Quinoline-based imidazole-fused heterocycles as new inhibitors of 15-lipoxygenase

Article abstract of DOI:10.1080/14756366.2016.1206087

A series of 2-chloro-quinoline-based imidazopyridines 6a–l and imidazothiazoles 6m–o bearing a bulky alkylamine side chain were synthesized as soybean 15-LOX inhibitors. The target compounds 6a–o were prepared via one-pot reaction of 2-chloroquinoline-3-carbaldehyde (3), heteroaromatic amidine 4, and alkyl isocyanides 5, in the presence of NH₄Cl. All compounds showed significant anti-15-LOX activity (IC₅₀ values ≤40 μM). Among the title compounds, the imidazo[2,1-b]thiazole derivative 6n bearing a tert-butylamine moiety showed the highest activity against soybean 15-LOX enzyme.

Full text of DOI:10.1080/14756366.2016.1206087

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Quinoline-based imidazole-fused heterocycles as
new inhibitors of 15-lipoxygenase
Shima Dianat, Setareh Moghimi, Mohammad Mahdavi, Hamid Nadri, Alireza
Moradi, Loghman Firoozpour, Saeed Emami, Arash Mouradzadegun, Abbas
Shafiee & Alireza Foroumadi
To cite this article: Shima Dianat, Setareh Moghimi, Mohammad Mahdavi, Hamid Nadri,
Alireza Moradi, Loghman Firoozpour, Saeed Emami, Arash Mouradzadegun, Abbas
Shafiee & Alireza Foroumadi (2016): Quinoline-based imidazole-fused heterocycles as new
inhibitors of 15-lipoxygenase, Journal of Enzyme Inhibition and Medicinal Chemistry, DOI:
10.1080/14756366.2016.1206087
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Date: 21 July 2016, At: 13:32

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ISSN: 1475-6366 (print), 1475-6374 (electronic)
J Enzyme Inhib Med Chem, Early Online: 1–5
2016 Taylor & Francis. DOI: 10.1080/14756366.2016.1206087
!
SHORT COMMUNICATION
Quinoline-based imidazole-fused heterocycles as new inhibitors of
15-lipoxygenase
1
2
3
4
4
3
Shima Dianat , Setareh Moghimi , Mohammad Mahdavi , Hamid Nadri , Alireza Moradi , Loghman Firoozpour ,
5
Saeed Emami , Arash Mouradzadegun , Abbas Shafiee , and Alireza Foroumadi
1
2
2,3
1
2
Department of Chemistry, Faculty of Science, Shahid Chamran University, Ahvaz, Iran, Department of Medicinal Chemistry, Faculty of Pharmacy
3
and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran, Drug Design and Development Research
4
Center, Tehran University of Medical Sciences, Tehran, Iran, Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University
5
of Medical Sciences, Yazd, Iran, and Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy,
Mazandaran University of Medical Sciences, Sari, Iran
Abstract
Keywords
A series of 2-chloro-quinoline-based imidazopyridines 6a–l and imidazothiazoles 6m–o bearing Docking study, enzyme inhibitors, 15-lipoxy-
a bulky alkylamine side chain were synthesized as soybean 15-LOX inhibitors. The target
compounds 6a–o were prepared via one-pot reaction of 2-chloroquinoline-3-carbaldehyde (3),
genase, imidazo[1,2-a]pyridine,
imidazo[2,1-b]thiazole
4
heteroaromatic amidine 4, and alkyl isocyanides 5, in the presence of NH Cl. All compounds
showed significant anti-15-LOX activity (IC50 values ꢀ40 mM). Among the title compounds, the
imidazo[2,1-b]thiazole derivative 6n bearing a tert-butylamine moiety showed the highest
activity against soybean 15-LOX enzyme.
History
Received 20 January 2016
Revised 10 June 2016
Accepted 21 June 2016
Published online 11 July 2016
Introduction
15-LOX. A part of attentions has been focused on small molecules
9,10
containing fused heterocyclic systems including indolizine
11,12
and
previously described (I, Figure 1)
Polyunsaturated fatty acids such as arachidonic acid are
implicated in the control of several physiological processes.
