Investigations concerning the COX/5-LOX inhibiting and hydroxyl radical scavenging potencies of novel 4,5-diaryl isoselenazoles

Article abstract of DOI:10.1016/j.ejmech.2007.09.007

The aim of this study was to investigate 4,5-diaryl isoselenazoles as multiple target non-steroidal anti-inflammatory drugs (MTNSAIDs) which can intervene into the inflammatory processes via different mechanisms of action creating a new class of compounds

Full text of DOI:10.1016/j.ejmech.2007.09.007

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1152e1159
http://www.elsevier.com/locate/ejmech
Original article
Investigations concerning the COX/5-LOX inhibiting and hydroxyl
radical scavenging potencies of novel 4,5-diaryl isoselenazoles
1
Michael Scholz , Holger K. Ulbrich , Gerd Dannhardt
1
*
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Johannes Gutenberg University, Staudingerweg 5,
DE-55128 Mainz, Germany
Received 12 March 2007; received in revised form 30 July 2007; accepted 6 September 2007
Available online 22 September 2007
Abstract
The aim of this study was to investigate 4,5-diaryl isoselenazoles as multiple target non-steroidal anti-inflammatory drugs (MTNSAIDs)
which can intervene into the inflammatory processes via different mechanisms of action creating a new class of compounds. Here we describe
the synthesis of COX/LOX inhibitors which additionally reduce the level of reactive oxygen species, such as hydroxyl radicals which are well
known for supporting inflammation processes in Parkinson’s disease, Alzheimer’s disease and rheumatoid arthritis.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: COX-1/2; 5-LOX; Dual inhibitors; Hydroxyl radical scavenging; Isoselenazoles
1. Introduction
attack and stroke) in patients on Vioxx a voluntary withdrawal
of Vioxx (rofecoxib) was announced on the worldwide market
since 1999. Consequently the American Gastroenterological
Association (AGA) differentiated the therapy for patients
with higher gastrointestinal (GI) risks or higher cardiovascular
(CV) risk in three cases [5].
Recently the target switched to a combined 5-LOX/COX
inhibition, interfering both pathways, the production of prosta-
glandins and the biosynthesis of leukotrienes (LTs) [4,6]. This
strategy led to substances like licofelone (formerly known as
ML3000), which avoid side effects related to COX inhibition.
Its anti-inflammatory and analgesic activities are comparable
to conventional NSAIDs and selective COX-2 inhibitors but
with an improved gastrointestinal safety profile. Substances
like licofelone offer a new quality of curative therapy for the
future [7e10].
Here we describe COX/LOX inhibitors which additionally
have the potential to reduce the level of reactive oxygen spe-
cies, like the hydroxyl radicals which support inflammatory
processes in Parkinson’s disease [11], Alzheimer’s disease
[12] and rheumatoid arthritis [13]. We combined the classical
diaryl heterocycle with the characteristic structure of ebselen
(Fig. 1), a synthetic antioxidant.
NSAIDs are basically used for the treatment of pain, in-
flammation and fever. The main mechanism of action of these
drugs is the inhibition of the cyclooxygenase enzymes (COX-1
and COX-2) [1,2], which are catalyzing the biotransformation
of arachidonic acid to the prostaglandins.
Gastrointestinal haemorrhage, ulceration and kidney failure
are the major side effects associated with all currently avail-
able NSAIDs [3]. These unwanted side activities are caused
by the interference of the physiological balance of prostaglan-
dins. To overcome this several approaches were undertaken.
One attempt haunts the strategy of selective inhibition of
COX-2. Nevertheless, clinical studies have suggested that se-
lective COX-2 inhibitors could cause typical COX-mediated
side effects such as gastrointestinal injury, increased systemic
blood pressure and hypersensitivity [4]. Due to safety concerns
of an increased risk of cardiovascular events (including heart
* Corresponding author. Tel.: þ49 6131 39 25728; fax: þ49 6131 39 23062.
E-mail address: dannhardt@uni-mainz.de (G. Dannhardt).
1
Both authors contributed equally.
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.09.007

M. Scholz et al. / European Journal of Medicinal Chemistry 43 (2008) 1152e1159
1153
Due to this rationale, we synthesized diaryl isoselenazoles
8ae8h, the combination of a diaryl heterocycle targeting the
aim of dual COX/5-LOX inhibitors with a potential radical
scavenging potency of the selenium moiety.
Fig. 1. Structure of ebselen.
