Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase inhibition

Article abstract of DOI:10.1021/jm701496h

New anti-inflammatory agents possessing dual cyclooxygenase/lipoxygenase (COX/LOX) inhibition were discovered by computer-aided prediction of biological activity for 573 virtually designed chemical compounds. Prediction of biological activity was performed by PASS, and prediction results were analyzed with PharmaExpert software. Nine 2-(thiazole-2-ylamino)-5-phenylidene-4- thiazolidinone derivatives differing by the phenyl group substitution were selected for synthesis and experimental testing as potential COX/LOX inhibitors. Eight tested compounds exhibited anti-inflammatory activity in the carrageenin-induced paw edema. It was shown that seven tested compounds (77.8%) were LOX inhibitors, seven compounds were COX inhibitors (77.8%), and six tested compounds (66.7%) were dual COX/LOX inhibitors. Analysis of lipophilicity of the compounds showed a negative correlation with inhibition of edema formation. The binding modes of the most active compounds of this series (2-(thiazole-2-ylamino)-5-(m-chlorophenylidene)-4-thiazolidinone for COX-1 and COX-2, and 2-(thiazole-2-ylamino)-5-(m-nitrophenylidene)-4-thiazolidinone for 15-LOX) were proposed on the basis of docking studies.

Full text of DOI:10.1021/jm701496h

J. Med. Chem. 2008, 51, 1601–1609
1601
Computer-Aided Discovery of Anti-Inflammatory Thiazolidinones with Dual Cyclooxygenase/
Lipoxygenase Inhibition
Athina A. Geronikaki,† Alexey A. Lagunin,*,‡ Dimitra I. Hadjipavlou-Litina,† Phaedra T. Eleftheriou,† Dmitrii A. Filimonov,‡
Vladimir V. Poroikov,‡ Intekhab Alam,§ and Anil K. Saxena§
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle UniVersity, Thessaloniki, 54124, Greece, Institute of Biomedical
Chemistry of Russian Academy of Medical Sciences, Pogodinskaya Street, 10, Moscow, 119121, Russia, and Medicinal Chemistry DiVision,
Central Drug Research Institute, Chattar Manzil Palace, Lucknow-226 001, India
ReceiVed July 24, 2007
New anti-inflammatory agents possessing dual cyclooxygenase/lipoxygenase (COX/LOX) inhibition were
discovered by computer-aided prediction of biological activity for 573 virtually designed chemical compounds.
Prediction of biological activity was performed by PASS, and prediction results were analyzed with
PharmaExpert software. Nine 2-(thiazole-2-ylamino)-5-phenylidene-4-thiazolidinone derivatives differing
by the phenyl group substitution were selected for synthesis and experimental testing as potential COX/
LOX inhibitors. Eight tested compounds exhibited anti-inflammatory activity in the carrageenin-induced
paw edema. It was shown that seven tested compounds (77.8%) were LOX inhibitors, seven compounds
were COX inhibitors (77.8%), and six tested compounds (66.7%) were dual COX/LOX inhibitors. Analysis
of lipophilicity of the compounds showed a negative correlation with inhibition of edema formation. The
binding modes of the most active compounds of this series (2-(thiazole-2-ylamino)-5-(m-chlorophenylidene)-
4-thiazolidinone for COX-1 and COX-2, and 2-(thiazole-2-ylamino)-5-(m-nitrophenylidene)-4-thiazolidinone
for 15-LOX) were proposed on the basis of docking studies.
Introduction
dual-acting antihypertensive agents (dual angiotensin-converting
enzyme/neutral endopeptidase inhibitors).3 The current version
of PASS predicts more than 3300 types of biological activity
including pharmacotherapeutic effects, mechanisms of action,
interaction with drug-metabolizing enzymes, side effects, and
toxicity. To analyze the PASS prediction results, taking into
account the mechanism-effect relationships, and to search for
compounds with the desirable profiles of biological activity,
PharmaExpert4 software was developed. The current version
of PharmaExpert, based on information extracted from the
literature, contains about 5700 mechanism-effect relationships.
The combination of PASS and PharmaExpert provides a unique
possibility to search for compounds with possible multitargeted
action. The purpose of the present study is to find compounds
with dual cyclooxygenase/lipoxygenase (COX/LOX) inhibition
as a mechanism of anti-inflammatory action.
