ.
(39b)
Yellowish oil (27 mg, 0.11 mmol, 73%);
½
a 2D5
ꢃ
¼ 99:8ꢂ
(c ¼ 0.02 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n 2974, 2927, 2363, 2160,
2001, 1716, 1610, 1528, 1472, 1451, 1426, 1364, 1340, 1303, 1279,
1229, 1206, 1180, 1161, 1076, 1046, 1023, 877, 829, 773, 756, 735,
4.4.6. (R)-5-(3-Chlorophenyl)-8-methoxy-1,3-dimethyl-3,4-
703, 674, 622, 611. 1H NMR (CDCl3)
d 7.39e7.18 (m, 6H, Ar-H), 6.78
dihydroisoquinoline (44a)
(d, 3J ¼ 8.8 Hz, 1H, Ar-H), 3.54e3.48 (m, 1H, CH), 2.83 (d, 4J ¼ 1.4 Hz,
3H, CNCH3), 2.75 (dd, 2J ¼ 16.0 Hz, 3J ¼ 4.5 Hz, 1H, CH2), 2.48 (dd,
2J ¼ 16.0 Hz, 3J ¼ 11.4 Hz, 1H, CH2), 1.33 (d, 3J ¼ 6.7, 3H, CH3). 13C
Yellowish oil (53 mg, 0.18 mmol, 64%);
½
a 2D5
ꢃ
¼ 104ꢂ
(c ¼ 0.1 mol/l). IR (KBr, cmꢀ1
) n 2927, 1614, 1453, 1398, 1323, 1267,
1234,1197,1133,1109,1075, 973, 838, 803, 764, 697. 1H NMR (CDCl3)
NMR (CDCl3) d 171.5, 168.2, 140.9, 137.3, 135.1, 129.7, 128.4, 127.1,
d
7.38e7.29 (m, 3H, Ar-H), 7.25 (m, 1H, Ar-H), 7.12 (m, 1H, Ar-H),
126.7, 120.6, 115.7, 49.5, 33.2, 25.3, 19.9. EI-MS (70 eV) m/z (%): 251
[M]þ (4), 91 (16), 83 (10), 70 (12), 69 (15), 67 (10), 57 (17), 44 (90),
43 (20), 41 (31). MS (ESI) exact mass calcd for C17H18NO: 252.13829
[M þ H]þ; found: 252.13829 [M þ H]þ.
6.91 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 3.89 (s, 3H, OeCH3), 3.17 (m, 1H, CH),
2.57 (s, 3H, CNCH3), 2.56 (m, 1H, CH2), 2.27 (dd, 2J ¼ 15.5 Hz,
3J ¼ 12.5 Hz, 1H, CH2), 13C NMR (CDCl3)
d 142.2, 138.3, 134.4, 133.2,
131.8, 129.7, 129.6, 129.6, 129.5, 127.8, 127.5, 127.4, 119.7, 110.2, 109.0,
55.8, 51.6, 32.7, 27.4, 21.7. EI-MS (70 eV) m/z (%): 302 (7), 301 (35),
300 (36), 299 [M]þ (100), 298 (50), 286 (18), 285 (11), 284 (47), 270
(12), 269 (12), 256 (12), 243 (6). MS (ESI) exact mass calcd for
C18H19NO: 300.11497 [M þ H]þ; found: 300.11497 [M þ H]þ.
4.5.2. (R)-1,3-Dimethyl-5-p-tolyl-3,4-dihydroisoquinolin-8-ol
(40b)
a 2D5
Yellowish oil (10 mg, 37.7
m
mol, 72%);
½
ꢃ
¼ 43:2ꢂ
(c ¼ 0.02 mol/l, CH2Cl2). IR (KBr, cmꢀ1
) n 2923, 2363,1611,1440,1301,
1203, 1019, 816, 698, 643, 632, 612. 1H NMR (CDCl3)
d 7.18e7.10 (m,
4.4.7. (R)-8-Methoxy-1,3-dimethyl-5-(naphthalen-1-yl)-3,4-
dihydroisoquinoline (45a)
5H, Ar-H), 6.77 (d, 3J ¼ 8.8 Hz,1H, Ar-H), 3.47 (m,1H, CH), 2.80 (s, 3H,
CH3), 2.74 (dd, 2J ¼ 16.1 Hz, 3J ¼ 4.6 Hz, 1H, CH2), 2.45 (dd,
2J ¼ 16.0 Hz, 3J ¼ 11.6 Hz, 1H, CH2), 2.37 (s, 3H, CH3), 1.31 (d,
Yellowish oil (28.7 mg, 91.0
m
mol, 78%);
½
a 2D5
ꢃ
¼ ꢀ129ꢂ
(c ¼ 1.00 mol/l, CH2Cl2). IR (KBr, cmꢀ1
)
n
2925, 2853, 1618, 1277,
3J ¼ 4.8 Hz, 3H, CH3). 13C NMR (CDCl3)
¼ 171.3, 168.1, 138.0, 137.4,
d
1022, 938. 1H NMR (CDCl3)
d
7.93e7.88 (m, 2H, Ar-H), 7.55e7.46 (m,
136.4,135.1,129.6,129.1,127.2,120.7,115.6, 49.6, 33.2, 25.4, 21.3, 20.0.
