Potent in vitro methicillin-resistant Staphylococcus aureus activity of 2-(1H-indol-3-yl)tetrahydroquinoline derivatives

Article abstract of DOI:10.1016/S0960-894X(01)00714-4

Novel antibacterials agents, 2-(1H-indol-3-yl)tetrahydroquinolines, were prepared using hetero Diels-Alder chemistry and found to be effective in vitro against methicillin-resistant Staphylococcus aureus (MRSA). A structure-activity relationship (SAR) study was conducted to determine the important features of this series and to increase the potency of these compounds. Compounds were prepared that had minimum inhibitory concentrations (MIC's) < 1.0 μg/mL against MRSA, but had no activity versus vancomycin-resistant Enterococcus (VRE).

Full text of DOI:10.1016/S0960-894X(01)00714-4

Bioorganic & Medicinal Chemistry Letters 12 (2002) 129–132
Potent In Vitro Methicillin-Resistant Staphylococcus aureus
Activity of 2-(1H-indol-3-yl)tetrahydroquinoline Derivatives
Michael Z. Hoemann,* Roger L. Xie, Richard F. Rossi, Sylvia Meyer, Alban Sidhu,
Gregory D. Cuny and James R. Hauske
Sepracor Inc., 111 Locke Dr., Marlborough, MA 01752, USA
Received 20 August 2001; accepted 4 October 2001
Abstract—Novel antibacterials agents, 2-(1H-indol-3-yl)tetrahydroquinolines, were prepared using hetero Diels–Alder chemistry
and found to be effective in vitro against methicillin-resistant Staphylococcus aureus (MRSA). A structure–activity relationship
(SAR) study was conducted to determine the important features of this series and to increase the potency of these compounds.
Compounds were prepared that had minimum inhibitory concentrations (MIC’s) < 1.0 mg/mL against MRSA, but had no activity
versus vancomycin-resistant Enterococcus (VRE). # 2002 Elsevier Science Ltd. All rights reserved.
We recently published on a group of novel antibacterial
agents effective versus resistant strains of Gram-positive
bacteria.1 The 2-(1H-indol-3-yl)quinolines were shown
to be effective in vitro versus methicillin-resistant Sta-
phylococcus aureus (MRSA), glycopeptide intermediate-
resistant S. aureus (GISA) and in some cases vancomy-
cin-resistant Enterococcus (VRE). These compounds
also exhibited promising in vivo activity and have dis-
played an interesting mechanism of action profile.2
During the course of our study, a new series of sub-
stituted 2-(1H-indol-3-yl)tetrahydroquinolines was pre-
pared and found to also possess antibacterial activity.
We now wish to report on the activity of these novel
compounds as well as discuss some of the unique struc-
ture–activity relationships (SARs) associated with this
series.
The 2-(1H-indol-3-yl)tetrahydroquinolines were readily
accessible utilizing hetero Diels–Alder chemistry devel-
oped by Kobayashi.3 Treatment of 4-chloroaniline, N-
Boc-5-bromoindol-3-yl carboxaldehyde and dihy-
drofuran with ytterbium triflate in acetonitrile in the
presence of molecular sieves at ambient temperature
afforded the protected tetrahydroquinolines 1 and 2 in
good yield as a 2:1 mixture of diastereomers (Scheme
1).4 Removal of the Boc protecting group from the
indole proved to be problematic due to the instability of
the ring system to acidic conditions. Instead, the tri-
methylsilylethylcarbamate (Teoc) protected cis- and
trans-diastereomers, 3 and 4, were prepared. The Teoc
protecting groups were readily removed with tetra-
butylammonium fluoride to give the cis- and trans-2-
(1H-indol-3-yl)tetrahydroquinolines, 5 and 6, in good
yield, respectively.5 The relative stereochemistry of all of
1
One of the concerns with the original 2-(1H-indol-3-
yl)quinolines was their high logP values leading to poor
solubility and high protein binding in plasma. It was
envisioned that reducing the core ring from a quinoline
to a tetrahydroquinoline, and thereby introducing a
more basic nitrogen, could lower the logP (compound
15, calcd LogP=3.56; compound 39 calcd LogP=4.19)
of these compounds and lead to more soluble com-
pounds with lower protein binding.
the compounds was assigned by comparison of the H
NMR and 13CNMR spectra with compounds 5 and 6.6
The C-4 proton was very different in chemical shift and
coupling constant for the cis- and trans-isomers (cis-5 d
5.16 ppm, J=8.1 Hz, trans-6 d 4.51 ppm, J=4.8 Hz). In
the case of 3-substituted anilines, two regioisomers were
obtained from the reaction. Both the 5-chloro and 7-
chlorotetrahydroquinolines were isolated from the
reaction of 3-chloroaniline with the 7-chloro product
being the major. The regioisomers and diastereomers
were separated by flash chromatography and the rela-
tive stereochemistry and regiochemistry of the cis-dia-
stereomer 9 was confirmed by X-ray crystallography
(Fig. 1).7
*Corresponding author. Fax: +1-508-481-7683; e-mail: mhoemann@
sepracor.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00714-4