For many years, clinicians have treated patients by combina-
tions of drugs with different pharmacotherapeutic actions. It is
being recognized that a balanced modulation of several targets
can provide a superior therapeutic effect and a favorable side
effect profile compared to the action of a selective ligand.1
Compared to drug combinations, there are several advantages
associated with ligands acting on multiple targets, such as the
more predictable pharmacokinetic and pharmacodynamic prop-
erties that are a consequence of the administration of a single
pharmaceutical substance, as well as improved patient compli-
ance.2 The molecular starting point of search for dual-acting
molecules is determined by rational design using a combination
of pharmacophores or by screening of compound libraries of
known drugs. This screening may be executed by both in vitro
and in silico. A study performed by Morphy and coauthors1
showed that it is most probable to discover molecules acting
on related proteins from the same or close protein families. Study
of structures of ligands acting on different targets jointly with
analysis of protein similarity, size, and features of their active
centers can be used to discover potential targets for dual-acting
agents. We have shown previously that the prediction of
biological activity spectra for substances on the basis of their
structural formulas by the computer program PASSa (Prediction
of Activity Spectra for Substances) can be used in search of
Inflammation is a multifactorial process. It reflects the
response of organism to various stimuli and is related to many
disorders such as arthritis, asthma, and psoriasis, which require
prolonged or repeated treatment. Cyclooxygenase (COX) and
lipoxygenase (LOX) produce two groups of arachidonic acid
metabolites, prostaglandins (COX products) and leucotrienes
(LOX products), that play a key role in inflammation. Traditional
nonsteroidal anti-inflammatory drugs (NSAIDs) act via the
inhibition of the COX-1 isoenzyme or the combined inhibition
of COX-1 and COX-2 isoenzymes. For example, acetylsalicylate
(aspirin) is a COX-1 selective inhibitor, whereas indomethacin
(Indocin) and naproxen (Naprosyn) are COX-1/COX-2 inhibi-
tors. Because COX-1 is mainly responsible for mucus formation
in the gastrointestinal (GI) tract, COX-1 inhibition is blamed
for inducing GI irritation, the main undesired side effect of such
drugs.5 Another side effect of selective COX-1 inhibitors, mild
bleeding diathesis, also results from the inhibition of the COX-1
catalyzed synthesis of the platelet aggregation factor, throm-
boxan (TXA2).6
* To whom correspondence should be addressed. Phone: +7 495 247-
3029. Fax: +7 495 245-0857. E-mail: alexey.lagunin@ibmc.msk.ru.
†
Aristotle University.
Institute of Biomedical Chemistry of Russian Academy of Medical
‡
Sciences.
§
Central Drug Research Institute.
a Abbreviations: COX, cyclooxygenase; CPE, carrageenin-induced paw
edema; LDL, low density lipoprotein; SAR, structure–activity relationships;
LOX, lipoxygenase; NSAID, nonsteroidal anti-inflammatory drug; PASS,
prediction of activity spectra for substances; RPTLC, reversed-phase thin-
layer chromatography; TNF, tumor necrosis factor.
10.1021/jm701496h CCC: $40.75
2008 American Chemical Society
Published on Web 02/27/2008

1602 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Scheme 1. Structure of the Tested Compounds
Geronikaki et al.
Because COX-2 isoenzyme was found to be overexpressed
during inflammation, drug investigation was focused on selective
COX-2 inhibition, hoping to prevent inflammation by sidestep-
ping the undesired side effect of COX-1 inhibitors.7,8 However,
drugs of the new generation of NSAIDs, which selectively
inhibit COX-2 isoenzyme, were associated with increased risk
of myocardial infraction and cardiovascular thrombotic events.
The thrombotic effect of these drugs seems to be due to the
decrease of the level of the prostacyclin (PGI2), a molecule with
vasodilatory and antiaggregatory properties, synthesized via the
action of COX-2. In addition, COX-2 was found to exhibit a
protective role in asthma9 and GI tract irritation.
Ziakas and co-workers18,19 tested a number of tolfenamic and
BHT derivatives for COX-1, COX-2, and LOX inhibition.
Results and Discussion
In this paper, we describe the computer-aided discovery of
dual COX/LOX thiazolidinone inhibitors (Scheme 1) that were
expected to offer protection against inflammation.
Computer Prediction of Biological Activity. Prediction of
biological activity spectra was obtained using PASS software.
The PASS prediction results for 573 chemical compounds
designed in silico by the Department of Pharmaceutical Chem-
istry of Aristotle University were analyzed using PharmaExpert
software. We took into consideration 40 known types of
molecular mechanisms of anti-inflammatory activity predicted
by PASS. The 573 virtually designed compounds are derivatives
of thiazole/benzothiazoles and benzoisothiazoles that may be
divided into several groups: (1) thiazole/benzothiazole amides
(e.g., 2/3-substituted N-(4,5-substituted-thiazole-2-yl)acetamides/
propionamides and N-(benzo[d]isothiazol-3-yl)-3-aminopropi-
onamide)); (2) ketone derivatives of thiazoles (e.g., 1-(2-
substituted 4-methyl-thiazol-5-yl)-3-substituted propane-1-one);
(3) guanidine-containing derivatives of benzoisothiazole (e.g.,
benzo[d]isothiazol-3-yl)guanidine derivatives); (4) sulfonamide
derivatives of thiazoles (e.g., N-(thiazol-2-yl)benzensoufona-
mide); (5) thiazolyl derivatives of coumarin; (6) Schiff bases
(e.g., N-substituted benzylidene/phenylbenzylidene)benzo[d]thi-
azol/isothiazol-3-amines); (7) thiazolidinones.
Thirty-one of the designed compounds were predicted to have
dual mechanism of anti-inflammatory activity acting as COX,
LOX, or TNF convertase inhibitors and as prostaglandin or
interleukin-1 antagonists with probability higher than 50%
(Table 1). Twenty of the selected compounds were predicted
to be nonspecific COX/LOX inhibitors, whereas 22 were
predicted to be nonspecific COX and specific 5-LOX inhibitors.
All 22 compounds predicted to be COX/5-LOX inhibitors were
2-(thiazole-2-ylamino)-5-phenylidene-4-thiazolidinone deriva-
tives differing in the thiazolyl group substitution and in the
phenyl group substitution. The nine compounds finally selected
for evaluation of their biological activity had no substituent at
the thiazolyl group and differed by the phenyl group substitution
(Scheme 1). In addition to the positive prediction results and
the fact that these compounds structurally belong to the same
subgroup, the selection of the final nine compounds was
The failure of COX-1 and COX-2 selective inhibitors evoked
the concept that inflammation should be considered as a
multifactorial process and all biochemical pathways should be
taken into account, including the LOX pathway.