EI-MS (70 eV) m/z (%): 266 (21), 265 [M]þ (100), 264 (37), 250 (21),
237 (21), 236 (10), 178 (10), 165 (8). MS (ESI) exact mass calcd for
C18H20NO: 266.15394 [M þ H]þ; found: 266.15394 [M þ H]þ.
3H, Ar-H), 7.43e7.28 (m, 3H, Ar-H), 6.89 (d, 3J ¼ 8.5 Hz, 1H, Ar-H),
3.96 (s, 3H, OeCH3), 3.28e3.15 (m, 1H, CH), 2.58 (d, 5J ¼ 1.9 Hz, 3H,
CNCH3), 2.26e2.15 (m, 1H, CH2), 2.07e1.93 (m, 1H, CH2), 1.20 (d,

5382
G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
4.5.3. (R)-5-(4-Hydroxyphenyl)-1,3-dimethyl-3,4-
dihydroisoquinolin-8-ol (41b)
3424, 2924, 2852,1633, 1026, 857, 698. 1H NMR (MeOD)
d 7.89e7.90
(m, 2H, Ar-H), 7.56e7.27 (m, 6H, Ar-H), 7.10 (d, 3J ¼ 8.6 Hz, 1H, Ar-
H), 3.85 (m, 1H, CH), 2.96 (s, 3H, CNCH3), 2.66 (dd, 2J ¼ 16.7 Hz,
3J ¼ 5.3 Hz, 1H, CH2), 2.44 (dd, 2J ¼ 16.7 Hz, 3J ¼ 10.9 Hz, 1H, CH2),
Yellowish oil (15.4 mg, 57.6
m
mol, 67%);
½
a 2D5
ꢃ
¼ 101ꢂ
(c ¼ 1.00 mol/l, CH2Cl2/MeOH). IR (KBr, cmꢀ1
) n 3430, 2925, 2853,
2360, 1632, 1026. 1H NMR (MeOD)
d
7.52 (d, 3J ¼ 8.6 Hz, 1H, Ar-H),
1.28 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (MeOD)
d
¼ 178.6, 162.6,
7.10 (d, 3J ¼ 8.6 Hz, 2H, Ar-H), 6.99 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 6.85 (d,
3J ¼ 8.6 Hz, 2H, Ar-H), 3.84 (m, 1H, CH), 2.99 (dd, 1H, 2J ¼ 16.7 Hz,
3J ¼ 5.1 Hz, 1H, CH2), 2.90 (d, 5J ¼ 1.5 Hz, 3H, CNCH3), 2.80 (dd,
142.0, 138.6, 138.6, 138.0, 135.3, 133.4, 132.2, 129.7, 128.9, 127.8,
127.3, 126.6, 126.4, 117.5, 114.4, 50.0, 32.9, 25.2, 17.9. EI-MS (70 eV)
m/z (%): 302 (5), 301 [M]þ (2), 289 (27), 288 (100), 259 (6), 231 (8),
215 (6), 202 (6), 136 (6). MS (ESI) exact mass calcd for C21H20NO:
302.15394 [M þ H]þ; found: 302.15409 [M þ H]þ.
