Novel thiazolyl, thiazolinyl and benzothiazolyl Schiff bases as possible lipoxygenase's inhibitors and anti-inflammatory agents

Article abstract of DOI:10.1016/S0014-827X(03)00065-X

In continuation of our previous research, several new thiazolyl/thiazolinyl/benzothiazolyl Schiff bases have been designed, synthesized and identified. The referred compounds are reported to act as lipoxygenase inhibitors affecting inflammation and/or psoriasis. The compounds were screened for their reducing activity (with the stable free radical 1,1-diphenyl-2-picryl-hydrazyl, DPPH) and for inhibition of soybean lipoxygenase (LOX). Anti-inflammatory activity was examined in vivo using the carrageenin induced mice paw edema (32.6-75%). The results are discussed in terms of structural and physicochemical characteristics of the compounds. Compound 2d possessed the highest inhibition 75%.

Full text of DOI:10.1016/S0014-827X(03)00065-X

Il Farmaco 58 (2003) 489ꢀ495
/
www.elsevier.com/locate/farmac
Novel thiazolyl, thiazolinyl and benzothiazolyl Schiff bases as
possible lipoxygenase’s inhibitors and anti-inflammatory agentsꢀ
Athina Geronikaki, Dimitra Hadjipavlou-Litina *, Maria Amourgianou
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece
Received 23 November 2002; accepted 15 February 2003
Abstract
In continuation of our previous research, several new thiazolyl/thiazolinyl/benzothiazolyl Schiff bases have been designed,
synthesized and identified. The referred compounds are reported to act as lipoxygenase inhibitors affecting inflammation and/or
psoriasis. The compounds were screened for their reducing activity (with the stable free radical 1,1-diphenyl-2-picryl-hydrazyl,
DPPH) and for inhibition of soybean lipoxygenase (LOX). Anti-inflammatory activity was examined in vivo using the carrageenin
induced mice paw edema (32.6ꢀ75%). The results are discussed in terms of structural and physicochemical characteristics of the
/
compounds. Compound 2d possessed the highest inhibition 75%.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Lipoxygenase inhibitors; Anti inflammatory agents; Schiff bases
1. Introduction
lipoxygenase (LO) pathways to hydroperoxyeicosate-
traenoic acids (HPETEs), hydroxyeicosatetranoic acids
(HETEs) and leukotrienes (LTs). The major products of
5-LO leukotrienes (LTs) are a family of important
biologically active mediators in a variety of conditions
including asthma, psoriasis, ulcerative colitis and rheu-
matoid arthritis [2,3]. The recent recognition of the
lipoxygenase products as mediators of inflammation
had led to a better understanding of the pathogenesis of
psoriasis and provides new targets for therapeutical
interventions. For this reason it is believed that restrict-
ing LT synthesis by inhibition of 5-LO will have
therapeutic utility for the treatment of a variety of
inflammatory conditions (e.g. asthma, rheumatoid ar-
thritis, psoriasis). Generally 5- and 12-LOs are attractive
targets for the development of anti-psoriatic drugs [3].
Evidence for a correlation between anti-psoriatic activ-
ity of drugs of diverse structure and inhibition of
lipoxygenases, came from assays using soybean LO [3].
Thiazolyl and benzothiazolyl groups are of impor-
tance in biological systems as anti-inflammatory, an-
algesic agents and inhibitors on lipoxygenase activities
[4,5]. Vanilloids, capsaicin analogs as well as several
phenols and catechols have been found [6] to possess
anti-inflammatory and antioxidant activities. Topical
application with the above-mentioned compounds was
Non steroidal anti-inflammatory drugs (NSAIDs) are
the main therapeutic agents for the treatment of
inflammatory diseases. The common mechanism of
action of this broad class of drugs is believed to be
inhibition of the enzyme cycloxygenase and consecu-
tively inhibition of the conversion of arachidonic acid
into prostaglandins [1]. Cyclooxygenase (CO) and 5-
Lipoxygenase (5-LO) are enzymes which catalyze the
rate-limiting steps in the biosynthesis of prostaglandins
(PGs) and leukotrienes (LT) respectively, from arachi-
donic acid [2,3].
The biosynthetic cascade of arachidonic acid has been
the object of intense research. Arachidonic acid liber-
ated from phospholipids by various stimuli can be
metabolized by the cyclooxygenase (COX) pathway to
prostaglandins (PGs) and thromboxane A2 or by
ꢀ A part of this research has been presented at the 9th Panhellenic
Pharmaceutical Conference, Athens, 7ꢀ
poster at the 2nd International Conference of the Chemical Societies of
the South Eastern European Countries, Halkidiki Greece, 6ꢀ9 June,
2000.