Leucotrienes and lipoxins produced via the LOX pathway
also play a role in inflammation. They are associated with
leucocyte activation and adhesion to vascular endothelium10 and
are involved in the pathogenesis of bronchial asthma11 and
edema formation. It is also believed that they play a role in the
damage of gastric mucosa.12–14 Enhanced 15-LOX activity has
an additional undesired side effect because it enhances athero-
matic plaque formation via LDL oxidation, resulting in elevated
probabilities of atheromatosis15 in patients suffering from
chronic inflammatory diseases.
Compounds that combine COX-1/2 and LOX inhibition
present multiple advantages because they act on the two major
arachidonic acid metabolic pathways and possess a wide range
of anti-inflammatory activity.12 Because leucotrienes have their
role in blood coagulation and gastric tract irritation, LOX
inhibitory action seems to be able to ameliorate GI tract irritation
resulting from COX-1 inhibition as well as the prothrombotic
tendency resulting from COX-2 inhibition. For the reasons
mentioned above, recent research has been focused on the
development of dual-acting COX/LOX inhibitors. Currently,
licofelone, a COX-2/5-LOX inhibitor, has been evaluated in
phase III clinical trials.16 Several derivatives containing pyra-
zoline, thiophene, di-tert-butylphenol, hydrazone, pyrrolidine,
and pyrazole subunits have been found to be potent dual
inhibitors.5 Most recently, Rao and co-workers17 tested a number
of 1,3-diarylprop-2-yn-1-ones as well as rofecoxib derivatives
for COX-1, COX-2, and 5,15-LOX inhibitory activity and

Anti-Inflammatory Thiazolidinones
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1603
(RPTLC)22 and to compare them with the corresponding
theoretically calculated ClogP values23 in n-octanol buffer (Table
2).
Table 1. Number of Compounds That Have >50% Probabilities of
Dual Mechanisms of Anti-Inflammatory Activity
Pa
no. (max),a
%
nameb
numberc
From our results (Table 2) it can be concluded that RM values
could not be used as a successful relative measure of the overall
lipophilic/hydrophilic balance of these molecules, as this is
indicated by the calculated ClogP values, which express their
theoretical log P in the standard octanol/water system (r < 0.5).
We could attribute this to the different nature of the hydrophilic
and lipophilic phases in the two systems and to the presence of
the nitrogen atom in the examined compounds, which could
disturb the absorption/desorption process.
1
2
3
4
5
6
7
8
9
83.7
78.3
74.2
73.3
71.3
69.9
66.9
65.8
54.4
5-LOX inhibitor/COX inhibitor
COX inhibitor/LOX inhibitor
22
20
2
COX inhibitor/interleukin 1 antagonist
COX inhibitor/prostaglandin antagonist
5-LOX inhibitor/prostaglandin antagonist
5-LOX inhibitor/interleukin 1 antagonist
interleukin 1 antagonist/lipoxygenase inhibitor
LOX inhibitor/prostaglandin antagonist
prostaglandin antagonist/TNF convertase
inhibitor
6
4
2
2
4
7
10
52.1
COX inhibitor/TNF convertase inhibitor
2
a Pa(max): maximal probability that was found in the PASS prediction
results for each dual mechanism of anti-inflammatory activity among the
573 compounds initially designed. b Name: dual mechanism of anti-
inflammatory activity predicted by PASS and selected by PharmaExpert.
c Number: number of compounds exhibiting more than 50% probability to
combine both activities.
Biological Results
In Vitro Experiments. COX-1 Inhibition. With the excep-
tion of compound 9, lacking the aryliden group, all compounds
inhibit COX-1 in a range from 8% to 90% when they were
added to the assay mixture at 200 µM (Table 3) and act as
competitive inhibitors because their inhibitory activity decreased
when increased substrate concentrations were used. No inhibi-
tion was observed when arachidonic acid was added in a
concentration of 100 µM, which is slightly higher than the
saturating substrate concentration, showing that inhibition can
be overcome by increasing substrate concentrations. The results
shown in Table 3 were obtained using an arachidonic acid
concentration of 1 µM. IC50 values were calculated for the most
active compounds (Table 4).
2-(Thiazole-2-ylamino)-5-(m-chlorophenylidene)-4-thiazoli-
dinone (7) exhibited the highest inhibitory activity (inhibition,
90%). The lower inhibitory activity of ortho- (8) and para- (6)
substituted derivatives (50% and 31%, respectively) shows that
the addition of the Cl substituent at the meta position of the
phenyl ring is more favorable. Addition of the hydroxy group
at the para position or nitro group at the meta or para position
of the phenyl ring also resulted in less active compounds (p-
OH (1), 62%; p-NO2 (4), 60%; m-NO2 (5), 25%) compared to
compound 7. High π values (π is the contribution of the group
to lipophilicity) of R are correlated with higher inhibitory activity
m-NO2 < m-Cl (π-NO2 ) -0.28; π-Cl ) 0.71). When a
methoxy substituent was added to the meta position (2) of the
p-hydroxy derivative, inhibition was even more reduced.
Moreover, replacement of the p-hydroxy (1) with a p-methoxy
(3) substituent diminished the inhibitory activity dramatically
(8% inhibition) probably because of stereochemical interactions
of the methyl group.
COX-2 Inhibition. All compounds showed no or low
(0-30%) COX-2 inhibition when they were added to the assay
mixture in a concentration of 200 µM. The results shown in
Table 3 were obtained at an arachidonic acid substrate concen-
tration of 0.1 µM. Increase of arachidonic acid concentration
led to loss of activity, showing that the compounds are
competitive inhibitors of the enzyme.