Lipoxygenases (LOXs) are a class of nonheme iron-containing
enzymes which regio- and stereospecifically catalyze the hydro-
peroxidation of polyunsaturated fatty acids . In humans, three
major families of LOXs were found as 5-LOX, 12-LOX, and
imidazo-fused heterocycles
as a potential inhibitors of 15-LOX. In a study by Wisniewska et al.,
imidazo[1,2-a]pyridine-3-yl-amine analog (EP6, II) was evaluated
13
as a 5-LOX inhibitor . On the other hand, a series of quinoline-
1
14–18
based compounds were reported as potent inhibitors of LOX
.
These findings convinced us to design a new core containing
quinoline and imidazole-fused system as a new 15-LOX inhibitors.
Thus, we describe here, synthesis, in vitro anti-15-LOX activity and
docking study of [2-(2-chloro-quinolin-3-yl)-imidazo[1,2-a]pyri-
din-3-yl]amines 6a–l and [6-(2-chloro-quinolin-3-yl)-imidazo[2,1-
b]thiazol-5-yl]amines 6m–o (Figure 1). Following our interests on
the chemistry aspects of this core meaning finding new catalysis for
1
5-LOX isoforms. These isoforms (5-, 12-, or 15-LOX) initiate
the biosynthesis of leukotrienes, lipoxins, and other compounds
by oxidizing the C-5, C-12, and C-15 positions of the key
2
,3
substrate, arachidonic acid . For example, 15-LOX oxidizes
arachidonic acid to produce mainly 15(S)-5Z,8Z,11Z,13E-hydro-
peroxyeicosatetraenic acid (15-HPETE). The bioactive metabol-
ites of 15-LOX hydroperoxidation (e.g. HETE and leukotriene
A4) are found to be potent signal transduction modifiers which
the synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-b]thia-
19,20
4
zol-quinoline derivatives and their further coupling reaction
,
affect the inflammatory processes . Furthermore, 15-LOX has
5
been implicated in neurodegenerative diseases , atheroscler-
herein, we report the synthesis of new quinolin imidazo[1,2-
a]pyridine derivatives and also evaluate their soybean 15-LOX
inhibitory activity.
6
osis , chronic obstructive pulmonary disease (COPD), and a
,7
8
variety of cancers .
Consequently, small molecules affecting the 15-LOX pathway
might be therapeutically useful in chronic inflammatory diseases, Experimental
cardiovascular disorders, and some types of tumors. Thus, medi-
cinal chemists have attended extensively to find new inhibitors of
15-LOX inhibition assay
To evaluate 15-LOX (Lipoxidase from Glycine max, soybean)
inhibitory activity of new synthesized compounds, the stock
solution of the compounds were prepared by dissolving them in
Address for correspondence: Alireza Foroumadi, Department of
Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical
Sciences Research Center, Tehran University of Medical Sciences,
Tehran, Iran. Tel: +98 21 66954708. Fax: +98 21 66461178. E-mail:
aforoumadi@yahoo.com
1
mL of DMSO. To prepare substrate solution (stock
concentration ¼ 38 mM), 12 mL linoleic acid was dissolved in
988 mL ethanol. This solution should be used the same day it is

2
S. Dianat et al.
J Enzyme Inhib Med Chem, Early Online: 1–5
Figure 1. Structures of reported LOX inhibi-
tors I and II, and designed compounds 6a–o
as new 15-LOX inhibitors.
S
CH3
N
N
N
N
R3
HN
R2
HN
I)
N
R1
O
(
EP6 (II)
R'
S
N
N
N
N
HN
HN
R
R
Cl
N
a-l
N
Cl
6
6m-o
made. The final concentration of substrate will be 122 mM. Five potential of 70 eV. Elemental analysis was performed with an
different concentrations of each compound were tested in Elementar Analysensysteme GmbH VarioELCHNS mode.
triplicate to obtain the inhibition range between 20 and 80%.
The test solution was a mixture of 3 mL phosphate buffer (0.1
M, pH ¼ 8), 50 mL enzyme solution (final concentration:
General procedure for the synthesis of compounds 6a–o
A mixture of 2-chloroquinolin-3-carbaldehyde 3 (1.0 mmol),
heteroaromatic amidine 4a–f (1.0 mmol), appropriate alkyl
isocyanide (1.2 mmol), and NH Cl (1.0 mmol) in toluene
1
67 U/mL), and 50 mL of target compound solution. Being
incubated for 4 min, the substrate (Linoleic acid, final
concentration: 122 mM) was added, and the change in absorb-
ance was measured for 60s at 234 nm. A control test was done
with the same volume of DMSO (50 mL) to eliminate the
effect of DMSO on enzyme activity.