2. Chemistry
In accordance with literature [14] ebselen can inactivate
highly reactive radicals, which was originally shown by
Maiorino et al. [15] and Schoneich et al. [16]. Furthermore eb-
¨
selen is a potent inhibitor of lipid peroxidase according to
a Fenton-type reaction of the transition metals with hydroper-
oxides [17,18]. For ebselen several other modes of action were
described: it very effectively reduces hydroperoxides, it is
a mimic of glutathione peroxidase and acts as an inhibitor of
5- and 15-lipoxygenases, NO synthase, NADPH oxidase, pro-
tein kinase C and Hþ/Kþ-ATPase [14].
To synthesize the isoselenazole ring systems we started
with a Grignard reaction (Scheme 1) to connect chloromethyl-
benzenes 1ae1c with various benzaldehydes 2ae2d gaining
the secondary alcohols 3be3i in very good yields (up to
95%) [19]. To obtain the methylsulfonyl derivative 3h, 3i
was oxidized with 3-chloroperbenzoic acid (Scheme 1). It
was important to oxidize the thioether 3i derivative quantita-
tively to 3h before the alcohol was oxidized to the analogous
ketone, because the thioether derivatives disturbed this second
Scheme 1. Method i: Mg in ether; method ii: 3-chloroperbenzoic acid, 0 ꢀC, in CH2Cl2; method iii: Na2Cr2O7, H2SO4 in CH2Cl2 3 h at rt; method iv: AlCl3 in
CH2Cl2, 0e20 ꢀC; method v: DMF, 5 ꢀC, POCl3, 80 ꢀC for 4 h; method vi: heating under reflux NH4Cl, KSeCN, acetone, 5 h.

1154
M. Scholz et al. / European Journal of Medicinal Chemistry 43 (2008) 1152e1159
oxidation reaction resulting in an increase of side products.
The oxidation reaction from the alcohols 3be3e, 3g and 3h
to the ketones 6be6e, 6g and 6h [20] was difficult, because
further oxidation products, e.g. the a-hydroxy ketones and
the diketone derivatives, could also be obtained. By avoiding
this problem the yield of the ketone increased up to 60%
(Scheme 1). The ketone 6f was synthesized in moderate yields
with a FriedeleCrafts acylation reaction connecting 2-(4-me-
thoxyphenyl)acetyl chloride 4 and chlorobenzene 5 [19].
The ketones 6ae6h reacted in the next step with phospho-
ryl chloride in DMF in a modified Vilsmeier reaction [21]
(Scheme 1) leading to the chloro formyl stilbene derivatives
7ae7h in high yields.
The synthesis strategy for diaryl isoselenazole derivatives
8ae8h was developed (Scheme 2) by modifying the condi-
tions of the isothiazole synthesis [22] using potassium seleno-
cyanate and ammonium chloride instead of ammonium
thiocyanate. After substitution of the chloride by selenocya-
nate, ammonia reacted with the formyl group to an imide,
which finally attacked selenocyanate releasing hydrogen cya-
nide (Scheme 2).
The mean inhibitory activity of compounds 8b, 8f and 8g is
about 10-fold higher compared to mean inhibitory activity of
the chlorine and methyl substituted compounds 8ce8e. The
weakest COX-1 inhibitory effect was found for 8h (38%
inhibition at 10 mM). Summarizing these data, it can be stated
that the rank order for COX-1 inhibition is: dimethoxy >
monomethoxy > methyl w chlorine > methylsulfonyl.
Only two compounds 8h (IC50: 0.6 mM) and 8a (IC50:
8 mM) behave as potent COX-2 inhibitors. It is worth to men-
tion that 8h is as potent as celecoxib (IC50: 1 mM) and both
share a similar COX-1/COX-2 ratio of about 10 in our assays.
The quotient of the IC50 values of COX-2/COX-1 inhibition is
an admitted and widely used parameter for the determination
of enzyme selectivity using different test systems [1].
COX-2 (PDB entry: 1CX2) docking studies confirm
(Fig. 2) that the substances 8a and 8h dock in a similar binding
modus like SC-558 (Fig. 3). The different substituents in p-
position of the phenyl groups undergo distinctive hydrogen
bonds. Compound 8a formed an H-bond from the methoxy
group with the oxygen as H-bond acceptor to histidine 90.
The methylsulfonyl derivative 8h forms 2H-bonds from the
sulfonyloxygens as H-bond acceptors to histidine 90 and
arginine 513 (Fig. 3).