2-(Thiazole-2-ylamino)-5-(m-chlorophenylidene)-4-thiazoli-
dinone (7) exhibited the best COX-2 inhibition (30%). Replace-
ment of the more lipophilic (π- Cl ) 0.71) meta-Cl (7)
substituent by the less lipophilic nitro group (5) gave a
compound with less than half-inhibitory action (12.1%). Sub-
stitution at the para (6) or ortho (7) position resulted in
compounds with practically no inhibitory action (0.0-6.2%).
According to the docking studies (Figure 2), the m-Cl substituent
of compound 7 is placed in a hydrophobic area of the molecule.
Consequently, substituents bringing polar or charged groups at
the proximity of the hydrophobic amino acids of the area would
not favor complex stability. 2-(Thiazole-2-ylamino)-4-thiazo-
Table 2. Experimentally (RM) and Theoretically Calculated
Lipophilicity Values (ClogP and logPsk)a
compd
Rf ((SD)
RM ((SD)
ClogP
logPsk
1
2
3
4
5
6
7
8
9
0.782 ( 0.012
0.726 ( 0.016
0.754 ( 0.011
0.838 ( 0.009
0.828 ( 0.009
0.809 ( 0.006
nd
-0.556 ( 0.032
-0.410 ( 0.034
-0.486 ( 0.027
-0.713 ( 0.028
-0.684 ( 0.026
-0.628 ( 0.018
nd
1.82
1.67
2.41
2.23
2.23
3.20
3.20
3.20
2.49
-0.393
0.367
0.226
0.020
0.144
1.065
nd
nd
nd
nd
nd
nd
nd
a Rf values are the mean from 10 measurements (SD < 10%) of the
coefficient in thin layer chromatography. RM values are the mean from 10
measurements (SD < 10%). nd: not determined.
supported by the fact that these compounds were found to be
potent antimicrobial agents.21 Because inflammation is often a
consequence of microbial infection, the production of agents
with combined antimicrobial and anti-inflammatory action would
be beneficial for treatment of infectious diseases. The selected
compounds were evaluated in vitro to determine their COX-
1/2 and LOX inhibitory activity and in vivo to determine their
anti-inflammatory activity.
It is clear from Table 3, presenting the prediction results and
the experimental data of studied compounds, that PASS suc-
cessfully predicted the anti-inflammatory activity and COX and
LOX inhibitory activity of eight of the nine compounds (89%).
Compounds with a predicted Pa value lower than 0.300 exhibited
no activity, as observed in 7 out of 9 cases (77.8%), or weak
activity in 2 out of 9 cases (22.2%). Compounds with predicted
Pa value greater than 0.350 exhibited activity in 28 out of 32
cases (87.5%).
Chemistry. 2-Chloro-N-(thiazol-2-yl)acetamide (II), synthe-
sized using procedures reported earlier21 starting from 2-ami-
nothiazole (I), upon heterocyclization in the presence of
ammonium thiocyanate in refluxing ethanol, efficiently produced
2-(thiazol-2-ylimino)thiazolidin-4-one (III).20 The 2-thia-
zolylimino-5-arylidene-4-thiazolidinones (1–8) were obtained
by refluxing III with appropriate aldehydes in buffered glacial
acetic acid (Scheme 2).
Physicochemical Studies. Since lipophilicity is a significant
physicochemical property determining distribution, bioavail-
ability, metabolism, and excretion, we tried to experimentally
determine the lipophilicity of the synthesized derivatives as RM
values from reversed-phase thin-layer chromatography

1604 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Geronikaki et al.
Table 3. Experimental Data and Prediction Results for the Studied Compounds
anti-inflammatory (CPE)a activity and COX/LOXb inhibitory activity
inhibition %
PASS prediction results of anti-inflammatory
(CPE) and COX/LOX inhibitory activity (Pa values)
compd
CPE%
COX-1
COX-2
LOX
CPE
COX
COX-1
COX-2
LOX
1
2
3
4
5
6
7
8
9
57.3 ( 3.4
72.7 ( 6.8
51.1 ( 4.2
66.1 ( 1.2
69.4 ( 2.3
54.2 ( 2.4
44.5 ( 1.8
62.0 ( 2.5
62.0
25.0
8.0
60.0
25.0
31.0
90.0
50.0
0.0
0.0
6.2
2.5
4.5
12.1
6.2
30.4
2.1
0.0
44.0
51.0
22.4
12.5
76.0
25.0
12.0
44.2
0.725
0.697
0.729
0.650
0.645
0.732
0.718
0.673
0.725
0.701
0.715
0.748
0.595
0.609
0.740
0.736
0.660
0.701
0.490
0.485
0.577
0.278
0.245
0.289
0.288
0.273
0.307
0.296
0.285
0.278
0.872
0.859
0.868
0.826
0.817
0.868
0.857
0.847
0.872
0.485
0.442
0.357
0.490
a Inhibitory activity on carrageenin-induced rat paw edema. The results are expressed as the mean (n ) 6–10) and SD (Standard deviation) of percentage
reduction of the difference in weight between the carrageenin-injected and uninjected paws following a 0.01 mmol/kg intraperitoneal injection of the test
compound. Each value represents the mean of two independent experiments with 6–10 animals in each group. b Values are the mean of three determinations,
and deviation from the mean is <10% of the mean value. Compound concentration in LOX inhibition assay was 100 µM and in COX-1 and COX-2
inhibition assays was 200 µM.