130
M. Z. Hoemann et al. / Bioorg. Med. Chem. Lett. 12 (2002) 129–132
This reaction worked remarkably well with most acti-
vated olefins examined. Interestingly, when dihy-
dropyran was utilized in this reaction, only one product,
the cis-isomer 11 was isolated in modest yield (Scheme
2). With Teoc protected dihydropyrrole, the reaction
behaved in a similar manner to the dihydrofuran reac-
tion with a 2:1 ratio of cis- to trans-isomers, 13 and 14,
respectively (Scheme 3). For the deprotection of these
two compounds, one Teoc group came off at room
temperature while the second required refluxing condi-
tions to give the pyrrolidine products 15 and 16 in good
yield.
Substitution of an alkyne group at the 6-position of the
tetrahydroquinoline was accomplished via a palladium
mediated coupling of 4-iodoaniline with the appropriate
alkyne prior to the hetero Diels–Alder reaction.
Attempts to introduce the alkyne group after cyclization
from various substituted 6-iodotetrahydroquinolines via
palladium mediated couplings were unsuccessful. A
representative example for the preparation of the cis-
and trans-piperidyl alkynes 17 and 18 is shown below
(Scheme 4).
Scheme 1. (a) Yb(OTf)3, 4 A molecular sieves, MeCN, rt, 24 h (75%);
(b) TBAF, THF, rt, 12 h (80%).
Scheme 2. (a) Yb(OTf)3, 4 A molecular sieves, MeCN, rt, 24 h (50%);
(b) TBAF, THF, rt, 12 h (65%).
Figure 1. Chem 3D drawing of the X-ray crystal structure of com-
pound 9 showing the all cis stereochemistry on the tetrahydroquino-
line ring.
Scheme 3. (a) Yb(OTf)3, 4 A molecular sieves, MeCN, rt, 24 h (60%);
(b) TBAF, THF, Á, 12 h (65%).