3. Results and discussion
Whereas a methylsulfonyl moiety in the case of 8h leads to
an increase in COX-2 activity, all compounds possess a moder-
ate 5-LOX inhibitory activity in a range from 67% (8c) to 42%
(8f) at a concentration of 10 mM. This indicates that the impact
of the substitution pattern of the phenyl moiety at 4-position is
low, since all tested isoselenazoles show a moderate 5-LOX
inhibition compared to the good activity of licofelone (IC50:
0.18 mM) [9] or NDGA (IC50: 1 mM). Noticeable is the fact
that the 5-LOX inhibition of the isoselenazoles is in the
same range as ebselen (IC50 w 10 mM).
The potency of anti-inflammatory drugs often depends es-
pecially on their lipophilicity. To test this hypothesis we eval-
uated the log P values by using method 2 of the three available
fragmentation methods for calculating log P in the ChemDraw
8.0 software. Despite the lipophilic cavity of the 5-LOX en-
zyme [24] the different lipophilicity of our compounds, repre-
sented by calculated log P values in a range from 2.46 (8h,
60% inhibition at 10 mM) to 4.53 (8c, 67% inhibition at
10 mM), did not influence the 5-LOX activity.
4,5-Diaryl isoselenazoles were evaluated in vitro to deter-
mine their COX-1/2 and 5-LOX inhibitory potencies and their
ROS scavenging efficacies. Table 1 summarizes the impact of
the R1 and R2 substituents. The structureeactivity relationship
(SAR) data show a broad range of inhibitory activities in the
COX-1 and COX-2 test systems (COX-1: IC50: 0.006 mM
(8a) to 38% inhibition at 10 mM concentration (8h), COX-2:
0.6 mM (8h) to [10 mM (8be8e)). In general, different
p-aryl substituted moieties were tolerated in maintaining
COX-1 inhibiting activity but the introduction of the typical
COX-2 sulfone moiety (8h) decreased the COX-1 activity sig-
nificantly. This is in line with the previous findings [23].
By comparing the different substituents R1 and R2, clear
decisions can be drawn with regard to the COX-1 activity.
The most potent COX-1 inhibitor in this series is the dime-
thoxy substituted (R1 and R2) compound 8a (IC50:
0.006 mM) which inhibits COX-1 about 3-fold more potent
compared to the monomethoxy substituted compounds 8b
(IC50: 0.02 mM), 8f (IC50: 0.01 mM) and 8g (IC50: 0.02 mM).
Ebselen was chosen as standard compound to study the
ROS inhibiting activity. Despite it was published that ebselen
Scheme 2. Proposed mechanism for the formation of 8ae8h.

M. Scholz et al. / European Journal of Medicinal Chemistry 43 (2008) 1152e1159
1155
Table 1
COX-1/2 and 5-LOX inhibiting activities and OH radical scavenging potency of the newly described 4,5-diaryl isoselenazoles
R1
N
Se
R2
8a-8h
a
IC50 (mM)
b
IC50 (mM)
Compound
R1
R2
COX-1
COX-2
5-LOX
OH radical scavenging
8a
8b
OCH3
CH3
CH3
Cl
OCH3
OCH3
Cl
0.006
0.02
0.2
8
58%c
64%c
67%c
45%c
44%c
42%c
53%c
60%c/8
14%d
0
0
8c
8d
0
0
CH3
Cl
0.05
0.2
0
0
8e
Cl
OCH3
Cl
0
0
8f
8g
Cl
OCH3
SO2CH3
0.01
0.02
38%c
65%c
2.1
31%c
n.t.
16%c
17%c
0.6
1
0
0
8h
F
34%d
27%d
6
Celecoxib
Ebselen
NDGA
Thioctic acid
a
0
54%c
1
10%c
n.t.
29
11
n.t.
Values are means of two determinations.
Values are means of three determinations.
Inhibition at a concentration of 10 mM.
b
c
d
Inhibition at a concentration of 100 mM, n.t.: not tested.
is not a very potent radical scavenger [14], we found a high
potency (IC50: 6 mM) in our experimental setting. In our assay
we induced the production of hydroxyl radicals by a Fenton
reaction. To quantify its effect the spintrap method was used.
Unfortunately most of the compounds show no significant
ROS inhibiting activity. Only compound 8h (38% inhibition
at 100 mM) displayed a weak activity. In context with manifold
enzyme inhibiting activities of ebselen (5- and 15-lipoxyge-
nases, NO synthase, NADPH oxidase, protein kinase C and
Hþ/Kþ-ATPase) shown in literature these features should be
subsequently kept in mind.
Taken together we were able to prepare the novel 4,5-diaryl
substituted isoselenazoles. To the best of our knowledge this is
the first time that this type of compounds was synthesized.