4
(5 mL) was heated under reflux for 12–24 h. After completion
of the reaction, as indicated by TLC, the solvent was
evaporated under reduced pressure, and the residue was
recrystallized from petroleum ether–EtOAc to afford target
compounds 6a–o in 65–93% yields.
Molecular modeling and docking stimulation
All docking simulations were performed using Autodock Vina
(ver. 1.1.1). First, the 3D structure of soybean LOX in
[
2-(2-Chloro-quinolin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-
(1,1,3,3-tetramethyl-butyl)-amine (6c)
complex with 13(S)-hydroproxy-9(Z)-2,11(E)-octadecadienoic
acid (code ID: 1IK3) was retrieved from protein databank
ꢁ
Yield: 0.32 g (80%); pale yellow solid; mp 168–170 C; IR (KBr):
ꢂ1
1
321, 2919, 2848, 1631, 1497, 754 cm ; H NMR (400 MHz,
3
(www.pdb.org). Then, the co-crystallized ligand and water
CDCl ): d 0.94 (s, 9H, C(CH ) ), 1.29 (s, 6H, C(CH ) ), 1.42 (s,
3
3 3
3 2
molecules were removed, and the protein was converted to
pdbqt format using Autodock Tools (1.5.4). To prepare the
ligands for docking, the 2D chemical structure of ligands was
sketched using MarvinSketch 5.8.3, 2012, ChemAxon (http://
www.chemaxon.com) and then converted to 3D format by
Openbabel (ver 2.3.1). Finally, pdbqt format of ligands was
prepared using an Autodock Tools python script, prepare_li-
gand4.py. The docking parameters were set as follow:
size_x¼ 20; size_y ¼ 20; size_z¼ 20; center_x ¼19.693; cen-
ter_y ¼ 0.054; center_z¼ 17.628. The exhaustiveness was set to
2
H, CH ), 3.48 (s, 1H, NH), 6.94 (dd, J ¼ 6.8, 4.0 Hz, 1H, H ),
2
6
7
.63 (t, J ¼ 7.5 Hz, 1H, H
0
), 7.80 (t, J ¼ 7.5 Hz, 1 H, H
0
), 7.93 (d,
7
6
J ¼ 8.0 Hz, 1H, H
0
), 8.09 (d, J ¼ 8.4 Hz, 1H, H
0
), 8.52 (dd,
8
5
J ¼ 6.8, 1.6 Hz, 1H, H ), 8.58–8.59 (m, 2H, H , H ), 8.63 (s, 1H,
7
8
5
1
3
H ); C NMR (100 MHz, CDCl ): d 29.0, 31.5, 31.7, 56.4, 59.4,
0
4
3
1
08.1, 112.0, 126.2, 127.2, 127.5, 127.9, 128.8, 129.0, 130.9,
31.2, 136.0, 141.8, 145.1, 148.0, 149.1, 150.0. MS: m/z (%) 408
1
(
+
15, [M + 2] ), 406 (49, M ). Anal. Calcd for C H ClN : C,
+
24 27 4
7
0.83; H, 6.69; N, 13.77. Found: C, 70.97; H, 6.49; N, 13.84.
1
00, and the max number of retrieved final docked poses was
set to 15 using num_modes parameter. The other docking [2-(2-Chloro-quinolin-3-yl)-8-methyl-imidazo[1,2-a]pyridin-3-
parameters were left as default. Finally, the most favorable yl]-cyclohexyl-amine (6d)
docked poses in terms of free binding energy were selected
ꢁ
Yield: 0.35 g (91%); pale yellow solid; mp 143–145 C; IR (KBr):
for analyzing of enzyme–inhibitor interactions.
