Synthesis and biological evaluation of new thiazolyl/benzothiazolyl-amides, derivatives of 4-phenyl-piperazine

Article abstract of DOI:10.1016/j.farmac.2005.06.014

A series of thiazolyl-N-phenyl piperazines has been synthesised and tested for anti-inflammatory activity. Their R_M values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and logPsk also performed. The effect of the synthesised compounds on inflammation, using the carrageenin induced mouse paw oedema model was studied. In general, the studied compounds were found to be potent anti-inflammatory agents (44-74.1%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesised compounds. An attempt was made to correlate their biological activity with some physicochemical parameters using a quantitative structure-activity relationship approach (QSAR).

Full text of DOI:10.1016/j.farmac.2005.06.014

Il Farmaco 60 (2005) 969–973
http://france.elsevier.com/direct/FARMAC/
Original article
Synthesis and biological evaluation of new
thiazolyl/benzothiazolyl-amides, derivatives of 4-phenyl-piperazine
Christina Papadopoulou, Athina Geronikaki *, Dimitra Hadjipavlou-Litina
Department of Pharmaceutical Chemistry, School of Pharmacy University Campus, Aristotle University, Thessaloniki 54124, Greece
Received 11 June 2005; accepted 22 June 2005
Available online 22 July 2005
Abstract
A series of thiazolyl-N-phenyl piperazines has been synthesised and tested for anti-inflammatory activity. Their RM values were deter-
mined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and logPsk also performed. The effect of
the synthesised compounds on inflammation, using the carrageenin induced mouse paw oedema model was studied. In general, the studied
compounds were found to be potent anti-inflammatory agents (44–74.1%). Anti-inflammatory activity was influenced by some structural
characteristics of the synthesised compounds. An attempt was made to correlate their biological activity with some physicochemical param-
eters using a quantitative structure–activity relationship approach (QSAR).
© 2005 Elsevier SAS. All rights reserved.
Keywords: Thiazole derivatives; Antiinflammatories; Lipophilicity
1. Introduction
Most NSAIDs are weak acids with pKa values ranging from
3 to 5 [4] and their side effects locally connected to their acidic
character. Thus, there is an increased interest in the develop-
ment of effective non-acidic anti-inflammatory agents. Basic
NSAIDs are gaining interest because of their improved bio-
logical properties.
Thiazolyl ring derivatives are known to possess anti-
inflammatory as well as antipyretic activities [5,6]. Meloxi-
cam, for example is a new NSAID with a thiazolyl group. A
number of thiazolyl-aminoketones was found to be strong
anti-inflammatory agents [7]. These results, along with ear-
lier studies, which showed that thiazolyl-amides exhibit sig-
nificant anti-inflammatory activity [8,9], prompted us to inves-
tigate other thiazolyl-amides.
NSAIDs have a broad spectrum of effects and it has been
suggested that the variations in both efficacy and their toler-
ability are partly due to differences in their physicochemical
properties which determine their distribution in the body and
their ability to pass through and to enter the interior of mem-
branes [10,11]. Thus, partition coefficients (log P values) as
RM values are performed also and compared with the corre-
sponding theoretically calculated values of n-octanol–water.
Non-steroidal anti-inflammatory drugs (NSAIDs) have
been used to treat various ailments for over 100 years. As a
class, these drugs possess anti-inflammatory, anti-allergy,
analgesic and antipyretic activity and are widely used to treat
chronic inflammatory states such as arthritis, psoriasis and
asthma. These agents exhibit an inhibitory action on the
cyclooxygenase (COX) that catalyses the biosynthesis of pros-
taglandins and thromboxane from arachidonic acid. For many
years it was believed that PGs were formed via the activity of
a single enzyme, COX. In recent years, two COX enzymes,
COX-1 and COX-2, have been discovered and it is agreed,
that inhibition of COX-2 is more selective for anti-
inflammatory effect [1–3]. All NSAIDs are approximately
equivalent in terms of anti-inflammatory efficacy but also
cause untoward side effects (e.g. in gastrointestinal), in a sig-
nificant fraction of treated patients and this frequently limits
therapy.
* Corresponding author. Tel.: +30 2310 997 616; fax: +30 2310 997 612.
E-mail address: geronik@pharm.auth.gr (A. Geronikaki).
0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2005.06.014