Scheme 2. Synthetic Pathway for the Preparation of Title
Compounds
activity by NSAIDs is qualitatively similar to the inhibition of
the rat mast cell LOX and can be used as a simple screen for
such activity.24,25
Analysis of percentage inhibition values shows that compound
5 is the most active within the set, followed by compounds 2,
8, and 1 (Table 3). Compound 5 with a m-NO2 group
demonstrates highly significant inhibition compared to the
corresponding m-Cl substituted derivative (7). Low π values
of R are correlated with higher inhibitory activity m-NO2 >
m-Cl (π-NO2 ) -0.28; π-Cl ) 0.71). The presence of the
vanillin moiety (2) is correlated with high inhibitory activity.
Presence of a free OH group (1) is also beneficial for the LOX
inhibitory activity, while compound 3 with a methoxy group
demonstrates lower activity.
The m-Cl (7) substitution of the aryliden group favors COX
inhibitory activity, whereas m-NO2 (5) substitution has the best
effect on LOX inhibitory action. The m-NO2 derivative, also
exhibiting COX inhibitory activity, has good anti-inflammatory
action. Compound 2 (m-OCH3, p-OH derivative), exhibiting the
greatest anti-inflammatory activity, is also one of the most potent
LOX inhibitors also exhibiting moderate COX-1 inhibitory
action.
Table 4. IC50 Values of COX/LOX Inhibition for Studied Compounds
IC50 (µM)
compd
COX-1
158.0
COX-2
LOX
In Vivo Experiment. Inhibition of the Carrageenin-
Induced Edema. In acute toxicity experiments, the compounds
examined in vivo did not present toxic effects in ip doses up to
0.5 mmol/kg body weight of the mouse.
1
2
3
4
5
6
7
8
9
116.0
99.5
122.2
251.2
89.1
120.0
125.9
114.6
141.3
125.0
The in vivo anti-inflammatory effect of the tested com-
pounds was assessed by using the functional model of
carrageenin-induced mouse paw edema and is presented as
the percentage of inhibition of induction of edema at the right
hind paw (Table 3). Edema was measured by weight increase
of the right hind paw in comparison to the uninjected left paw.
Carrageenin-induced edema is a nonspecific inflammation that
is highly sensitive to nonsteroidal anti-inflammatory drugs
(NSAIDs), and so carrageenin has been accepted as a suitable
agent for the study of new compounds with anti-inflammatory
activity. As shown in Table 3, the majority of the investigated
compounds induced protection against carrageenin-induced paw
edema. The protection ranged up to 72.7%, while the reference
drug, indomethacin, induced 47% protection at an equivalent
dose. Low π values of R are correlated with higher anti-
inflammatory activity; e.g., for compounds 4 and 6, p-NO2 >
p-Cl (π-NO2 ) -0.28; π-Cl ) 0.71), and for compounds 1
and 3, p-OH > p-OCH3).
262.0
lidinone (9) exhibited no COX-2 inhibition, leading to the
conclusion that the phenylidene substituent is probably important
for the inhibitory action on both COX isoenzymes.
When indomethacin at 200 µM was tested for COX-1 or
COX-2 inhibitory activity at the same conditions as our
compounds, it exhibited a 100% inhibition. All our compounds
are less potent COX-1/2 inhibitors than indomethacin. Addition
of naproxen to the reaction mixture at 200 µM caused a 60.0%
inhibition of COX-2 and a 52.2% inhibition of COX-1 at a
substrate concentration of 0.1 µM. All our compounds are less
potent COX-2 inhibitors than naproxen, but some of them are
better COX-1 inhibitors.
LOX Inhibition. Compounds were further evaluated for
inhibition of soybean lipoxygenase by the UV absorbance based
enzyme assay. It has been shown that inhibition of plant LOX
Although based on very preliminary results, it seems that
molecular hydrophilicity (low lipophilicity values, ClogP23)

Anti-Inflammatory Thiazolidinones
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1605
Figure 1. Docking of 2-(thiazole-2-ylamino)-5-(m-chloroyphenylidene)-4-thiazolidinone (7) in the active site of human COX-1. Green lines represents
H-bonding. H-atoms are not shown for clarity.
partly affects the anti-inflammatory activity, as can be concluded
from the following equation:23
having the lowest inhibitory activity, lacks the favorable
H-bonding interaction between the N3 atom of the thiazole ring
and Asn515 (distance 3.76 Å). Moreover, the methoxy sub-
stituent of the phenyl ring is in proximity to the polar amino
acid residues Gln192 and Gln 351, resulting in unfavorable
stereochemical interactions.
log CPE% ) -0.125(0.097)ClogP + 2.067(0.239) (1)
No clear correlation of in vivo activity, expressed in CPE%
values, and in vitro activity, expressed as COX1/2 and LOX
inhibition, can be established. This is not surprising because it
is commonly observed as the results of many researchers.14
Because other mechanisms are involved at the first steps of
edema formation, a straight correlation between in vivo results
and LOX and COX inhibition cannot be obtained.
Docking. Docking studies were undertaken to gain insight
into the binding mode of the most active compounds of this
series: 2-(thiazole-2-ylamino)-5-(m-chlorophenylidene)-4-thia-
zolidinone (7) for COX-1 and COX-2; 2-(thiazole-2-ylamino)-
5-(m-nitrophenylidene)-4-thiazolidinone (5) for 15-LOX.