2J ¼ 16.7 Hz, 3J ¼ 11.6 Hz, 1H, CH2), 1.38 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13
C
NMR (MeOD)
d
¼ 178.9, 162.0, 158.4, 141.6, 137.2, 134.1, 131.7, 131.4,
117.4, 116.5, 114.5, 55.0, 33.2, 25.1, 18.2. EI-MS (70 eV) m/z (%): 268
(22), 267 [M]þ (100), 266 (41), 254 (19), 252 (18), 239 (23), 238 (12),
165 (10), 81 (10). MS (ESI) exact mass calcd for C17H18NO2:
268.13321 [M þ H]þ; found: 268.13266 [M þ H]þ.
4.5.8. (R)-1,3-Dimethyl-5-(naphthalen-2-yl)-3,4-
dihydroisoquinolin-8-ol (46b)
Yellowish solid (20.3 mg, 67.5 m
mol, 99%); mp 235 ꢂC (CH2Cl2/
MeOH). ½a 2D5
ꢃ
¼ 41ꢂ (c ¼ 1.00 mol/l, CH2Cl2/MeOH). IR (KBr, cmꢀ1
) n
4.5.4. (R)-5-(4-Chlorophenyl)-1,3-dimethyl-3,4-
3430, 2924, 2851, 2359, 1633, 1028. 1H NMR (MeOD)
d 7.93e7.80 (m,
dihydroisoquinolin-8-ol (42b)
3H, Ar-H), 7.73 (s, 1H, Ar-H), 7.61 (d, 3J ¼ 8.7 Hz, 1H, Ar-H), 7.53e7.43
(m, 2H, Ar-H), 7.37 (dd, 3J ¼ 8.3 Hz, 4J ¼ 1.5 Hz, 1H, Ar-H), 7.04 (d,
3J ¼ 8.5 Hz, 1H, Ar-H), 3.82 (m, 1H, CH), 2.97 (dd, 2J ¼ 16.8 Hz,
3J ¼ 5.2 Hz, 1H, CH2), 2.90 (s, 3H, CNCH3), 2.84 (dd, 2J ¼ 16.8 Hz,
3J ¼ 11.6 Hz, 1H, CH2), 1.32 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (MeOD)
Bright yellow solid (10.2 mg, 35.7 m
mol, 99%); mp 115 ꢂC (CH2Cl2/
MeOH). ½a 2D5
ꢃ
¼ 22ꢂ (c ¼ 1.00 mol/l, CH2Cl2/MeOH4:1). IR(KBr, cmꢀ1
)
n
3418, 2925, 2854, 1385, 1027. 1H NMR (CD3COCD3)
d 7.54 (d,
3J ¼ 8.6 Hz,1H, Ar-H),7.45(d, 3J ¼ 8.6 Hz,2H,Ar-H),7.29(d, 3J ¼ 8.6 Hz,
2H, Ar-H), 7.04 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 3.30 (m, 1H, CH), 2.62 (s, 3H,
CNCH3), 2.63 (dd, 2J ¼ 12.7 Hz, 3J ¼ 4.3 Hz, 1H, CH2), 2.33 (dd,
2J ¼ 12.6 Hz, 3J ¼ 3.2 Hz, 1H, CH2), 1.27 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13C
d
¼ 178.8,162.3,141.4,137.4,137.7,134.7,134.1,133.9,129.4,129.3,129.1,
128.8,128.3,127.7,127.5,117.5,114.5, 50.1, 33.1, 25.1,18.0. EI-MS (70 eV)
m/z (%): 303 (40), 302 (91), 301 [M]þ (100), 300 (32), 287 (10), 286 (13),
274 (14), 273 (19), 228(11), 215 (13), 202(11). MS (ESI) exact mass calcd
for C21H20NO: 302.15394 [M þ H]þ; found: 302.15336 [M þ H]þ.
NMR (MeOD)
d
¼ 178.7, 162.4, 141.1, 139.0, 137.4, 134.8, 132.6, 114.5,
132.1,129.8,117.5, 50.2, 33.0,30.8,18.0.EI-MS(70 eV)m/z(%):287(27),
286 (29), 285 [M]þ (79), 283 (100), 272 (43), 269 (18), 257 (20), 178
(20), 97 (22), 83 (23), 69 (30), 57 (43). MS (ESI) exact mass calcd for
C17H17ClNO: 286.09932 [M þ H]þ; found: 286.09949 [M þ H]þ.