M. Z. Hoemann et al. / Bioorg. Med. Chem. Lett. 12 (2002) 129–132
131
The SARs defined around the tetrahydroquinoline ser-
ies could be divided into four different aspects: (i) the
substitution of the indole portion, (ii) the stereo-
chemistry of the tetrahydroquinoline, (iii) the substitu-
tion on the tetrahydroquinoline and (iv) the ring fused
to the 3,4-position of the tetrahydroquinoline.
all had measurable activities, but were less potent. The
only substitution that was not tolerated was methyl-
ation of the tetrahydroquinoline nitrogen (Table 3). The
N-methyl derivative 35 was devoid of activity.
The ring fused to the 3,4-position of the tetra-
hydroquinoline could be modified and activity retained
(Table 4). For example, the tetrahydropyran 36 was
equally potent as the corresponding tetrahydrofuran 5.
However, changing the oxygen to a nitrogen, even when
the nitrogen was non-basic, led to diminished activity.
The effect on activity by the substituent on the indole
ring paralleled the original 2-(1H-indol-3-yl)quinoline
series (Table 1).8 A halogen is required in the 5-position
of the indole with 5-bromoindole being optimal.
In all but one case, the cis-isomer was found to be more
potent than the corresponding trans-isomer. For exam-
ple, the cis-isomer 5 was a full log-fold more active than
its trans-isomer 6.
One interesting aspect of the original 2-(1H-indol-3-
yl)quinoline series was that the activity versus VRE
seems to require the presence of a basic amine spaced
with a linker some distance off of the 4-position of the
quinoline. All of the compounds in the quinoline series,
The SARs around the substituents on the tetra-
hydroquinoline ring did not seem to have as dramatic
an effect as the indole ring, but some trends were evi-
dent (Table 2). Substitution with a halogen at the 6-
position was preferred with the 6-chloro (MIC=0.31
mg/mL) and 6-iodo (MIC < 0.39 mg/mL) derivatives, 5
and 26, being the most potent. The electron rich 6-OMe
derivative 33 and the alkynyl derivatives, (17, 32 and 34)
Table 2. Structure–activity relationships around the tetra-
hydroquinoline portion
Compd
R
MIC (mg/mL) Compd
MRSA
R
MIC (mg/mL)
MRSA
26
5
9
27
28
29
6-I
6-Cl
8-Cl
6-F
8-F
6-CF3
< 0.39
0.31
3.13
0.78
6.25
30
31
32
17
33
34
5,7-diCl
6,8-diCl
R1
1.56
1.56
3.13
1.56
1.56
12.5
R2
OMe
R3
0.78
Scheme 4. (a) Propargyl bromide, piperidine, Pd(PPh3)4, CuI, 45 ꢀC,
18 h.
Table 3. Structure–activity relationships around the ring fused to the
3,4-position of the tetrahydroquinoline
Table 1. Structure–activity relationships around the indole portion
and relative stereochemistry of the tetrahydroquinoline
Compd
R
Isomer
MIC (mg/mL)
MRSA
5
5-Br
5-Cl
H
6-F
2-Me
5-Br
5-Cl
H
cis
cis
cis
cis
0.31
0.78
>25
6.25
>25
3.13
3.13
6.25
12.5
19
20
21
22
6
23
24
25
Compd
MIC (mg/mL)
MRSA
Compd
MIC (mg/mL)
MRSA
cis
trans
trans
trans
trans
35
36
37
>25
<39
0.78
38
15
16
1.56
3.13
6.25
6-F

