Structure-activity relationship of indoloquinoline analogs anti-MRSA

Article abstract of DOI:10.1016/j.bmcl.2015.10.058

Indolo[3,2-b]quinoline analogs (3a-3s), 4-(acridin-9-ylamino) phenol hydrochloride (4), benzofuro[3,2-b]quinoline (3t), indeno[1,2-b]quinolines (3u and 3v) have been synthesized. Those compounds were found to exhibit anti-bacterial activity towards Methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship studies were conducted that indoloquinoline ring, benzofuroquinoline ring and 4-aminophenol group are essential structure for anti-MRSA activity.

Full text of DOI:10.1016/j.bmcl.2015.10.058

Bioorganic & Medicinal Chemistry Letters 25 (2015) 5551–5554
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship of indoloquinoline analogs
anti-MRSA
⇑
Min Zhao, Tomonori Kamada, Aya Takeuchi, Hiromi Nishioka, Teruo Kuroda, Yasuo Takeuchi
Faculty of Pharmaceutical Sciences, Okayama University, Kitaku-Tsushima-naka 1-1-1, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Indolo[3,2-b]quinoline analogs (3a–3s), 4-(acridin-9-ylamino) phenol hydrochloride (4), benzofuro[3,2-
b]quinoline (3t), indeno[1,2-b]quinolines (3u and 3v) have been synthesized. Those compounds were
found to exhibit anti-bacterial activity towards Methicillin-resistant Staphylococcus aureus (anti-MRSA
activity). Structure–activity relationship studies were conducted that indoloquinoline ring, benzofuro-
quinoline ring and 4-aminophenol group are essential structure for anti-MRSA activity.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 16 June 2015
Revised 25 September 2015
Accepted 20 October 2015
Available online 21 October 2015
Keywords:
Indoloquinoline
Benzofuroquinoline
Indenoquinoline
Anti-MRSA
Structure–activity
Vancomycin that it was introduced in the 1960s by Eli Lilly, has
been used in the treatment of Methicillin-resistant Staphylococcus
aureus (MRSA) in clinical in the 1980s.1 But because of the presence
of Vancomycin-resistant Staphylococcus aureus in 2002,2 the devel-
opment of novel and potent anti-MRSA agents has become an
urgent medical need.
quinoline, and indeno[1,2-b]quinoline compounds were synthe-
sized. And their anti-MRSA activity against OM481 and OM584
strains of S. aureus were evaluated.
In order to understand the structure–activity relationship of
indoloquinoline analogs, indoloquinoline analogs (3a–3m and 3s)
with kinds of substitution groups at different positions of the
11-N-phenyl ring, (3o–3q) with different kinds of substitution
groups at C-7, 3n and 3r with N-methyl group were synthesized.
Also, 4-(acridin-9-ylamino)phenol hydrochloride (4) was synthe-
sized to ascertain the effect of number of ring. And benzofuro-
quinoline (3t) and indenoquinoline (3u and 3v) were synthesized
to estimate the effect of kinds of ring.
Indolo[3,2-b]quinoline analogs (3a–3n) were synthesized by
using a modification of the method of Gorlitzer and Weber,12 as
shown in Scheme 1. As starting materials, anthranilic acid was
converted to 2-(2-chloroacetamido)benzoic acid (5) by reaction
with chloroacetyl chloride at reflux in toluene. The amination of
5 with corresponding aniline (6a–6e) afforded corresponding
2-(2-phenylamino)acetamido benzoic acids (7a–7e). Cyclization
of 7a–7e by heating with boron trifluoride-diethyl ether (BF3ꢀOEt2)
gave the corresponding indolo[3,2-b]quinolones (8a–8e), which
were converted to chlorides (9a–9e) by treatment with phospho-
rus oxychloride (POCl3). The amination of (9a–9e) with corre-
sponding aniline gave final products 3a–3r (Scheme 1). And, the
acetylation of 3d by treatment with acetic anhydride gave final
product 3s (Scheme 1).
There are a lots of Letter about compounds with quinonic skele-
tons that have wide ranging pharmaceutical activities, for example
antitumor,3,4 antibacterical5,6 activities have been reported. In our
laboratory, Yamato et al.7 studied antitumor activity of fused quino-
line analogs based on the acridine and found that compound 1 has
remarkably potent antitumor activity with dose of 6.25 mg/kg, T/C%
300 against Leukemia P388 in vivo. So, we think compound 1
(Fig. 1) including the novel skeleton of indoloquinoline8–10 and its
analogs might have antibacterical activity and measured compound
1’s activity of anti-MRSA against OM481 and OM584,11 which were
clinical isolated from Okayama University hospital Japan. The
result showed no activity towards MRSA. However we measured
anti-MRSA activities of the analogs of compound 1 and found that
compound 2 (Fig. 1) which was prepared in the study of 1, exhibited
anti-MRSA activity with a minimum inhibitory concentration (MIC)
of 8 lg/mL (OM481) and 16 lg/mL (OM584). So, based on the
indoloquinoline skeleton of the lead compound 2, a series of
indoloquinoline analogs, including indolo[3,2-b]quinoline analogs,
4-(acridin-9-ylamino)phenol hydrochloride, benzofuro[3,2-b]
4-(Acridin-9-ylamino)phenol hydrochloride (4) was synthe-
⇑
sized according to the reported method.13 Anthranilic acid was
Corresponding author.
E-mail address: take@pharm.okayama-u.ac.jp (Y. Takeuchi).
http://dx.doi.org/10.1016/j.bmcl.2015.10.058
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