Compound 8a is equipotent to celecoxib concerning COX-2
inhibition (IC50: 1 mM vs. 0.6 mM) but more potent with re-
gard to the COX-1 inhibition (IC50: 0.006 mM vs. w10 mM),
however, the 5-LOX inhibition compared to licofelone (IC50:
10 mM vs. 0.18 mM [8]) is lower. The most balanced com-
pound in this series was compound 8h including COX-1,
COX-2 and 5-LOX inhibitory activities and weak hydroxyl
radical scavenger potency.
Fig. 2. Binding mode of 8a (left) and 8h (right) docked in COX-2 active site (COX-2 PDB file: 1CX2) using the ICM-Pro software (version 3.3-02a). Hydrogens of
amino acids are not depicted for clarity.

1156
M. Scholz et al. / European Journal of Medicinal Chemistry 43 (2008) 1152e1159
After exact 90 s the EPR experiment was started. Instrumental
parameters were as follows: receiver gain 3.99 ꢁ 105, modula-
tion amplitude 3.0 G, time constant 0.64 ms, conversion time
81.92 ms, attenuation 4 ms. The spectra were analyzed with
the WinEPRÒ (Version 1.0) software. The raw data were inte-
grated, the background noise was subtracted and the heights of
the second peaks were analyzed. Each concentration was
tested three times. Thioctic acid in concentrations of 10, 1
and 0.1 mM/l was used as standard substance in every test se-
ries. For an amount of 30 spectra totalling six zero values as
control were analyzed.
The EPR spectra were acquired on a Bruker EMX EPR
spectrometer. Melting points were determined with a Buchi
¨
apparatus according to Dr. Tottoli and are uncorrected.
1H NMR spectra (300 MHz) were recorded on a Bruker AC
300 spectrometer. Combustion analyses were performed with
a Carlo Erba Strumentiazione 1106 analyzer. Column chroma-
tography was performed with Merck silica gel 60 (0.063e
0.200 mm). The progress of the reactions was monitored by
thin layer chromatography (TLC) performed with Merck silica
gel 60 F-245 plates. All reagents and solvents were obtained
from commercial sources and used as received. Reagents
were purchased from SigmaeAldrich Chemie Steinheim,
Germany, or Acros, Nidderau, Germany.
Fig. 3. Overlapping of 8a, 8h, and SC-558 in COX-2 (COX-2 PDB file: 1CX2)
active site. Hydrogens of amino acids are not depicted for clarity.
4. Experimental section
4.3. Molecular modeling studies
4.1. Enzyme assays
Docking experiments were performed using ICM-Pro soft-
ware (version 3.3-02a) by Molsoft. The coordinates for the
X-ray crystal structure of the enzymes COX-2 were obtained
from the RCSB Protein Data Base (COX-2 PDB file:
1CX2). The structure data were revised by adding the missing
aromatic p systems and ionic attributes to the amino acids in
the binding pocket and by adding hydrogen to all amino acids.
The revised protein data were converted in the ICM format,
the binding pockets were defined by searching the neighbours
of the co-crystallized structure of COX-2 and SC-558, the re-
COX-1 inhibition was determined by using platelets iso-
lated from bovine blood, incubated with the test substance,
and stimulated by the Ca ionophor A23187. The inhibition
of COX-1 was assessed by quantitative HPLC determination
of the formation of 12-hydroxyheptadecatrienoic acid [25].
COX-2 inhibition was determined by using aliquots of hu-
man blood samples, containing sodium heparin. The samples
were incubated in the absence and presence of LPS and the
test substances as described [26].
˚
ceptor grid maps were calculated with a grid spacing of 0.5 A,
5-LOX inhibition was investigated by using bovine poly-
morphonuclear leucocytes, incubated with the test substance,
and stimulated by the Ca ionophor A23187. The inhibition
of 5-LOX was assessed by quantitative HPLC determination
of the formation of leukotriene B4 [25].
the grid was defined in such a way that it included the ligand
and key residues in each of the x, y, z directions. For the li-
gands, 2De3D conversion is followed by energy minimization
using the MMFF option as a force field. The docking algo-
rithm implemented in ICM-Pro (version 3.3-02a) optimized
the entire ligand in the receptor field, applying a multistart
Monte Carlo minimization procedure in internal coordinate
space.