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C. Papadopoulou et al. / Il Farmaco 60 (2005) 969–973
2. Experimental procedure
N
-(4-Methylthiazol-2-yl)-2-(4-phenylpiperazin-1-yl)ace-
tamide (2).
1H-NMR: (CDCl3, DMSO) d: 2.4 (s, CH3), 2.85–2.98 (m
2.1. Materials
4H, a-piperazine), 3.18–3.33 (m, 6H, b-piperazine, –CH2–),
6.82–7.22 (m, 5H phenyl, H–C5 thiazole) , 8.96 (s, NH). MS:
M+ 317(22%).
Melting points were obtained with a MELTEMP II capil-
lary apparatus (LAB. Devices Holliston, MA, USA) and are
reported without correction. Infrared spectra (Nujol mulls)
were recorded on a spectrophotometer. UV–Vis were deter-
mined on a Perkin–Elmer 554 UV–Vis spectrophotometer.
Proton NMR spectra were obtained on a BruckerAW 80 appa-
ratus at 80 MHz and are reported in ppm downfield from tet-
ramethylsilane (TMS). Analyses indicated by the symbols of
elements were within 0.4% of theoretical values. Mass spec-
tra (MS) were determined on aVG-250 instrument (VG Labs.
Tritech, UK) with the ionisation energy maintained at 70 eV.
The reactions were monitored by TLC on silica gel 60 F254
(Merck). All the chemicals used were of analytical grade and
commercially available by Merck (KgaA 64271 Darmstaadt,
Germany). Carrageenin K-type was commercially available.
2-(4-Phenylpiperazin-1-yl)-N-(phenylthiazol-2-
yl)acetamide (3).
1H-NMR: (CDCl3, DMSO) d: 2.59–3.0 (m, 4H,
a-piperazine), 3.25–3.45 (m, 6H, b-piperazine, –CH2–), 6.59–
7.08 (m, 5H–Ph–N), 7.22–7.48 (m, 6H, Ph, thiazole, C5–H).
MS: M+ 378(93%).
2-(4-Phenylpiperazin-1-yl)-N-(methoxyphenylthiazol-2-
yl)acetamide (4).
1H-NMR: (CDCl3, DMSO) d: 2.6–3 (m, 4H, a-piperazine),
3.15–3.6 (m, 6H b-piperazine, CH2), 3.75 (s, 3H, CH3O–
Ph), 6.75–7.1 (m, 5H–Ph–N), 7.1–7.9 (m, 5H thiazole C5–H,
CH3O–Ph). MS: M+ 408(73%).
3-(4-Phenylpiperazin-1-yl)-N-(thiazol-2-
yl)propionamide (5).
1H-NMR: (CDCl3, DMSO) d: 2.28–2.64 (m, 4H,
a-piperazine), 3.45 (m, 8H, 2CH2–, b-piperazine), 6.59–7.08
(m, 5H–Ph–N), 6.56 (d, H, thiazole C5–H) 7.53 (d, H, C4–thia-
zole). MS: M+ 317(8%).
2.2. Synthesis
2.2.1. Synthesis of precursors
2-Aminothiazole, 2-amino-4-methylthiazole, 2-amino-4-
phenylthiazole and 2-amino-4-(4-methoxyphenyl) thiazole
were synthesised as described previously [12].
General synthetic procedure for the synthesis of the
2-chloroacetamido- and 3-chloropropionylamido thiazoles
and benzothiazoles [12].
3-(4-Phenylpiperazin-1-yl)-N-(phenylthiazol-2-yl)propio-
namide (6).
1H-NMR: (CDCl3, DMSO) d: 2.28–2.64 ((m, 4H,
a-piperazine), 3.45 (m, 8H, 2CH2–, b-piperazine), 6.59–7.08
(m, 5H–Ph–N), 6.6–7.48 (m, 5H, Ph, thiazole C5–H).