5552
M. Zhao et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5551–5554
12 by treatment with 4-aminophenol gave the final product 3t
(Scheme 2).
Anthranilic acid and 1-indanone (13u) or 3-methyl-1-indanone
(13v) by heating gave indeno[1,2-b]quinoline (14u and 14v), which
were converted to chlorides (15u and 15v) by treatment with
phosphorus oxychloride (POCl3). The amination of 15u and 15v
by treatment with 4-aminophenol gave the final products 3u15
and 3v (Scheme 3).
N
N
H
HN
O
S
Me
O
MeO
N
H
1
Anti-MRSA activity was measured in terms of minimum inhibi-
tory concentrations (MICs, lg/mL). The MRSA strains used for the
evaluation of anti-MRSA activity were OM481 and OM584 that
were clinical isolated from Okayama University hospital Japan as
a prototype of Japanese hospital-associated MRSA strains. The
assay results are summarized in Table 1.
These results indicate that tetracyclic indoloquinoline com-
pounds are critical for anti-MRSA activity against both OM481
and OM584 strains than tricyclic compound 4. The position and
kinds of substitution group is important to anti-MRSA activity
against both strains, especially indoloquinoline analogs 3d showed
7
6
5
4
1
N
8
MIC (μg/mL)
OM481a) OM584b)
3
2
9
N
H
10
11
HN
2
8
16
6′
5′
1′
2
1
vancomycin
2′
4′
MeO
OH
3′
a) Methicillin-resistant S. aureus OM481.
b) Methicillin-resistant S. aureus OM584.
2
apparent anti-MRSA activity towards OM481 with MIC’s of 4
lg/
mL and OM584 with MIC’s of 2
l
g/mL. This implies that the 40-
Fig. 1. Structure of compounds 1, 2 and 2’s anti-MRSA activity.
hydroxy group is important to anti-MRSA activity against both
strains. The introduction of substitution groups in 7-position of
indoloquinoline analogs (3o–3q) showed anti-MRSA activity, espe-
cially methoxy group (3p) showed apparent anti-MRSA activity
converted to 2-(2-phenoxyacetamido)benzoic acids (10)14 by
reaction with phenoxyacetyl chloride in aqueous sodium hydroxide.
Treatment of 2-(2-phenoxyacetamido)benzoic acids with polyphos-
phoric acid gave benzofuro[3,2-b]quinolin-11(5H)-one (11) which
was converted to 11-chlorobenzofuro[3,2-b]quinoline (12) by
treatment with phosphorus oxychloride (POCl3). The amination of
towards both strains, with MIC’s of 2 lg/mL each. Indenoquinoline
(3u) and methylindenoquinoline (3v) showed weak anti-MRSA
activity. However benzofuroquinoline (3t)10 showed apparent
anti-MRSA activity towards both strains, with MIC’s of 2 lg/mL
each. So the SAR indicated that the number and kinds of ring,
NHR2
1
R
1
R
H
H
R1
H
N
NH
2
N
ClCH COCl
2
N
BF •OEt
2
Cl
6a-6e
3
N
R
O
toluene
reflux, 10 min
92%
DMF
140 , 3 h
2
ഒ
COOH
O
N
R
COOH
90ഒ 3 h-12 h
COOH
2
37-78%
O
5
7a-7e
8a-8e
1
R
1
NH2
7a, 8a, 9a: R1 = R2 = H; 7b, 8b, 9b: R1 = Cl, R2 = H;
7c, 8c, 9c: R1 = OMe, R2 = H; 7d, 8d, 9d: R1 = Me, R2 = H;
7e, 8e, 9e: R1 = H, R2 = Me.
R
N
R3
N
POCl
3
N
R
3a: R1 = R2 = R3 = H; 3b: R1 = R2 = H, R3 = 2’-OH;
3c: R1 = R2 = H, R3 = 3’-OH; 3d: R1 = R2 = H, R3 = 4’-OH;
3e: R1 = R2 = H, R3 = 2’-OMe; 3f: R1 = R2 = H, R3 = 3’-OMe;
3g: R1 = R2 = H, R3 = 4’-OMe; 3h: R1 = R2 = H, R3 = 2’-Cl;
3i: R1 = R2 = H, R3 = 3’-Cl; 3j: R1 = R2 = H, R3 = 4’-Cl;
3k: R1 = R2 = H, R3 = 4’-F; 3l: R1 = R2 = H, R3 = 4’-Me;
3m: R1 = R2 = H, R3 = 4’-NO2;
130ഒ, 1 h
2-ethoxyethanol
145
2
N
R
HN
4-56% (2 steps)
ഒ
2
3
Cl
R
9a 9e
-
3a 3m, 3o-3r
-
3o: R1 = Cl, R2 = H, R3 = 4’-OH; 3p: R1 = OMe, R2 = H, R3 = 4’-OH;
3q: R1 = Me, R2 = H, R3 = 4’-OH; 3r: R1 = H, R2 = Me, R3 = 4’-OH;
3s: R1 = R2 = H, R3 = 4’-OAc.
MeHN
N
N
• 1/2 H2SO4
OH
N
H
N
2-ethoxyethanol
145ഒ, 32 h
19%
H
N
Cl
Me
9a
3n
OH
acetic anhydride
pyridine
N
N
N
N
rt, 1 h
56%
•HCl
H
H
HN
HN
OH
OAc
3d
3s
Scheme 1.