4.2. EPR spin trapping
Test assay for hydroxyl radical scavenging: DEPMPO was
purchased from Calbiochem (San Diego, USA). The test solu-
tion was prepared by adding 2 ml of a solution of the test sub-
stance in acetonitrile (concentration 10, 1 or 0.1 mM/l) or pure
acetonitrile, as zero value, to 192 ml demineralized water in
a 1.5 ml micro-centrifuge tube. DEPMPO solution of 2 ml
(20 mM/l), 2 ml FeSO4 solution (5 mM/l) and 2 ml hydrogen
peroxide solution (2.5 mM/l) were put on different points on
the wall of the tube. The reaction was started by vortexing
the tube. After 10 s a sample was gathered with a 100 ml ring-
Many detailed information about the COX-2 active site
are known [27e29]. It was possible to get structural infor-
mation with high-resolution X-ray analysis from co-crystal-
lized inhibitor enzyme complexes. In order to study the
interactions we used the docking software ICM-Pro (version
3.3-02a) and the COX-2 enzyme protein data co-crystallized
with SC-558 (PDB entry: 1CX2). After converting the
PDB data in an ICM format, defining the receptor active
site and generating the receptor grid maps we were able
to calculate the interaction of the substances 8a and 8h
with COX-2.
cap from HIRSCHMANNÒ Laborgerate and closed with wax.
¨

M. Scholz et al. / European Journal of Medicinal Chemistry 43 (2008) 1152e1159
1157
4.4. log P values
(52.5 mM) was added dropwise. Subsequently chlorobenzene
5 (50 mM) was added at a temperature below 20 ꢀC and stirred
overnight. The mixture was poured cautiously into crushed ice
and Al(OH)3 precipitate was dissolved in concentrated hydro-
chloric acid. The reaction mixture was extracted with di-
chloromethane, the organic layers were washed with water,
caustic soda solution (2% m/V) and water, dried over anhy-
drous NaSO4 and concentrated under reduced pressure to ob-
tain 40% of the 1,2-diphenylethanone derivative 6f.
ChemDraw 8.0 from Cambridge Software was used to cal-
culate log P values. To calculate the molecules containing se-
lenium atoms method 2 is used. Method 2 is based on 120
atomic contributions evaluated from 893 molecules by least
squares analysis. In addition to the atoms introduced for
method 1, it can handle molecules that contain phosphorus
and selenium atoms. This method works with a standard devi-
ation of 0.50 log P units.
4.5.5. Method v: general procedure for
4.5. Chemistry
the synthesis of 3-chloro-2,3-diarylacrylaldehydes (7)
Phosphoryl chloride (4 g, 26 mM) was added dropwise to
a cooled (0 ꢀC) solution of 1,2-diphenylethanone 6ae6h
(11.7 mM) in DMF (30 ml) and the temperature was kept be-
low 10 ꢀC. The mixture was allowed to reach rt and stirred for
an hour changing the colour to yellow. Subsequently it was
heated to 80 ꢀC for 4 h (the colour changes to orange and to
dark brown at the end). Vilsmeier complex was hydrolyzed
by pouring it into an aqueous solution of sodium acetate
(3 mol/l, 50 ml) and crushed ice if necessary. The crude prod-
uct precipitated and was recrystallized from ethanol to obtain
50e95% of 3-chloro-acrylaldehyde 7ae7h.
All compounds were analyzed for C, H, N. Elemental
analysis were within 0.4% for elements unless indicated
otherwise.
4.5.1. Method i: general procedure for the
synthesis of 1,2-diaryl ethanoles (3)
To magnesium chippings (1.21 g, 50 mM) in anhydrous di-
ethyl ether (10 ml) chloromethylbenzene 1ae1c (50 mM) in
anhydrous diethyl ether (10 ml) was added. The mixture was
heated for half an hour. After cooling it down to rt, a solution
of benzaldehyde 2ae2d (45 mM) in anhydrous diethyl ether
(10 ml) was added dropwise and thereafter heated for 2 h. After
hydrolysis of the mixture with crushed ice, diluted hydro-
chloric acid was added and it was extracted with diethyl ether.
The organic layer was dried over anhydrous Na2SO4, concen-
trated under reduced pressure and after column chromatogra-
phy (silica gel, ethyl acetate/petroleum ether 3:7) 24e95% of
the alcohols 3be3e, 3g or 3i were obtained as colourless solid.
4.5.6. Method vi: general procedure for the synthesis of 4,
5-diaryl isoselenazoles (8)
A mixture of 3-chloro-acrylaldehydes 7ae7h (33.34 mM),
ammonium chloride (5.34 g, 100 mM), and potassium seleno-
cyanate (14.4 g, 100 mM) in acetone (80 ml) was heated under
reflux for 5 h (caution: HCN formation!). After cooling to rt
the mixture was poured into a solution of saturated aqueous
sodium hydrogen carbonate (100 ml) and extracted three times
with ether. The combined organic layers were dried over anhy-
drous Na2SO4 and concentrated under reduced pressure. After
column chromatography (silica gel, ethyl acetate/petroleum
ether 3:7) 30e60% of isoselenazoles 8ae8h were obtained
as yellow oil. Some of them gave hygroscopic yellow solids
after drying under reduced pressure.