* Corresponding author.
/9 November, 1998 and as a
/
E-mail address: hadjipav@pharm.auth.gr (D. Hadjipavlou-Litina).
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00065-X

490
A. Geronikaki et al. / Il Farmaco 58 (2003) 489ꢀ495
/
found to improve psoriatic skin lesions. Capsaicin
analogs [7] in which the alkyl chain part of the molecule
(amides of vanillylamine/homovanilic acid) is varied,
have been reported to exert antinociceptive and anti-
inflammatory effects.
values. MS spectra were determined on a VG-250
spectrometer (VG-Labs., Tritech, UK) with ionization
energy maintained at 70 eV. All the compounds gave
spectra consisted with the structures. Elemental analyses
were obtained on an acceptable range (9
/
0.4%) in a
The effective role of azomethine linkage in certain
biological reactions [8] is well documented. Simple stable
molecules containing the hydroxamic acid [9] function-
PerkinꢀElmer 240B CHN analyzer (The Perkinꢀ
/
/
Elmer
Corporation Ltd., Lane Beaconsfield, Bucks, UK). Thin
layer chromatography (TLC) was performed on silica
gel (60 F254, Merck, Darmstadt, Germany). Acetylsa-
licylic acid was also purchased by Merck, Darmstadt,
Germany.
All the chemicals used were of analytical grade and
commercially available by Merck. Carrageenin K-type
was commercially available.
CDCl3, DMSO-d6, tetramethylsilane, Nujol, nordihy-
droguaretic acid (NDGA) and 1,1-diphenyl-2-picrylhy-
drazyl free stable radical were purchased from the
Aldrich Chemical Co., Milwaukee, WI. Soybean lipox-
ygenase, linoleic acid sodium salt and indomethacin
came from Sigma Chemical Co., St. Louis, MO.
ality as well as methoxy ꢀalkylthiazoles and 6-hydroxy-
/
benzothiazoles [10] were reported as LOs inhibitors.
According to our previous findings (Table 1) [11], Schiff
bases were found to be inhibitors of soybean lipoxygen-
ase and potent anti-inflammatories.
As a part of a program to develop improved anti-
inflammatory/anti-allergy agents, we tried: (a) to replace
an H (R1) by a Br atom (except of iodine); (b) to put a
second bulky as well as highly lipophilic group at
position 5 of the thiazolyl ring; (c) to have no substituent
at position 6 (R3ꢁH) of the benzothiazolyl ring, on the
/
contrary to have a Cl atom at position 5, replacing the
H; and (d) to replace the thiazolyl/benzothiazolyl ring
moiety by a thiazolinyl ring in order to delineate the role
of the nature of the ring on the biological activity.
In this paper, we have prepared some new substituted
derivatives and we describe the synthesis, their antiox-
idant activity (as % interaction to DPPH), their activity
against soybean lipoxygenase and their effect on the
carrageenin induced mice paw edema [6].
2.2. Synthesis
2.2.1. General procedure A [8,11]
Substituted 2-amino-thiazoles (0.01 mol), vanillin or
p-hydroxybenzaldehyde (0.01 mol), respectively, in
ethanol (30 ml) and some drops of piperidine, were
refluxed in a water bath for 3 h. After cooling the final
products were precipitated, filtered and recrystallized
from ethanol 95%.
2. Experimental
2.2.2. General procedure B [11,12]
A mixture of 5-/ or not substituted-2-amino-ben-
zothiazole (0.01 mol) and vanillin or 5-iodo- or 5-
bromo-vanillin or p-hydroxy-benzaldehyde or syringic
aldehyde (0.01 mol), respectively, in dry benzene, in the
presence of a small amount of p-toluene-chloro-sulpho-
2.1. Chemistry
Melting points (uncorrected) were determined on a
MEL-Temp II (Lab. Devices, Holliston, MA). UV (in
1
absolute ethanol), IR (film neat or as Nujol mulls), H
nic acid was heated in a DeanꢀStark apparatus. The
/
NMR (in CDCl3 for the bases, DMSO-d6 for the salts,
tetramethylsilane as internal standard). Spectra were
recorded with Perkinꢀ
solution was cooled and the final products were
precipitated, filtered and recrystallized from ethanol
95%.