132
M. Z. Hoemann et al. / Bioorg. Med. Chem. Lett. 12 (2002) 129–132
Table 4. In vitro potency versus vancomycin-resistant Enterococcus
faecium (VRE)
40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, Toronto, ON, Sept 17–20, 2000; American
Society for Microbiology: Washington, DC, 2000, Paper #
2180. (b) Oliva, B.; Cuny, G. D.; Hoemann, M. Z.; Hauske,
J. R.; Chopra, I. Abstracts of Papers, 40th Interscience
Conference on Antimicrobial Agents and Chemotherapy,
Toronto, ON, Sept 17–20, 2000; American Society for Micro-
biology: Washington, DC, 2000, Paper # 2181.
3. (a) Kobayashi, S.; Ishitani, H.; Nagayama, S. Chem. Lett.
1995, 423. (b) Kobayashi, S.; Ishitani, H.; Nagayama, S.
Synthesis 1995, 1195.
Compd
MIC (mg/mL)
MRSA
MIC( mg/mL)
VRE
4. General procedure: cis-5 and trans-6. To a solution of 4-
chloroaniline (4.19 mmol) and N-Teoc-5-bromoindol-3-yl
carboxaldehyde (4.19 mmol) in 20 mL of acetonitrile was
added 4 A molecular sieves (1.05 g), ytterbium triflate (0.4
mmol), and enol ether (8.37 mmol). The reaction mixture
was stirred for 12 h at 20 ꢀC. The reaction mixture was
diluted with DCM (50 mL) and filtered through Celite. The
filter pad was washed with DCM (100 mL) and the com-
bined organics concentrated in vacuo. The crude solid was
purified by flash chromatography (silica gel, hexanes/EtOAc
10:1) to give both the cis-3 and trans-4 separately in a 2:1
ratio (74% yield). To a solution of cis-3 (0.91 mmol) in
THF 10 mL was added 1.0 M TBAF in THF (1.1 mmol).
The reaction was stirred for 1 h at 20 ꢀC. The reaction
mixture was diluted with DCM (25 mL) and washed with
satd NH4Cl (25 mL), dried (MgSO4), filtered and con-
centrated in vacuo. The crude solid was purified by flash
chromatography (silica gel, DCM/MeOH 20:1) to give cis-5
(80% yield). The trans-6 isomer was deprotected in an
identical procedure (80% yield).
39
40
15
16
0.78
0.60
3.13
6.25
1.56
>25
>25
>25
lacking such an amine, were devoid of activity versus
VRE (MIC’s>25 mg/mL). Only one set of distereomers
in the tetrahydroquinoline series, 15 and 16, had a basic
nitrogen directly attached to the 4-position of the tetra-
hydroquinoline. These two compounds were also both
devoid of activity versus VRE suggesting that at least a
one atom spacer may be needed between the core ring
and the basic nitrogen for activity versus VRE.
In conclusion, a novel structural class of 2-(1H-indol-3-
yl)tetrahydroquinoline antibacterials with potent in
vitro (<1.0 mg/mL) activity versus methicillin resistant
S. aureus has been discovered. A SAR study revealed
that the indole portion was sensitive to structural chan-
ges while the tetrahydroquinoline was tolerant to sev-
eral modifications. Studies are currently underway to
evaluate the in vivo efficacy of this series of compounds.
1
5. All compounds tested were characterized by H NMR, 13C
NMR, and MS. A representative example: compound 5. 1H
NMR, (DMSO), (300 MHz) d 11.26 (s, 1H), 7.88 (d, J=2.2
Hz, 1H), 7.42 (d, J=2.6 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 7.21
(dd, J=8.5, 2.0 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.00 (dd,
J=8.7, 2.8 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 6.03 (s, 1H), 5.16
(d, J=8.1 Hz, 1H), 4.90 (d, J=2.9 Hz, 1H), 3.60 (m, 2H), 2.83
(m, 1H), 1.98 (m, 1H), 1.43 (m, 1H), 13CNMR, (DMSO),
(300 MHz) d 145.08, 134.94, 128.93, 127.46, 123.99, 123.93,
123.66, 121.12, 120.42, 116.38, 115.52, 113.57, 111.26, 74.59,
Acknowledgements
1
65.90, 49.06, 43.79, 25.16, MS (APCI) m/z 403 [MH]+. 6: H
The authors are grateful to Dr. Robert Smith for pro-
viding many insightful suggestions. Dr. William Arm-
strong at Boston College kindly provided the X-ray
data for compound 9.
NMR, (DMSO), (300 MHz) d 11.30 (s, 1H), 7.83 (d, J=2.1
Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.23
(dd, J=5.2, 2.0 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.07 (dd,
J=8.4, 2.2 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.39 (s, 1H), 4.51
(d, J=4.8 Hz, 1H), 3.89 (m, 2H), 3.67 (q, J=6.2 Hz, 1H), 2.56
(m, 1H), 1.97 (m, 1H) 1.61 (m, 1H), 13CNMR, (DMSO),
(300 MHz) d 146.0, 136.1, 130.9, 128.8, 128.6, 126.8, 124.4,
122.5, 121.8, 119.9, 116.7, 115.0, 114.5, 111.9, 75.9, 64.9, 50.3,
41.6, 29.7, MS (APCI) m/z 403 [MH]+.
References and Notes
1. Hoemann, M. Z.; Kumaravel, G.; Xie, R. L.; Rossi, R. F.;
Meyer, S.; Sidhu, A.; Cuny, G. D.; Hauske, J. R. Bioorg. Med.
Chem. Lett. 2000, 10, 2675.
2. (a) Oliva, B.; Miller, K.; Caggiano, N.; Cuny, G. D.; Hoe-
mann, M. Z.; Hauske, J. R.; Chopra, I. Abstracts of Papers,
6. For a description of reagents and instrumentation, see ref 1.
7. X-ray crystal structure obtained by Dr. Armstrong’s group
at Boston College.
8. For a description of the MICdeterminations, see ref 1.