4.5.2. Method ii: general procedure for the
synthesis of methylsulfonyl derivative (3h)
To a cooled (0 ꢀC) solution of the thioether 3i (10 mM) in
dichloromethane (20 ml) was added 3-chloroperbenzoic acid
(3.45 g, 20 mM) and stirred for 2 h (TLC control). The mix-
ture was filtered, washed with sodium hydroxide solution
(5% m/m) and water, dried over anhydrous Na2SO4 and con-
centrated to obtain 90% of methylsulfonyl 3h.
4.5.7. Structural data of 1,2-diaryl ethanoles (3)
4.5.3. Method iii: general procedure for the
synthesis of 1,2-diaryl ethanones (6ae6e, 6g, 6h)
4.5.7.1. 1-(4-Methoxyphenyl)-2-p-tolylethanol (3b). Method i;
reactants: 1a, 2a; yield: 25%; 1H NMR (DMSO) 7.18 (d,
8.62 Hz, 2H), 6.99 (s, 4H), 6.82 (d, 8.57 Hz, 2H), 5.12 (d,
4.55 Hz, 1H), 4.63 (dd, 11.47 Hz, 6.38 Hz, 1H), 3.70 (s,
3H), 2.79 (dq, 13.42 Hz, 13.42 Hz, 13.39 Hz, 6.71 Hz, 2H).
To a solution of the alcohol 3ae3e, 3g, 3h (20 mM) in di-
chloromethane (60 ml) a solution of sodium dichromate
(1.76 g, 6.7 mM) and concentrated sulfuric acid (1.5 ml) in wa-
ter (10 ml) was slowly added (approximately 15 min). The mix-
ture was stirred for 3 h at rt, extracted with dichloromethane,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. After column chromatography (silica gel, ethyl ace-
tate/petroleum ether 1:1) between 20% and 60% of 1,2-diphe-
nylethanone 6ae6e, 6g, 6h were obtained as a colourless solid.
4.5.7.2. 1-(4-Chlorophenyl)-2-p-tolylethanol (3c). Method i;
reactants: 1a, 2b; yield: 55%; 1H NMR (DMSO) 7.26 (d,
8.26 Hz, 2H), 7.18e7.16 (d, 7.35 Hz, 2H), 7.15 (d, 8.02 Hz,
2H), 7.08 (d, 7.73 Hz, 2H), 5.23 (d, 4.52 Hz, 1H), 4.67 (m,
1H), 2.83 (d, 6.54 Hz, 2H), 2.25 (s, 3H).
4.5.4. Method iv: general procedure for the synthesis of
1-(4-chlorophenyl)-2-(4-methoxyphenyl)ethanone (6f)
To a cooled (0 ꢀC) suspension of AlCl3 (8 g, 60 mM) in di-
chloromethane (50 ml) 2-(4-methoxyphenyl)acetyl chloride 4
4.5.7.3. 2-(4-Chlorophenyl)-1-p-tolylethanol (3d). Method i;
reactants: 1b, 2c; yield: 50%; 1H NMR (DMSO) 7.26 (d,
8.41 Hz, 2H), 7.19e7.16 (d, 7.92 Hz, 2H), 7.15 (d, 8.34 Hz,

1158
M. Scholz et al. / European Journal of Medicinal Chemistry 43 (2008) 1152e1159
2H), 7.08 (d, 7.95 Hz, 2H), 5.23 (d, 4.62 Hz, 1H), 4.68 (m,
1H), 2.83 (d, 6.57 Hz, 2H), 2.25 (s, 3H).
8.59 Hz, 2H), 7.35 (d, 8.18 Hz, 2H), 7.26 (d, 7.89 Hz, 2H), 7.04
(d, 8.56 Hz, 2H), 4.33 (s, 2H), 3.83 (s, 3H).
4.5.7.4. 1,2-Bis(4-chlorophenyl)ethanol (3e). Method i; reac-
4.5.8.7. 2-(4-Fluorophenyl)-1-(4-(methylsulfonyl)phenyl)etha-
none (6h). Method iii; reactant: 3h; yield: 60%; 1H NMR
(DMSO) 8.26 (d, 8.46 Hz, 2H), 8.08 (d, 8.47 Hz, 2H), 7.30
(dd, 8.43 Hz, 5.75 Hz, 2H), 7.15 (t, 8.89 Hz, 2H), 4.49 (s, 2H),
3.28 (s, 3H).