MS: M+ 392(13%).
To a solution of 2-aminothiazole/aminobenzothiazole or
suitable 4-substituted aminothiazole/benzaminothiazole
(0.02 mol) in dry benzene a cooled solution of chloroacetyl
or 3-chloropropionyl chloride (0.033 mol) in dry benzene
(7.5 ml) was added dropwise. The reaction mixture was
refluxed in a water bath at 80 °C for 3 h. Benzene and excess
3-chloropropionyl chloride were removed by distillation. The
residue was washed with aqueous sodium bicarbonate (5%
w/v) followed by cold water. The crude product was dried
and crystallised from ethanol.
3-(4-Phenylpiperazin-1-yl)-N-(methoxyphenylthiazol-2-
yl)propionamide (7).
1H-NMR: (CDCl3, DMSO) d: 2.6–2.68 (m, 4H,
b-piperazine), 3.15–3.6 (m, 6H a-piperazine, CH2), 3.77 (s,
3H, CH3O–Ph), 6.75–7.1 (m, 5H–Ph–N), 7.1–7.9 (m, 5H thia-
zole C5–H, CH3O–Ph). MS: M+ 422(1%).
N-(benzo[d]-thiazol-2-yl)-2-(4-phenylpiperazin-1-
yl)acetamide (8).
1H-NMR: (CDCl3, DMSO) d: 2.7–3 (m, 4H, a-piperazine),
3.2–3.55 (m, 6H, b-piperazine, CH2), 6.75–7.95 (m, 8H, aro-
matic). MS: M+ 352(24%).
General method of the synthesis of the 2-(N-substituted
aminoacetamido)/3-(N-substituted aminopropioamido) thia-
zoles [12].
N-(6-fluorobenzo[d]-thiazol-2-yl)-2-(4-phenylpiperazin-
1-yl)acetamide (9).
1H-NMR: (CDCl3, DMSO) d: 2.7–3 (m, 4H, a-piperazine),
3.2–3.5 (m, 6H, b-piperazine, –CH2–), 6.8–7.9 (m, 8H, aro-
matic). MS: M+ 370(18%).
A mixture of 2-chloroacetamido or 3-chloropropionamido
thiazole/benzothiazole (0.006 mol), amine (phenyl pipera-
zine 0.7 mol), absolute ethanol (15 ml) and anhydrous sodium
carbonate (1.48 g) was heated under reflux in a water bath for
12 h. The excess of amine and ethanol was removed by dis-
tillation and the residue was treated with 5% sodium bicar-
bonate solution to remove acid impurities, filtered, washed
with water and dried. It was crystallised from ethanol (95%)
to give white crystals.
2-(4-Phenylpiperazin-1-yl)-N-(thiazol-2-yl)acetamide (1).
1H-NMR: (CDCl3, DMSO) d: 2.7–2.9 (m, 4H,
a-piperazine), 3.15–3.5 (m, 6H, b-piperazine, –CH2–), 6.75–
7.1 (m, 5H phenyl), 7.1 (d, H, thiazole C5–H), 7.6 (d, H,
C4–thiazole) .MS: M+ 302(10%).
N-(6-ethoxybenzo[d]-thiazol-2-yl)-2-(4-phenylpiperazin-
1-yl acetamide (10).
1H-NMR: (CDCl3, DMSO) d: 1.33 (t, 3H, CH3–CH2O),
3.98 (q, 2 h OCH2–CH3).
2.59–3.25 (m, 4H, a-piperazine),3.45 (m, 6H, b-piperazine,
–CH2–), 6.59–7.08 (m, 6H, –Ph–N, thiazole C5–H), 8.12 (d,
H C4–thiazole).
N-(benzo[d]-thiazol-2-yl)-3-(4-phenylpiperazin-1-yl) pro-
pionamide (11).
1H-NMR: (CDCl3, DMSO) d: 2.28–2.64 (m, 4H,
a-piperazine), 3.45 (m, 8H, b-piperazine, 2CH2–), 6.59–7.08