4.6. Biological tests
In vitro assays (in Basel) with T. brucei rhodesiense STIB900,
P. falciparum K1, T. cruzi Tulahuen Lac Z C4 strain, L. donovani axenic
amastigotes, and rat skeletal myoblast (L6) cells were carried out as
previously reported [51]. IC50 values are means of two independent
assays. Individual measurement differed less than 50%. In vitro
assays (in Würzburg) with L. major promastigotes, T. brucei brucei,
and J774.1 macrophages were assessed as described earlier [9,12].
In the in vivo studies each treatment group includes three mice.
Infected and not treated mice die between day 6 and 8 post
infection. The chloroquine-treated group (4 ꢁ10 mg/kg i.p.)
showed an activity of 99.6% and a mean survival time of 20 days.
Compound 44b did not show toxicity at the tested dose.
4.5.5. (R)-1,3-Dimethyl-5-(4-(trifluoromethyl)phenyl)-3,4-
dihydroisoquinolin-8-ol (43b)
Yellow oil (92 mg, 28.8 mmol, 93%); ½a D25
ꢃ
¼ 29:2ꢂ (c ¼ 0.01 mol/
l, CH2Cl2). IR (KBr, cmꢀ1
) n 2964, 1720, 1612, 1520, 1434, 1324, 1279,
1163, 1124, 1070, 1017, 829, 618, 607. 1H NMR (CD3COCD3)
d 7.75 (d,
3J ¼ 8.1 Hz, 2H, Ar-H), 7.53 (d, 3J ¼ 7.9 Hz, 2H, Ar-H), 7.22 (d,
3J ¼ 8.7 Hz, 1H, Ar-H), 6.93 (d, 3J ¼ 8.6 Hz, 1H, Ar-H), 3.28 (m, 1H,
CH), 2.62 (dd, 2J ¼ 13.3 Hz, 3J ¼ 4.4 Hz, 1H, CH2), 2.60 (s, 3H, CNCH3),
2.35 (dd, 2J ¼ 14.0 Hz, 3J ¼ 9.8 Hz, 1H, CH2), 1.26 (d, 3J ¼ 5.4 Hz, 3H,
CH3). 13C NMR (CD3COCD3)
d 166.9, 146.6, 146.0, 137.8, 135.1, 131.1,
130.5, 130.2, 129.4, 128.8, 128.4, 126.0, 118.8, 117.5, 51.6, 33.5, 26.8,
21.5. EI-MS (70 eV) m/z (%): 319 [M]þ (27), 318 (11), 291 (7), 175 (5),
149 (10), 70 (11), 63 (15), 43 (100). MS (ESI) exact mass calcd for
C18H17F3NO: 320.12568 [M þ H]þ; found: 320.12569 [M þ H]þ.
4.7. Methods
4.7.1. Data set
4.5.6. (R)-5-(3-Chlorophenyl)-1,3-dimethyl-3,4-
dihydroisoquinolin-8-ol (44b)
Compound 29 was sketched in MOE (Version 2009.10, Chemical
Computing Group) and afterwards the geometry was optimized
using the default MOE force field (MMFF94ꢁ) with default
parameters. This compound was used as a template for all other
compounds, which were obtained by modifying the template
accordingly. The basic amino function in 32 and 33 was used in its
protonated form since this would resemble the protonation state
under physiological conditions. The modified parts of each mole-
cule were subjected to a renewed geometry optimization while the
common substructure with 29 was kept fixed. Since all compounds
show a substantial maximum common substructure, this proce-
dure was found to work well. It resulted in a data set that was
implicitly superimposed since it was based on the same template.