The binding pockets of COX-125 and COX-2 were found to
be similar except one amino acid residue at position 523 where
COX-2 has a smaller Val residue, while COX-1 has Ile at that
position. This minor difference in the binding site produces a
secondary pocket extending off the primary binding site in COX-
2, which is absent in COX-1. The combined volume of the
primary binding site and the secondary pocket in COX-2 is about
25% larger (394 Å3) than the volume of the COX-1 binding
site (316 Å3).26 The various isoforms of LOX also have different
volumes of binding site; 5-LOX binding site has larger volume
(470 Å3) than 15-LOX (390 Å3).27
It was shown that 2-(thiazole-2-ylamino)-5-(m-chlorophe-
nylidene)-4-thiazolidinone (7) binding within COX-1 includes
a favorable H-bonding interaction between the N3 atom on the
thiazole ring and the NH of the side chain of Asn515 (distance
2.438 Å). The other thiazole ring was found in proximity to
the amino acids Phe91, His90, Thr94, His513, and Pro514, while
the phenyl ring of the compound is found in the vicinity of the
amino acids Gly354, Gln192, Gln351, Ser353, and His581,
which are within a distance of 4.5 Å from the ligand (Figure
1). These results suggest that this compound docks well in the
binding pocket17 and explains its high inhibitory action. 2-(Thia-
zole-2-ylamino)-5-(p-methoxyphenylidene)-4-thiazolidinone (3),
Docking of 2-(thiazole-2-ylamino)-5-(m-chlorophenylidene)-
4-thiazolidinone (7) in COX-2 shows that this compound docks
well in the active site that consists of the amino acids Phe518,
Ser353, Gly354, Ile517, Arg513, His90, Tyr355, and Arg120
(Figure 2). The nitrogen of the thiazole ring forms a hydrogen
bond (distance 2.76 Å) with Arg120 of COX-2. The other
thiazole ring is located in the vicinity of amino acids Tyr355,
Val523, Leu359. The chlorophenyl ring settles in a hydrophobic
cavity lined by Tyr135, Phe381, Met522, Trp387, and Phe518.
The chlorophenyl ring is optimally oriented to make π-π
interaction with the phenyl ring of Tyr385. It can be seen that
a meta substitution favors the phenyl ring optimal orientation
between Tyr385 and Phe381. In contrast, para substitution (6)
prohibits this orientation because of steric interaction with
Met522. This may explain the higher activity of the m-Cl
analogue.
It is interesting to note that compounds 5 and 7, which are
structurally very similar to one another, show strikingly different
binding modes. As proved by the docking studies, the existence
of a m-NO2 substituent favors an orientation of compound 5
opposite that of compound 7; i.e., the aryl ring of 5 goes where
the thiazole ring of 7 settles, while the thiazole ring of 5 settles
in the hydrophobic cavity where the chlorophenyl ring of 7 is
located. This difference in binding mode may be attributed to
the highly electronegative nature of NO2 group which favors
an orientation that enables hydrogen bonding between the -NO2
group and Arg120. However, this orientation results in an
unfavorable settlement of the thiazole ring in the hydrophobic
cavity. Because of the different orientation, compound 5 lacks
the hydrogen bonding between the thiazole ring and Arg120
and the π-π interactions of the phenyl ring with Tyr385. This
different binding mode appears to be the reason behind the

1606 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Geronikaki et al.
Figure 2. Docking of 2-(thiazole-2-ylamino)-5-(m-chloroyphenylidene)-4-thiazolidinone (7) in the active site of mouse COX-2. Green lines represents
H-bonding. H-atoms are not shown for clarity.
Figure 3. Docking of 2-(thiazole-2-ylamino)-5-(m-nitrohenylidene)-4-thiazolidinone (5) in the active site of rabbit 15-LOX. Green lines represents
H-bonding. H-atoms are not shown for clarity.
difference in binding affinity and subsequently in activity of
compounds 5 and 7.
The binding site of 15-LOX is a boot shaped cavity consisting
of amino acid residues Phe353, Ile418, Met419, and Ile593
located at the base of the binding site with the charged Arg403
residue present at the opening of the binding cavity. Docking
of the most active compound, 2-(thiazole-2-ylamino)-5-(m-
nitrohenylidene)-4-thiazolidinone (5), showed favorable hydro-
gen bonding interactions between compound 5 and Asn406 and
Arg403 of LOX (Figure 3). The CO group of compound 5 is
making hydrogen bond interactions with the free NH2 of Arg
403 (distance 3.51 Å), while the amino group on the ligand is
making hydrogen bond interaction with the backbone CO of
this residue (distance 3.43 Å). This amino nitrogen of compound

Anti-Inflammatory Thiazolidinones
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6 1607
Computer Prediction of Biological Activity. PASS is a
computer program for evaluation of general biological potential in
a molecule on the basis of its structural formulas.3,28–31 The list of
predictable biological activity contains 2820 types (PASS, 2006
version) including main and side pharmacological effects (antihy-
pertensive, hepatoprotective, anti-inflammatory, etc.), mechanisms
of action (5-hydroxytryptamine agonist, cyclooxygenase inhibitor,
adenosine uptake inhibitor, etc.), specific toxicities (mutagenicity,
carcinogenicity, teratogenicity, etc.), and metabolic terms (CYP1A
substrate, CYP3A4 inhibitor, CYP2C9 inducer, etc.).
The results of prediction are represented as a list of probable
biological activity types for which the probability to be revealed
(Pa) and the probability not to be revealed (Pi) are calculated. PASS
estimates Pa and Pi values for each activity type independently. Pa
and Pi values vary from 0 to 1.