1
tants: 1b, 2b; yield: 24%; H NMR (DMSO) 7.32 (m, 4H),
7.26 (d, 8.30 Hz, 2H), 7.14 (d, 8.32 Hz, 2H), 5.41 (d,
4.55 Hz, 1H), 4.74 (m, 1H), 2.84 (d, 6.4 Hz, 2H).
4.5.7.5. 2-(4-Chlorophenyl)-1-(4-methoxyphenyl)ethanol (3g).
1
Method i; reactants: 1b, 2a; yield: 87%; H NMR (DMSO)
4.5.9. Structural data of 3-chloro-2,3-diarylacrylaldehydes (7)
7.26 (d, 8.35 Hz, 2H), 7.19 (d, 8.6 Hz, 2H), 7.14 (d,
8.35 Hz, 2H), 6.83 (d, 8.6 Hz, 2H), 5.21 (d, 4.55 Hz, 1H),
4.66 (m, 1H), 3.7 (s, 3H), 2.84 (m, 2H).
4.5.9.1. (Z )-3-Chloro-2,3-bis(4-methoxyphenyl)acrylaldehyde
(7a). Method v; reactant: 6a; yield: 95%; H NMR (DMSO)
9.48 (s, 1H), 7.59 (d, 8.55 Hz, 2H), 7.19 (d, 8.5 Hz, 2H), 7.09
(d, 8.55 Hz, 2H), 6.98 (d, 8.5 Hz, 2H), 3.84 (s, 3H), 3.78 (s, 3H).
1
4.5.7.6. 2-(4-Fluorophenyl)-1-(4-(methylsulfonyl)phenyl)ethanol
1
(3h). Method ii; reactant: 3i; yield: 90%; H NMR (DMSO)
4.5.9.2. (Z )-3-Chloro-3-(4-methoxyphenyl)-2-p-tolylacrylalde-
hyde (7b). Method v; reactant: 6b; yield: 64%; 1H NMR
(DMSO) 9.49 (s, 1H), 7.60 (d, 8.77 Hz, 2H), 7.23 (d, 7.84 Hz,
2H), 7.13 (d, 8.09 Hz, 2H), 7.09 (d, 8.78 Hz, 2H), 3.83 (s, 3H).
7.84 (d, 8.33 Hz, 2H), 7.56 (d, 8.30 Hz, 2H), 7.20 (d,
8.50 Hz, 2H), 7.02 (d, 8.83 Hz, 2H), 5.74 (s, 1H), 4.84 (dd,
7.38 Hz, 5.48 Hz, 1H), 3.17 (s, 3H), 2.85 (dd, 12.49 Hz,
5.02 Hz, 2H).
4.5.9.3. (Z )-3-Chloro-3-(4-chlorophenyl)-2-p-tolylacrylalde-
hyde (7c). Method v; reactant: 6c; yield: 68%; 1H NMR
(DMSO) 9.49 (s, 1H), 7.7 (d, 8.11 Hz, 2H), 7.62 (d, 6.42 Hz,
2H), 7.24 (d, 7.34 Hz, 2H), 7.18 (d, 7.09 Hz, 2H), 2.33 (s, 3H).
4.5.7.7. 2-(4-Fluorophenyl)-1-(4-(methylthio)phenyl)ethanol
(3i). Method i; reactants: 1c, 2d; yield: 95%; 1H NMR
(DMSO) 7.22 (d, 8.36 Hz, 2H), 7.15 (m, 4H), 7.03 (t,
8.93 Hz, 2H), 5.27 (d, 4.53 Hz, 1H), 4.67 (q, 6.31 Hz,
10.89 Hz, 1H), 2.83 (d, 6.55 Hz, 2H), 2.43 (s, 3H).
4.5.9.4. (Z )-3-Chloro-2-(4-chlorophenyl)-3-p-tolylacrylalde-
hyde (7d). Method v; reactant: 6d; yield: 57%; 1H NMR
(DMSO) 9.47 (s, 1H), 7.57 (d, 7.26 Hz, 2H), 7.5 (d, 6.84 Hz,
2H), 7.36 (d, 7.9 Hz, 2H), 7.3 (d, 8.24 Hz, 2H), 2.39 (s, 3H).
4.5.8. Structural data of 1,2-diaryl ethanones (6)
4.5.8.1. 1-(4-Methoxyphenyl)-2-p-tolylethanone (6b). Method
iii; reactant: 3b; yield: 55%; 1H NMR (DMSO) 8.00 (d,
8.83 Hz, 2H), 7.13 (d, 8.02 Hz, 1H), 7.08 (d, 8.11 Hz, 2H),
7.02 (d, 8.93 Hz, 2H), 4.23 (s, 2H), 3.82 (s, 3H).