/
Elmer 597, a 554 double beam
spectrophotometer (The Perkinꢀ
/Elmer Corporation
The general method [11,12] employed to prepare the
Ltd., Lane Beaconsfield, Bucks, England) and a Bruker
Analytische Messtechnik GmbH, Rheinstetten, Ger-
many). Chemical shifts were expressed in d (ppm)
final compounds is shown in Scheme 1 (Tables 2ꢀ4).
/
2.3. Biological evaluation
2.3.1. In vitro assays
Table 1
Previous series of Schiff bases for the general structure: Zꢀ
C6H5R1R2OH
/
NÄ
/
CHꢀ
/
2.3.1.1. Interaction of the tested compounds with 1,1-
diphenyl-2-picryl-hydrazyl (DPPH) stable free radical.
Series of derivatives
R1, R2
Typical compounds synthesized above in 10ꢂ4
M
a
b
c
H, H
H, OCH3
OCH3, OCH3
I, OCH3
ethanolic solution, were added to an equal molar
ethanolic solution of DPPH (10ꢂ4 M). The mixture
was kept at room temperature. After 20 min the
absorbance at 517 nm was measured and the percent
reduction according to Refs. [11,13] was estimated.
d
Zꢁ/C3H2SN, 4-C6H5 ꢀ
/
C3HSN, 6-OC2H5 ꢀ/C7H3SN, 6-FꢀC7H3SN,
/
6-CH3 ꢀ
/
C7H3SN, 4-CH3 ꢀ
/
C3HSN.

A. Geronikaki et al. / Il Farmaco 58 (2003) 489ꢀ
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495
491
Scheme 1. Reaction series of the synthesized compounds.
Ethanol was of analytical grade, iron content less than
10ꢂ5% (as a standard nordihydroguaretic acid 94%).
pregnant excluded. The animals, bred in our laboratory,
were housed under standard conditions and received a
diet of commercial food pellets and water ad libitum.
Four hours before carrageenin treatment, food was
withdrawn from all animals with water freely available.
2.3.1.2. Soybean lipoxygenase inhibition [11]. The con-
version of sodium linoleate to 13-hydroxy-peroxylino-
leic acid at 234 nm, was recorded. As a reference
compound nordihydroguaretic acid was used (83%).
The tested compounds, dissolved in 60% aqueous
ethanol (final concentrations 0.1 mM) with sodium
linoleate (0.1 mM), 0.15 ml of enzyme solution (1/10
w/v in saline) were evaluated in room temperature. The
conversion of sodium linoleate in pH 9.00 by Tris, to 13-
hydroxy-peroxy-linoleic acid with appropriate standard,
in each case, at 234 nm was compared.
2.3.2.2. Inhibition of the carrageenin-induced edema
[11]. Edema was induced in the right hind paw of
AKR or A mice (20ꢀ
/
30 g, 2ꢀ 3 months old) by the
/
intradermal injection of 0.05 ml 2% w/v carrageenin in
water. These studies were in accordance with recognized
guidelines on animal experimentation (guidelines for the
care and use of laboratory animals published by the
Greek Government 160/1991, based on EU regulations
86/609).
2.3.2. In vivo assay
All the tested compounds 0.5 mmol/kg body weight
(with the exception of compound 7, 0.25 mmol/kg body
weight), were suspended in water, with few drops of
Tween 80 and ground in a mortar before use and were
2.3.2.1. Animals. AKR or A mice (20ꢀ
/
30 g, groups of
six, 2ꢀ3 months old), both sexes were used. Females
/
Table 2
Characterization data of the synthesized Schiff bases
N
R1
R2
R3
Yield (%)
M.p. (8C)
Rf
Mꢃ (m/z) (%)
MF a
1a
1b
1c
2d
2e
2f
H
H
H
38
40
48
42
39
40
205ꢀ
166ꢀ
196ꢀ
136ꢀ
152ꢀ
169ꢀ
/
7
0.737
0.836
0.644
0.730
0.539
0.705
254 (65)
284 (100)
314 (18)
410 (12)
C14H10N2OS
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
/8
C15H12N2O2S
C16H14N2O3S
C15H11N2O2SI
C15H11N2O2SBr
C15H11N2O2SCl
H
/9
I
H
/8
Br
H
H
5-Cl
/4
364 (22)
b
/72
a
Elemental analyses for molecular formulas MF.
b
ꢁ
/
no results for a molecular ion peak; eluent system benzene/ethanolꢁ9/1.