Yellowish oil (19.0 mg, 66.5
m
mol, 69%);
) n 3651, 3639, 2982, 1969,
½
a 2D5
ꢃ
¼ 133ꢂ
(c ¼ 0.01 mol/l, CH2Cl2). IR (KBr, cmꢀ1
1591, 1562, 1524, 1422, 1361, 1339, 1298, 1204, 1157, 1076, 1043,
1004, 879, 825, 785, 763, 729, 700, 645, 626, 606. 1H NMR (CDCl3)
d
7.28e7.21 (m, 3H, Ar-H), 7.14e7.08 (m, 2H, Ar-H), 6.76 (d,
3J ¼ 8.8 Hz,1H, Ar-H), 3.50 (m,1H, CH), 2.81 (s, 3H, CNCH3), 2.71 (dd,
2J ¼ 16.0 Hz, 3J ¼ 4.6 Hz, 1H, CH2), 2.45 (dd, 2J ¼ 16.0 Hz, 3J ¼ 11.4 Hz,
1H, CH2), 1.32 (d, 3J ¼ 6.7 Hz, 3H, CH3). 13C NMR (CDCl3)
d 142.7,
137.4, 135.1, 134.2, 130.3, 129.7, 129.6, 128.4, 127.9, 126.9, 125.5,
121.3, 115.3, 49.3, 33.1, 25.3, 19.8. EI-MS (70 eV) m/z (%): 287 (34),
286 (32), 285 [M]þ (100), 270 (19), 257 (29), 256 (14), 179 (11), 178
(22), 176 (10), 165 (17), 152 (13). MS (ESI) exact mass calcd for
C17H17ClNO: 286.09932 [M þ H]þ; found: 286.09987 [M þ H]þ.
4.7.2. GRID/PLS
The aforementioned data set was input into GRID (Version 22a,
Molecular Discovery) using a grid spacing of 1 Å and a grid size that
extended the superimposed molecules by 4 Å in each dimension.
Molecular-interaction fields (MIF) for the following probes were
computed: N1, O, C3, and DRY. The energy cut-off was set to 0 kcal/
4.5.7. (R)-1,3-Dimethyl-5-(naphthalen-1-yl)-3,4-
dihydroisoquinolin-8-ol (45b)
Yellow solid (23.8 mg, 79.0 m
mol, 99%); mp 202 ꢂC (CH2Cl2/
MeOH) ½a 2D5
ꢃ
¼ 13ꢂ (c ¼ 1.00 mol/l, CH2Cl2/MeOH). IR (KBr, cmꢀ1
) n

G. Bringmann et al. / European Journal of Medicinal Chemistry 45 (2010) 5370e5383
5383
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A. Stich, J. Morschhäuser, U. Hentschel, W. Ziebuhr, Patent WO2008037482A1
(2007).
[13] A. Ponte-Sucre, T. Gulder, T.A.M. Gulder, G. Vollmers, G. Bringmann, H. Moll,
J. Med. Microbiol. 59 (2010) 69e75.
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(2007) 188e194.
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G.W. Kirby, R.E. Moore, C. Tamm (Eds.), Prog. Chem. Org. Nat. Prod., vol. 82,
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mol (i.e. GRID directive EMAX ¼ 0). The MIFs for each probe were
scaled blockwise to assure that each MIF showed equal variance. The
scaled MIFs were arranged to obtain one matrix of the dimension
28 ꢁ 26,928. This matrix was thinned by only using those columns
that showed the top 1% variance. The thinned matrix was related to
bioactivity using partial least squares regression (PLS), where the
optimal number of PLS factors was determined by leave-one-out
cross-validation. Test set predictivity was assessed using leave-
multiple out cross-validation in an outer loop [52], i.e., in the outer
loop three test set objects were set aside. The remaining 25 molecules
were used to form the GRID/PLS model. After all model parameters
were estimated, the test set objects were predicted, which assured
that the test set prediction was independent of the model selection.
100 partitions into test and training data set were computed to obtain
a reliable estimate of test set predictivity. The ensemble average based
on the 100 cross-validation runs was computed for the left out
objects. All statistical figures of merit as well as the residual plot are
based on these ensemble averages for the test objects [53]. Back-
projection of the MIFs onto the molecules was done in the standard
fashion by multiplying the PLS regression coefficients by the standard
deviation of the respective column of the MIF. Displayed are the
results of the O probe at a cut-off level of ꢄ0.011.
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This work was supported by the Deutsche Forschungsgemeinschaft
(Br 699/14e2; SFB 630 “Recognition, Preparation, and Functional
Analysis of Agentsagainst Infectious Diseases”,projectsA2,B3,andZ1),
the Fonds der Chemischen Industrie (fellowship toT. Gulder and funds)
and the Hochschul- und Wissenschaftsprogramm of the University of
Würzburg (fellowship to T. Gulder). We thank Dr. M. Grüne and E.
Ruckdeschel for the NMR experiments, Dr. M. Büchner and F. Dadrich
for the mass spectra, J. Rath and M. Schultheis for performing the
biological tests, Dr. T. Ölschläger for supervising the biological testing,
and Dr. H. Bruhn for the quality management.
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