5 is also having a hydrogen bond interaction with Asn406,
contributing to additional stability (distance 2.68 Å). The
nitrophenyl ring settles in a cavity marked by Phe175, His366,
Leu597, and Ile663. According to docking results, compound
7 exhibits a binding mode similar to that of compound 5.
However, His336 present at the active site of LOX predomi-
nantly favors electrostatic interactions and the NO2 group of 5
enables such an interaction better than Cl of compound 7. Thus,
the observed difference in binding affinity between compounds
5 and 7 may be due to the highly electrostatic nature of LOX
active site which favors the presence of NO2. In contrast to
COX-2, where hydrophobicity plays a major role, the NO2
derivative exhibits higher inhibition of LOX activity.
As mentioned above in the discussion of the COX 1/2 and
LOX inhibitory action of the compounds, the docking results
explain well the inhibitory potential of the most effective
compounds.
The training set of the current version of PASS contains 781
cyclooxygenase inhibitors, while the number of lipoxygenase
inhibitors is currently 679. The accuracy of prediction for these
compounds calculated by the leave-one-out cross-validation pro-
cedure is 92.4% for the cyclooxygenase inhibitors and 93.4% for
the lipoxygenase inhibitors.
Conclusions
PharmaExpert is a software package that includes a knowledge
base of several thousand activity-activity relationships and provides
a flexible tool for selection of prospective compounds with the
desirable pharmacological profile and estimation of probable
drug-drug interactions.4 Since PharmaExpert contains the informa-
tion about mechanism-effect relationships, it can be applied to
search for compounds with multitargeted action. This possibility
was used for selection of compounds with dual COX/LOX
inhibition among 573 virtually designed molecules that could be
synthesized by the Department of Pharmaceutical Chemistry of
Aristotle University.
General Procedure for Synthesis of 2-Thiazolylimino-5-
arylidene-4-thiazolidinones (1–8).21 To a well-stirred solution of
2-(thiazol-2-ylimino)thiazolidin-4-one (0.8 g, 4 mM) in acetic acid
(35 mL) buffered with sodium acetate (8 mM), the appropriate
arylaldehyde (6 mM) was added. The solution was refluxed for
4 h and then poured into ice-cold water. The precipitate was filtered
and washed with water, and the resulting crude product was purified
by recrystallization from dioxane.
Eight tested compounds exhibited anti-inflammatory activity.
It was shown that 7 out of 9 (77.8%) tested compounds were
LOX inhibitors, 7 out of 9 (77.8%) were COX inhibitors, and
6 (66.7%) tested compounds were dual COX/LOX inhibitors.
The compounds can be considered as LOX inhibitors and less
potent COX-1 inhibitors. One of the compounds exhibited
COX-2 inhibitory activity as well.
Compounds 2 (m-OCH3, p-OH derivative) and 5 (m-NO2
derivative), which exhibit the highest anti-inflammatory activity,
also have the best LOX inhibition. Moreover, they combine
LOX inhibitory activity with moderate COX-1 inhibitory action.
They inhibit effectively inflammation, acting on enzymes
involved in both arachidonic acid catabolic pathways, and thus
are promising anti-inflammatory agents with reduced undesired
side effects. The fact that these compounds were found to be
potent antimicrobial agents21 increases the importance of
discovery of their anti-inflammatory activity because inflam-
mation is often a consequence of microbial infection and the
production of agents with combined antimicrobial and anti-
inflammatory action would be beneficial for treatment of
infectious diseases.
Physicochemical Studies.
(a) Determination of Lipophilicity as RM Values. Reversed
phase TLC (RPTLC) was performed on silica gel plates impregnated
with 55% (v/v) liquid paraffin in light petroleum ether.32 The mobile
phase was a methanol/water mixture (75/25, v/v) containing 4%
aqueous ammonia (27%). The plates were developed in closed
chromatography tanks saturated with the mobile phase at 24 °C.
Spots were detected under UV light or by iodine vapors. RM values
were determined from the corresponding Rf values (coefficient in
thin layer chromatography from 10 individual measurements) using
the equation RM ) log [(1/Rf) -1 ] (Table 2).
The most active compounds dock well in the active site of
the related enzymes. Inhibitory activity of the most potent
compounds is explained mostly by hydrogen bonding and
electrostatic or π-π interactions within the active site of the
enzymes. Hydrophilicity and steric requirements are also the
most important factors in terms of SAR.
(b) Determination of Lipophilicity as ClogP. Lipophilicity was
theoretically calculated as ClogP values in n-octanol buffer by the
CLOGP program of Biobyte Corp.23
From our results, the PASS program in collaboration with
the PharmaExpert software can successfully predict COX and
LOX inhibitory action in a qualitative manner. Considerable
activity was confirmed for Pa values greater than 0.350.
Despite IC50 values of the studied compounds varying from
10-4 to 10-5 mol/L for COX/LOX inhibition, anyone should
take into account that they are the first known compounds among
thiazolidinones with such a mechanism of anti-inflammatory
action. Therefore, they may be considered as basic structures
for further optimization.
Biological Assays. In Vitro Experiments. In the in vitro assays
each experiment was performed at least in triplicate and the standard
deviation of absorbance was less than 10% of the average values.