ꢂ1
1
327, 2971, 1640, 1568, 781 cm ; H NMR (400 MHz, CDCl ):
3
3
d 1.01–1.69 (m, 10 H, 5CH , cyclohexyl), 2.41 (s, 3H, CH ), 2.67
2
3
Chemistry
(
s, 1H, NCH), 3.32 (s, 1H, NH), 6.79 (t, J ¼ 6.4 Hz, 1H, H ), 7.02
0
7 6
6
Commercially available chemicals and reagents were purchased (d, J ¼ 6.4 Hz, 1H, H
from Merck and Fluka Chemical Company and used without (m, 1H, H
), 7.92 (d, J ¼ 8.0 Hz, 1H, H
further purification. Melting points are measured with a Kofler
), 8.24 (d, J ¼ 6.4 Hz, 1H, H ), 8.61 (s, 1H, H
hot stage apparatus and are uncorrected. H and C NMR spectra (100 MHz, CDCl ): d 21.4, 24.6, 25.6, 33.8, 56.7, 111.6, 121.7,
), 7.61 (t, J ¼ 7.6 Hz, 1H, H
), 7.78–7.82
0
0
5
), 8.10 (d, J ¼ 8.4 Hz, 1H,
7
1
3
H
0
0
); C NMR
4
8
5
1
13
3
were run on a Bruker FT-400 in CDCl , using TMS as an internal 123.4, 125.7, 127.0, 127.1, 127.3, 127.4, 128.4, 129.7, 130.5,
standard. IR spectra were recorded on a Shimadzu 470 spectro- 135.6, 140.8, 141.3, 147.1, 149.0. MS: m/z (%) 392 (19,
3
+
photometer (KBr disks). MS were recorded with an Agilent [M + 2] ), 390 (58, M ). Anal. Calcd for C23
+
H23ClN : C,
4
Technology (HP) mass spectrometer operating at an ionization 70.67; H, 5.93; N, 14.33. Found: C, 70.45; H, 6.13; N, 14.12.

DOI: 10.1080/14756366.2016.1206087
15-LOX inhibitors
3
Scheme 1. Preparation of 2-chloro-quinoline-
based imidazopyridines and
imidazothiazoles.
O
O
CH COCl
POCl3
3
H
Acetone
NH2
DMF
N
N
Cl
3
0°C
H
8
0°C
1
2
3
NC
+
N
NH2
4
a
5a
PTSA, Toluene
Reflux
N
N
HN
N
Cl
6
a
[6-Chloro-2-(2-chloro-quinolin-3-yl)-imidazo[1,2-a]pyridin-3-
yl]-(1,1,3,3-tetramethyl-butyl)-amine (6k)
expressed as mean ± SD of three independent experiments)
were listed in Table 1. All compounds showed significant
inhibitory activity with the IC50 values ꢀ40 mM. Among them,
compound 6n possessing IC50 value of 11.5 mM was the most
potent compound. Furthermore, compounds 6g and 6i with IC50
values of 15.3 and 14.1 mM were more active than remaining
compounds. As seen in Table 1, compounds 6a–l were
imidazopyridine derivatives, and compounds 6m–o had imida-
zothiazole substructure. The most potent compound 6n was
imidazothiazole derivative. On the other hand, the potent
compounds 6 g and 6i were imidazopyridine analogs. In the
imidazopyridine series, introduction of bromo or chloro
substituent at 6-position decreased the inhibitory activity. The
effect of methyl group at 7 or 8 position of imidazopyridine
ring depended on the alkyl side chain connected to the amine
group. For example, while 7-methyl-imidazopyridine derivative
ꢁ
Yield: 0.33 g (75%); yellow solid; mp 145–147 C; IR (KBr):
3
ꢂ1
1
274, 2828, 1624, 1607, 1330, 772 cm ; H NMR (400 MHz,
CDCl ): d 0.91 (s, 6H, C(CH ) ), 0.96 (s, 9H, C(CH ) ), 1.48 (s,
3
3 2
3 3
2
7
7
H, CH ), 3.39 (s, 1H, NH), 7.19 (dd, J ¼ 9.6, 2.0 Hz, 1H, H ),
2
7
.54 (dd, J ¼ 9.6, 0.8 Hz, 1H, H ), 7.61–7.65 (m, 1H, H
0
), 7.77–
6
8
.81 (m, 1H, H
0
), 7.93 (d, J ¼ 8.0 Hz, 1H, H
0
), 8.11 (d,
5
7
J ¼ 8.0 Hz, 1H, H
0
), 8.24 (dd, J ¼ 2.0, 0.8 Hz, 1 H, H ), 8.51 (s,
8
5
1
3
1
5
1
H, H ); C NMR (100 MHz, CDCl ):d 30.0, 31.5, 31.7, 56.5,
0
4
3
9.2, 118.6, 120.7, 121.0, 126.1, 127.4, 127.7, 127.9, 128.0,
28.5, 129.0, 131.1, 134.9, 140.7, 141.0, 147.4, 149.0. MS: m/z
+
+
+
(%) 444 (10, [M + 4] ), 442 (58, [M + 2] ), 440 (90, M ). Anal.