/

492
A. Geronikaki et al. / Il Farmaco 58 (2003) 489ꢀ495
/
Table 3
Characterization data of the synthesized Schiff bases
N
R1
R2
Yield (%)
M.p. (8C)
Rf
Mꢃ (m/z) (%)
MF a
3a
3b
3c
H
H
37
41
45
129ꢀ
/
30
0.78
0.84
0.68
476 (15)
506 (98)
536 (25)
C30H40N2OS
C31H42N2O2S
C32H44N2O3S
H
OCH3
OCH3
OCH3
91ꢀ2
/
b
a
Elemental analyses for molecular formulas MF.
b
Decomposes upon heating; eluent system benzene/ethanolꢁ9/1.
/
given intraperitoneally (i.p) at the same time as the
carrageenin. The animals were euthanized 3.5 h after
carrageenin injection. The experiment was repeated
twice for each compound (two groups of six animals).
The difference between the weight of the injected and
uninjected paws was calculated for each animal. The
change in paw weight was compared with that in control
animals (injected with water) and expressed as a percent
inhibition of the edema (CPE % values Table 4).
Indomethacin in 0.11 mmol/kg (44%) was administered
3. Results and discussion
3.1. Chemistry
The general method employed to prepare the final
compound is shown in Scheme 1. Overall the reactions
proceeded smoothly in good yields. In the synthesis of
the derivatives of benzothiazolyl series, problems were
overcome by heating the reactants in a DeanꢀStark
/
apparatus, using p-toluene-chloro-sulphonic acid as a
catalyst. It is assumed that the harsher conditions are
required to overcome steric hindrance of these bulky
groups. Under these experimental conditions we suc-
ceeded in resulting higher yields of the benzothiazolyl
Schiff bases. The structures of the synthesized com-
pounds and their physicochemical properties are shown
as a standard comparative drug (P B/0.01 compared
with control values).
2.4. Statistical analysis
in Tables 2ꢀ4. All intermediates and final products gave
/
In vivo results are means9
mean less than 10%. Each in vitro experiment was
performed at least in triplicate and the standard devia-
/
SEM standard error of the
satisfactory analytical and spectroscopic data in full
accord with their assigned structures [8,11]. IR spectra
showed a sharp band at 3460 cmꢂ1 (free OH) and a
1640 cmꢂ1 (NÄ
/
CH). In
the 1H NMR spectra thiazol-2-yl-amino derivatives
tion in absorbance values was less than 9
results were evaluated using Student’s t-test.
/10%. The
sharp band in the region 1625ꢀ
/
Table 4
Characterization data of the synthesized Schiff bases
N
R1
R2
Yield (%)
M.p. (8C)
Rf
Mꢃ (m/z) (%)
MF a
4b
4c
H
OCH3
OCH3
OCH3
31
85
75ꢀ
Oil
/8
0.37
0.29
235 (47)
266 (13)
C11H12N2O2S
C12H14N2O3S
Eluent system benzene/ethanolꢁ
/
7/3.
Elemental analyses for molecular formulas MF.
a

A. Geronikaki et al. / Il Farmaco 58 (2003) 489ꢀ
/
495
493
showed peaks in the region of d 6.91ꢀ
azomethine and 3H aromatic) whereas, benzothiazol-2-
yl-amino showed peaks in the region of d 7.3ꢀ8.1, m
/
7.40 (m, H
Antioxidants of hydrophilic or hydrophobic character
are both needed to act as radical scavengers in the
aqueous phase or as chain-breaking antioxidants in
biological membranes. In our case no relationship
between LO inhibition and lipophilicity was found.
There are many structurally unrelated compounds that
have been prepared with the goal of developing LO
inhibitors or have been discovered as such. The most of
the LO inhibitors are antioxidants or free radical
scavengers [3], since lipoxygenation occurs via a carbon
centered radical. Moreover, many LO inhibitors also
inhibit lipid peroxidation [3]. Some studies suggest a
relationship [3] between LO inhibition and the ability of
the inhibitors to reduce Fe3ꢃ at the active site to the
/
(aromatic protons), d 9.3 (H azomethine), d 3.97
(methoxy, s, 3H); d 8.84 (hydroxy, s, 1H).). In the MS
the existence of daughter ions is assigned by suggested
fragmentation patterns which are in agreement with the
findings from pertinent studies of simpler compounds
[8,11]. All substances gave stable molecular ions. Other
characteristic fragments observed, were formed by the
loss of COꢀ
peaks have also been observed (Tables 2ꢀ
/
, CNꢀ
/
, HCN radicals. The [Mꢃꢂ
4).