Soybean Lipoxygenase Inhibition Study in Vitro. Lipoxyge-
nase inhibition was evaluated as reported previously.25 The tested
compounds, dissolved in DMSO, were added to the reaction mixture
at a final concentration of 100 µM and were preincubated for 4
min at 28 °C with soybean lipoxygenase at a concentration of 7 ×
10-7 w/v. Enzyme reaction was initiated by the addition of sodium
linolate at a final concentration of 0.1 mM. The conversion of
sodium linoleate to 13-hydroperoxylinoleic acid was measured at
234 nm. Nordihydroguaretic acid, an appropriate standard inhibitor,
was used as positive control (inhibition ) 94.4% at 0.1 mM).
COX Inhibitor Screening Assay. The COX-1 and COX-2
activities of the compounds were measured using ovine COX-1
and human recombinant COX-2 enzymes included in the “COX
Inhibitor Screening Assay” kit provided by Cayman (Cayman
Experimental Section
Materials. All used chemicals were analytical grade and
commercially available. Soybean lipoxygenase, linoleic acid sodium
salt, and indomethacin were obtained from Sigma Chemical, Co.
(St. Louis, MO). For the in vivo experiments, male and female
mice (g) were used. The kit for COX activity assay was purchased
from Cayman.

1608 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 6
Geronikaki et al.
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trends in dual 5-LOX/COX inhibition. Curr. Med. Chem. 2002, 9,
941–962.
(6) Altman, H.; Luciardi, L.; Muntaner, J.; Herrera, R. N. Therapeutic
role of dual inhibitors of 5-LOX and COX, selective and non-selective
non-steroidal anti-inflammatory drugs. Ann. Rheum. Dis. 2003, 62,
501–509.
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oxygenase isoenzymes. How recent findings affect thinking about
nonsteroidal anti-inflammatory drugs. Drugs 1997, 53, 563–582.
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induction and suppression of prostaglandin H2 synthase (cyclooxy-
genase) in human monocytes. J. Biol. Chem. 1990, 265, 16737–16740.
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G.; et al. Morphological and functional changes of coronary vasculature
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isolated heart of rabbit. Blood 1996, 87, 1824–1832.
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necrotizing agents and indomethacin in the rat stomach. Gastroenterol-
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Chemical Co., Ann Arbor, MI). The assay directly measures PGF2a
produced by SnCl2 reduction of COX-derived PGH2. The prostanoid
production was quantified via enzyme immunoassay using a broadly
specific antibody that binds to all the major prostaglandin com-
pounds.18 In an attempt to study the type of inhibition, the inhibitory
activity of the compounds was tested at various concentrations of
arachidonic acid (from 0.1 to 100 µM). The final estimation of %
inhibition (Table 3) was performed at a substrate concentration
much lower than the saturating concentration. For better visualiza-
tion of compound differences in a 0–100% inhibition scale, COX-1
inhibitory activity was tested at an arachidonic acid concentration
of 1 µM and COX-2 inhibitory activity was tested at an arachidonic
acid concentration of 0.1 µM. The compounds were added to the
reaction mixture at a final concentration of 200 µM. IC50 values
were calculated for the most active compounds. Naproxen and
indomethacin, used as positive controls, were added to the reaction
mixture at the same concentration, 200 µM, as the tested compounds.
In Vivo Experiments. Inhibition of the Carrageenin-
Induced Edema. Edema was induced in the right hind paw of mice
(AKR) by the intradermal injection of 0.05 mL of 2% carrageenin
in water. Both sexes were used, but pregnant females were excluded.
Each group was composed of 6–10 animals. The animals, which
have been bred in our laboratory, were housed under standard
conditions and received a diet of commercial food pellets and water
ad libitum prior to experimentation, but they were fasted during
the experimental period. The tested compounds (0.01 mmol/kg body
weight) were suspended in water with a few drops of Tween-80
and ground in a mortar before use and were given intraperitoneally
simultaneously with the carrageenin injection. The mice were
euthanized 3.5 h after the carrageenin injection. The difference
between the weight of the injected and uninjected paws was
calculated for each animal. It was compared with that in control
animals (treated with water) and expressed as a percent inhibition
of the edema CPE% values (Table 3). Each experiment was
performed in duplicate, and the standard deviation was less than
10%.
Docking Analysis. For the docking studies we used GOLD
3.0.133 software running on windows based PC. The docked poses
were scored using a total of seven scoring functions, Goldscore
(GS),33 ChemScore (CS),34 PLP 1 and 2,35 LigScore 1 and 2,36
and PMF,37 to find the better docking pose. Reference protein
coordinates for the docking studies were taken from Protein Data
Bank (PDB). The protein-ligand complexes of COX-2 (PDB code
1cx2) and 15-LOX (PDB code 1lox) were minimized up to a
gradient of 0.01 kcal/(mol Å), and the hydrogens were added using
the force field AMBER99 available in the software MOE. Charges
on the protein were assigned using the force field AMBER99, while
the charges on the ligands were assigned by using force field
MMF94X available in the software MOE. In the case of COX-1
(PDB code 1prh), the protein molecule was superimposed on the
COX-2 protein–ligand complex. COX-2 protein was then removed,
and COX-1 was minimized up to a gradient of 0.01 kcal/(mol Å)
with the ligand (SC558) of COX-2 using the force field AMBER99
available in the software MOE. The ligand binding sites of COX-
1, COX-2, and 15-LOX were analyzed.
(22) Kontogiorgis, C. A.; Hadjipavlou-Litina, D. J. Synthesis and antiin-
flammatory activity of coumarin derivatives. J. Med. Chem. 2005, 48
(20), 6400–6408.
(23) C-QSAR; Biobyte Corp. (201 West 4th Street, Suite 204, Claremont,
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alkanoic acids and 4-(2-carboxyphenyl)aminobenzenealkanoic acids.
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