Calcd for C H Cl N : C, 65.31; H, 5.94; N, 12.69. Found: C,
2
4
26
2 4
6
5.24; H, 5.83; N, 12.76.
6
i bearing a 1,1,3,3-tetramethyl-butylamine residue was more
Results and discussion
potent than 6c, but 7-methyl-imidazopyridine 6h containing a
tert-butyl group found to be as potent as 6b. The comparison of
Chemistry
7
6
- and 8-methyl regioisomers revealed that 7-methyl derivatives
g and 6i exhibiting more potent activity in respect to their 8-
In the synthetic route to target compounds 6a–o, initially aniline
(1) was converted to N-phenylacetamide (2) via the acetylation
methyl analogs 6d and 6f. In contrast, (7-methyl-imidazopyr-
idin-3-yl)amine 6h was less potent than its 8-methyl regioi-
somer 6e.
reaction in the presence of acetyl chloride and potassium
carbonate under mild condition (Scheme 1). Then, 2-chloroqui-
nolin-3-carbaldehyde (3) was prepared using the Vilsmeier–Haak
2
1
reaction in the presence of POCl in DMF . The final compounds
3
6
a–o were synthesized via one-pot condensation reaction of Docking study
aldehyde 3, an appropriate isocyanide 5a–c and various hetero-
aromatic amidine 4a–f, in the presence of catalytic amount of
ammonium chloride in toluene. After recrystallization from
petroleum ether–EtOAc, pure compounds 6a–o were obtained in
The docking study was performed to clarify the binding mode of
the target compounds in the active site of 15-LOX. For this
purpose, the tested compounds were docked onto the active site of
2
3,24
enzyme using Autodock Vina (ver. 1.1.1)
. Then, the best
6
5–93% yields.
docked poses in terms of free binding energy were further
analyzed to clarify interactions between ligands and the 15-LOX
enzyme. Because of similar orientation of compounds in the
1
5-LOX inhibitory activity
The inhibitory activity of synthesized compounds was deter- active site of 15-LOX, further analysis was performed on the most
2
2
mined against 15-LOX, and the obtained IC50 values (IC50 active compound 6n. As shown in Figure 2, the target compound

4
S. Dianat et al.
J Enzyme Inhib Med Chem, Early Online: 1–5
Table 1. Used amidine (4) and isocyanide (5) derivatives for the one-pot synthesis of compounds 6a–o including
their 15-Lox inhibitory activity.
N
N
HN
R
N
Cl
6
a-o
Compound
2-amino azines 4
Isocyanide (R) 5
IC50 (mM)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
2-amino pyridine
2-amino pyridine
2-amino pyridine
cyclohexyl
tert-butyl
1,1,3,3-tetramethylbutyl
cyclohexyl
tert-butyl
1,1,3,3-tetramethylbutyl
cyclohexyl
tert-butyl
1,1,3,3-tetramethylbutyl
cyclohexyl
1,1,3,3-tetramethylbutyl
tert-butyl
cyclohexyl
tert-butyl
1,1,3,3-tetramethylbutyl
–
21.2 ± 1.0
27.9 ± 1.3
40.0 ± 1.8
26.0 ± 1.2
21.8 ± 1.0
20.5 ± 0.9
15.3 ± 0.7
28.9 ± 1.3
14.1 ± 0.6
44.3 ± 2.0
39.9 ± 1.8
37.6 ± 1.9
2-amino-3-methyl pyridine
2-amino-3-methyl pyridine
2-amino-3-methyl pyridine
2-amino-4-methyl pyridine
2-amino-4-methyl pyridine
2-amino-4-methyl pyridine
2-amino-5-chloro pyridine
2-amino-5-chloro pyridine
2-amino-5-bromo pyridine
2-aminothiazole
a
40
2-aminothiazole
2-aminothiazole
11.5 ± 0.5
19.8 ± 0.9
30
Quercetine
–
a
Percentage (%) of inhibition at 25 mM.
Figure 2. The best docked pose of compound
n in the active site of 15-LOX.