/OH]
/
catalytically inactive Fe2ꢃ
.
3.2. Biological studies
Lipoxygenases contain a non-heme iron per molecule
in the enzyme active site as high -spin Fe2ꢃ in the native
state, and high-spin Fe3ꢃ in the activated state. Iron is
also present in human 5-LO and is essential for enzyme
activity3. Several LO-inhibitors are excellent ligands for
Fe3ꢃ. It has been demonstrated that their mechanism of
action is presumably related to its coordination with a
catalytically crucial Fe3ꢃ-ion. In our case, it could not
be able to synthesize an iron chelate, using the examined
compounds as a ligand. Thus, we concluded that they
might not produce LO inhibition as iron chelators [3].
The reducing abilities were determined by their
interaction with the stable DPPH radical. This interac-
tion indicates if the compounds have the ability to
scavenge free radicals. All the tested compounds were
found to interact slightly from 12.3 to 29.7%, whereas
compound 3a was almost inactive and compound 1c did
not show any result. Compounds 2f, 3b, 3c, 4b and 4c
possessed dissolution problems and it could not be
possible to be tested under the same experimental
conditions.
The biological activity of the compounds was mea-
sured against isolated enzyme (soybean lipoxygenase). It
has been previously reported [11], that Schiff bases
inhibited the soybean LOX activity and demonstrated
good anti-inflammatory activity. Our newly compounds
tested were not found to highly inhibit soybean LO
(20.6ꢀ29%, Table 5) under the reported experimental
/
conditions (0.1 mM). It is important to be noticed that
during our experimental procedure, the solutions of
compounds 3b, 3c, 4b and 4c became cloudy and the
determination was not possible to be performed. For the
thiazolyl series the existence of both a phenyl group and
a CH3(CH2)13ꢀ chain has a negative effect on the overall
/
stereochemistry of the molecule and through it on the
biological effect.
Lipophilicity is an important physicochemical para-
meter for the kinetics of biologically active compounds.
Table 5
Biological results
Taking into consideration that Schiff bases can act as
anti-inflammatory agents [11], the compounds prepared
were tested for such an activity. The mice carrageenin-
induced paw edema assay was employed as a model for
acute inflammation and indomethacin was included as a
reference drug. The model represents reliable the
responses of clinically observed inflammatory diseases
and predicts the anti-inflammatory ability of the
NSAIDs. During the second phase, it detects com-
pounds that are anti-inflammatory as a result of
inhibition of prostaglandin amplification [14,15]. The
in vivo data are summarized in Table 5.
Compound 2d possessed the highest inhibition 75%
whereas compounds 1b, 1c, 2e, 3a, 3c, 4b, produced
approximately 56.1% edema reduction. Compounds 1a,
2f, 3b, 4c, exhibited mild activity. From the point of the
magnitude of the administered dose, compound 2f
should be more effective, since the carrageenin-induced
paw edema inhibition, produced by 0.25 mmol/kg body
weight, was 52.3%. Concerning the structures of the
No
LO (%)
Clog P
CPE (%)
DPPH (%)
1a
1b
1c
2d
2e
2f
29
3.614
3.473
3.220
4.324
2.33
36*
54
12.3
26.9
No
27.7
22.2
Nr
No
No
20.6
No
No
No
Nr
Nr
Nr
Nr
24
49.5
75
63
44
3.54
3a
3b
3c
4b
4c
5 a
6 a
7 a
10.665
10.524
10.271
1.405
1.152
2.420
2.61
64.2
47.6
58.5
52.3
38.7
47.3
23.9
24.3
7.3
Nr
Nr
Nr
Nr
77.9
Nr
Nr
37.3
2.80
29.7
No tested compound was found to be inactive under the reported
experimental conditions and in comparison to the controls under the
same experimental conditions; Nr, no results were found under the
reported experimental conditions.
a
Reported in Ref. [11] compounds are derivatives of Zꢁ
/6-CH3 ꢀ
/
C7H3SN, and of a, b, c series.
* P B0.05; all the others are statistically significant as P B0.01.