M. Zhao et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5551–5554
5553
H
N
BF3•OEt2
O
O
O
Cl
H
O
NH2
N
N
POCl3
O
H
N
PPA
130ഒ, 1 h
NaOH aq. (2 eq)
0ഒ, 1 h
O
O
COOH
64% (2 steps)
130 , 2 h
COOH
ഒ
68%
Cl
O
NH2
O
10
11
12
N
OH
O
2-ethoxyethanol
conc. HCl
145ഒ, 3 h
69%
HN
OH
3t
Scheme 2.
R
O
NH2
OH
N
H
NH2
N
N
13u, 13v
POCl3
130 , 2 h
200 , 1.5 h
ഒ
2-ethoxyethanol
R
ഒ
HN
COOH
conc. HCl
R
R
O
Cl
145ഒ, 3 h
OH
3u : R = H (63%)
3v
14u : R = H
15u : R = H (24% 2 steps)
15v
14v
: R = Me
: R = Me (46% 2 steps)
: R = Me (55%)
Scheme 3.
Table 1
Anti-MRSA activities of indoloquinoline analogs 3a–3v
R1
7
6
5
N
4
1
N
8
3
9
1X0
11
2
•HCl
HN
6′ R2
N
5′
R4
1′
2′
R3
OH
4
4′
3′
3a-3v
Grey shade is shown in a compound having about the same activity standard compound (vancomycin).
a Compound 3b and 3s are hydrochloride.

5554
M. Zhao et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5551–5554
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activity. Further structural development studies are under way.
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Supplementary data
Supplementary data associated with this article can be found, in
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