4.5.9.5. (Z )-3-Chloro-2,3-bis(4-chlorophenyl)acrylaldehyde
(7e). Method v; reactant: 6e; yield: 90%; H NMR (DMSO)
9.47 (s, 1H), 7.73 (d, 8.55 Hz, 2H), 7.63 (d, 8.42 Hz, 2H),
7.52 (d, 8.45 Hz, 2H), 7.32 (d, 8.47 Hz, 2H).
1
4.5.8.2. 1-(4-Chlorophenyl)-2-p-tolylethanone (6c). Method
iii; reactant: 3c; yield: 30%; 1H NMR (DMSO) 8.03 (d,
8.55 Hz, 2H), 7.58 (d, 8.55 Hz, 2H), 7.11 (m, 4H), 4.31 (s,
2H), 2.25 (s, 3H).
4.5.9.6. (Z)-3-Chloro-3-(4-chlorophenyl)-2-(4-methoxyphenyl)-
acrylaldehyde (7f). Method v; reactant: 6f; yield: 64%; 1H
NMR (DMSO) 9.49 (s, 1H), 7.69 (d, 8.56 Hz, 2H), 7.61 (d,
8.60 Hz, 2H), 7.22 (d, 8.69 Hz, 2H), 6.99 (d, 8.72 Hz, 2H),
3.78 (s, 3H).
4.5.8.3. 2-(4-Chlorophenyl)-1-p-tolylethanone (6d). Method
1
iii; reactant: 3d; yield: 27.5%; H NMR (DMSO) 7.93 (d,
8.1 Hz, 2H), 7.42e7.3 overlapping signals (t, 7.73 Hz, 4H),
4.37 (s, 2H), 2.36 (s, 3H).
4.5.9.7. (Z )-3-Chloro-2-(4-chlorophenyl)-3-(4-methoxyphenyl)-
acrylaldehyde(7g). Methodv;reactant:6g;yield:64%;1HNMR
(DMSO) 9.48 (s, 1H), 7.63 (d, 8.69 Hz, 2H), 7.5 (d, 8.41 Hz, 2H),
7.3 (d, 8.41 Hz, 2H), 7.1 (d, 8.73 Hz, 2H), 3.85 (s, 3H).
4.5.8.4. 1,2-Bis(4-chlorophenyl)ethanone (6e). Method iii; re-
1
actant: 3e; yield: 62%; H NMR (DMSO) 8.04 (d, 8.62 Hz,
2H), 7.61 (d, 8.61 Hz, 2H), 7.37 (d, 8.47 Hz, 2H), 7.27 (d,
8.46 Hz, 2H), 4.42 (s, 2H).
4.5.9.8. (Z )-3-Chloro-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)
phenyl)acrylaldehyde (7h). Method v; reactant: 6h; yield:
1
20%; H NMR (DMSO) 9.46 (s, 1H), 8.08 (d, 8.06 Hz, 2H),
7.96 (d, 8.13 Hz, 2H), 7.42e7.20 (m, 4H), 3.29 (s, 3H).
4.5.8.5. 1-(4-Chlorophenyl)-2-(4-methoxyphenyl)ethanone (6f).
Method iv; reactants: 4, 5; yield: 50%; 1H NMR (DMSO) 8.03
(d, 7.0 Hz, 2H), 7.58 (d, 6.94 Hz, 2H), 7.155 (d, 6.86 Hz, 2H),
6.86 (d, 6.9 Hz, 2H), 4.29 (s, 2H), 3.7 (s, 3H).
4.5.10. Structural data of 4,5-diaryl isoselenazoles (8)
4.5.10.1.
4,5-Bis(4-methoxyphenyl)-1,2-selenazole
(8a).
1
4.5.8.6. 2-(4-Chlorophenyl)-1-(4-methoxyphenyl)ethanone (6g).
Method iii; reactant: 3g; yield: 44%; 1H NMR (DMSO) 8.01 (d,
Method vi; reactant: 7a; yield: 56%; mp: 79 ꢀC; H NMR
(DMSO) 9.48 (s, 1H), 7.59 (d, 8.69 Hz, 2H), 7.19 (d, 8.69 Hz,

M. Scholz et al. / European Journal of Medicinal Chemistry 43 (2008) 1152e1159
1159
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9.29 (s, 1H), 7.46 (d, 8.3 Hz, 2H), 7.44 (d, 8.02 Hz, 2H),
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8.37 Hz, 2H), 7.2 (d, 8.55 Hz, 2H), 6.94 (d, 8.54 Hz, 2H),
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