/
/

494
A. Geronikaki et al. / Il Farmaco 58 (2003) 489ꢀ495
/
tested compounds the anti-inflammatory efficacy de-
creases by the presence of a second methoxy group at
position R1. The replacement of an H (R1) by an I or a
Br atom increases the inhibition. The increase in the
inflammation is a complex phenomenon involving
interrelationship between humoral and cellular reactions
no much evidence on QSAR studies on NSAIDs is
found.
hydrophobic contribution of group R1 (Iꢀ
values, affects positively the inhibition of carrageenin
induced mice paw edema (pꢁ1.12 for iodine and pꢁ
0.86 for Bromine, compounds 2d 75%ꢀ2e 63%). The
/
Br), as p
/
/
4. Conclusion
/
replacement of a 5-H by a 5-Cl in R3 (C5), decreases the
anti-inflammatory ability. In general, in all the series
(thiazolyl/thiazolinyl/benzothiazolyl) the presence of a
The present study has shown that certain Schiff bases
designed after previous findings, structurally related to
vanilloids, possess high anti-inflammatory activity. Only
two compounds 1a and 2d are inhibiting in vitro
soybean LO. Compound 2d exerts significant 75%
anti-inflammatory and not a high LO inhibitory activ-
ity. The present results did not correlate LO inhibiting
and carrageenin edema properties. These are prelimin-
ary results and further investigation is in progress to
delineate the anti-inflammatory action of the modified
derivatives.
second methoxy group at position 5 (R1ꢁ
/
R2ꢁOCH3)
/
of the aldehydic moiety, decreases the efficacy.
Concerning the structure of the Z ring, the order of
increasing activity in the series of compounds was 3b
(47.6%)B
(49.5%)B
lyl/ benzothiazolyl), between the derivatives with R1ꢁ
R2ꢁH, more potent is the one of the thiazolyl ring, e.g.
1a (36%)B3a (64%).
/
4b (52.3%)B
/
1b (54 5%) and 4c (38.7%)B1c
/
/3c (58.5%). In general, in both series (thiazo-
/
/
/
For the series of derivatives of benzothiazolyl-bases,
the order of increasing activity in this series of com-
Acknowledgements
pounds was 1a (36%)B
/
1c (49.5%)B1b (54%). The
/
replacement of 6-CH3 by a 6-H highly influences the
anti-inflammatory activity (5, 6 and 7). Compounds 1a,
1b and 1c were found to be less potent than the
corresponding 6-ethoxy derivatives (values CPE % are
taken from literature) [11].
Regression analysis was performed [16] to find out
whether any correlation exists between the percentage
inhibition of carrageenin mice paw edema (CPE %) and
several physicochemical parameters (lipophilicity, steric
and electronic variables). However, the anti-inflamma-
We gratefully acknowledge the partial support of this
work by the International Association for the promo-
tion of cooperation with scientists from the New
Independent States of the Former Soviet Union (grant
INTAS-2000-0711). We would like to thank the Thea-
genium Anticancer Hospital for providing mice for our
in vivo experiments. We are thankful to Dr. C. Hansch
for providing the C-QSAR program. Thanks are also
directed to D. Rigas, Lab. of Organic Chemistry,
Chemistry Department, for accurate mass measure-
ments of the examined Schiff bases.
tory effect in correlation with lipophilicity*
cally calculated (clog P) and I-1 (an indicator variable
assigning 1 for the presence of one R2ꢁOCH3 group)
gave the following equation:
/theoreti-
/
References
Log CPE %ꢁ0:023clog Pꢃ0:159I-1 ꢃ1:555
nꢁ9, rꢁ 0.747, sꢁ0.059, F2,8 11.619, aꢁ
0.864, r2ꢁ
0.01.
/
/
/
/
ꢁ
/
/
[1] D.R. Robinson, Prostaglandin and the mechanism of action of
anti-inflammatory drugs, Am. J. Med. 75 (1983) 26ꢀ
[2] S.D. Brain, T.J. Williams, Leukotrienes and Inflammation,
Pharm. Ther. 46 (1990) 57ꢀ66.
[3] K. Muller, 5-Lipoxygenase and 12-lipoxygenase: attractive targets
for the development of novel antipsoriatic drugs, reviews and
/31.
The above correlation is statistically significant with a
high F value but low correlation coefficient r. Both the
intercept and the slope are contributing to the equation
in a significant manner. Two compounds were omitted,
2f and 3b. Compound 2f was the only one with
asubstituent on the benzothiazolyl moiety, whereas
compound 3b was the less active within the series of
the CH3(CH2)13-substituted thiazolyl derivatives.The
equation has a low correlative power but it could
describe the reduction of the carrageenin induced raw
edema from a qualitative point of view. This indicates
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