6
3
was laid near the Fe ion in the 15-LOX active site. In this Ile557, Leu560, Ala561, and Leu565. The ligand also estab-
+
3
+
position, the ligand interacted with Fe ion through a ꢀ-cation lished another remarkable hydrophobic interaction via the orien-
interaction via phenyl ring of its 2-chloroquinoline moiety. A tation of tert-butylamino group toward a hydrophobic pocket
careful inspection of the binding pocket indicated that this moiety including side chains of Leu515, Val571, Ile572, Phe576, and
oriented toward a hydrophobic cavity comprised of Trp519, Val769.

DOI: 10.1080/14756366.2016.1206087
15-LOX inhibitors
5
Conclusions
8. Kuhn H, Walther M, Kuban RJ. Mammalian arachidonate 15-
lipoxygenases: structure, function, and biological implications.
Prostaglandins Other Lipid Mediat 2002;68–69:263–90.
9. Gundersen LL, Malterud KE, Negussie AH, et al. Indolizines as
novel potent inhibitors of 15-lipoxygenase. Bioorg Med Chem 2003;
We synthesized a series of 2-chloro-quinoline-based imidazopyr-
idines 6a–l and imidazothiazoles 6m–o bearing a bulky
alkylamine side chain as soybean 15-LOX inhibitors. The in
vitro evaluation of title compounds against 15-LOX demonstrated
that all compounds had significant inhibitory activity (IC50
values ꢀ40 mM). The most potent compound 6n with IC value
1
1:5409–15.
1
0. Teklu S, Gundersen LL, Larsen T, et al. Indolizine 1-sulfonates as
potent inhibitors of 15-lipoxygenase from soybeans. Bioorg Med
Chem 2005;13:3127–39.
5
0
of 11.5 mM was belong to the imidazo[2,1-b]thiazole series. 11. Barazandeh Tehrani M, Emami S, Asadi M, et al. Imidazo[2,1-
However, the imidazopyridine derivatives 6g and 6i showed
substantial inhibition against 15-LOX (IC50 values ꢀ15.3 mM).
The limited SAR study revealed that the effect of substituent on
imidazopyridine ring depended on the attached alkylamine side
chain. The docking study indicated that the target compound 6n
b]thiazole derivatives as new inhibitors of 15-lipoxygenase. Eur J
Med Chem 2014;87:759–64.
2. Hofmann B, Franke L, Proschak E, et al. Scaffold-hopping cascade
yields potent inhibitors of 5-lipoxygenase. ChemMedChem 2008;3:
1
1
1
535–8.
3. Wisniewska JM, R o¨ dl CB, Kahnt AS, et al. Molecular character-
ization of EP6-a novel imidazo[1,2-a]pyridine based direct 5-lipox-
ygenase inhibitor. Biochem Pharmacol 2012;83:228–40.
3
+
was laid near the Fe ion in the 15-LOX active site. A ꢀ-cation
interaction of 2-chloroquinoline with Fe ion and hydrophobic
3
+
interactions had important roles in the favorable binding of the 14. Dub e´ D, Blouin M, Brideau C, et al. Quinolines as potent
5-lipoxygenase inhibitors: synthesis and biological profile of
L-746,530. Bioorg Med Chem Lett 1998;8:1255–60.
inhibitor with the enzyme active site.
1
1
1
5. Werz O, Greiner C, Koeberle A, et al. Novel and potent inhibitors of
5-lipoxygenase product synthesis based on the structure of pirinixic
acid. J Med Chem 2008;51:5449–53.
6. Golitzer K, Fabian J, Frohberg P, Drutkowski G. Pyrrolo[2,3-
c]quinolones and pyrrolo[3,4-d]qunolines-synthesis and investiga-
tion of lipoxygenase inhibition. Pharmazie 2002;57:243–9.
7. White JD, Yager KM, Stappenbeck F. Synthesis and conformation of
Supporting information
1
13
Experimental details and H and C NMR spectra are available,
via the supplementary content section of this article’s web page.
Declaration of interest
2
-[[3-(1-hydroxyhexyl)phenoxy]methyl]quinolone,
lipoxygenase inhibitor and leukotriene antagonist. J Med Chem
993;58:3466–8.
a
5-
The authors report no declarations of interest. This work was
supported and funded by Research council of Tehran University
1
of Medical Sciences (TUMS); Grant no: 95-01-92-31756; and 18. Musser JH, Kreft AF. 5-lipoxygenase: properties, pharmacology, and
Iran National Science Foundation (INSF).
the quinolinyl(bridged)aryl class of inhibitors. J Med Chem 1992;35:
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Supplementary materials online only – For review only at proofing stage