C. Papadopoulou et al. / Il Farmaco 60 (2005) 969–973
971
Fig. 1. The synthetic pathway.
(m, 5H,Ph–N), 7.55 (q, 2H, C5–C6 benzothiazole), 8.12 (d,
H, C7–benzothiazole), 8.23 (d, H, C4–benzothiazole).
3. Results and discussion
3.1. Chemistry
2.2.2. Physicochemical studies [8]
The general method employed is shown in Fig. 1. The
structure of the derivatives and their physicochemical prop-
erties are given in Tables 1a, b. The compounds of the title
were prepared in two steps. Initial amino/substituted amino
thiazoles and benzothiazoles were treated with
chloracetyl/propionyl chloride in benzene to give the corre-
sponding chloroacetamides/propionamides, which in the sec-
ond step undergo condensation with phenylpiperazine in etha-
nol to give the title compounds. Overall the reactions proceed
smoothly in good yields. The amides were identified both by
elemental analyses as well as by their spectroscopic analy-
ses.
The structure of all compounds was identified both by
elemental analyses as well as by spectroscopic analysis (UV,
IR, 1H-NMR, MS). The UV and the IR spectra were in agree-
ment with the proposed structures: in the UV spectra charac-
teristic absorptions ekmax = 14242 at kmax = 275.5 nm,
ekmax = 25575 at kmax = 226.5 nm and ekmax 24818 at 210 nm
(2-phenylpiperazin-N-benzothiazole acetamide). IR spectra
showed a sharp band in the region 1692 cm−1 (NHC = O), as
well as in region 1606 (aromatic). Also there is a week band
Reversed phase TLC (RPTLC) was performed on silica
gel plates impregnated with 5% (v/v) liquid paraffin in light
petroleum ether [8]. Mobile phase: methanol/water mixture
(70:30, v/v) containing 2% aqueous ammonia (27%). The
plates were developed in closed chromatography tanks satu-
rated with the mobile phase at 24 °C. Spots were detected
under UV light or by iodine vapours. RM values were deter-
mined from the corresponding Rf values (from 10 individual
measurements) using the equation RM = log [(1/Rf) – 1]. For
results see Table 2.
Theoretical calculations of lipophilicity as clog P and
Suzuki–Kudo’s method [13] were performed (Table 2). The
program CLOG P [14], has been designed to calculate the
lipophilicity of a molecule using the method of additivity.
2.2.3. Inhibition of carrageenin induced paw oedema [4]
Oedema was induced in the right hind paw of AKR or A
mice (20–30 g, 2–3 months old) by the intradermal injection
of 0.05 ml 2% carrageenin in water. Both sexes were used.
Females pregnant were excluded. The animals were housed
under standard conditions and received a diet of commercial
food pellets and water ad libitum during the maintenance,
but they were entirely fasted during the experiment period.
Our studies were in accordance with recognised 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).
Table 1a
Characterisation data of the synthesised thiazole amides
N
R
N
Yield Rf
(%)
m.p.
(°C)
Ms
Molecular
structure b
All tested compounds were suspended in water with few
drops of Tween-80 and ground in a mortar before use. Groups
of five to six AKR mice weighing 20–30 g were used. A dose
of 0.2 mmol kg was chosen in order to be possible for us to
compare the new results with previous findings [9]. The com-
pounds as well as indomethacin were administered intraperi-
toneally i.p., simultaneously to the administration of the phlo-
gistic agent: carrageenin (2%, 0.05 ml was injected
intradermal i.d. into the right foot pad, the left serving as con-
trol). Results are given in Table 2.
1
2
3
4
H
1
1
1
1
74.2 0.759 170–1 302
98.3 0.827 219–21 316
84.0 0.810 142–3 378
C
C
C
C
15H18N4OS
16H20N4OS
21H22N4OS
22H24N4O2S
CH3
Ph
Ph–OCH3
95.1 0.879 170–
0.5
408
5
6
7
H
2
2
2
73.6 0.824 135–6 316
60.3 0.760 154–5 392
C
C
C
16H20N4OS
22H24N4OS
23H26N4O2S
Ph
Ph–OCH3
78.0 0.808 196–
0.5
422

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C. Papadopoulou et al. / Il Farmaco 60 (2005) 969–973
Table 1b
Characterisation data of the synthesised benzothiazole amides
N
8
R
N
1
1
1
2
Yield (%)
76.0
Rf
m.p. (°C)
180–2
Ms
Molecular structure b
H
0.853
0.787
0.795
0.811
352
370
380
366
C
C
C
C
19H20N4OS
19H19N4OSF
21H24N4OS
20H22N4OS
9
F
77.5
190–2
10
11
OC2H5
H
67.0
191.5–2
205–0.5
58.6
Elemental analysis for molecular formulas ( 0.40).
at 3175 cm−1 corresponding to the protonated tertiary amine
group (+N–H). Coordination of aromatic and side chain pro-
tons was observed in the 1H-NMR spectra and the exact num-
ber of protons was given by integration. In the MS spectra
almost all substances gave stable molecular ions. Character-
istic fragments were formed by the loss of HCl (M+–HCl).
The lipophilicity of the synthesised compounds expressed
as RM values ranging from −0.204 − 0.618, as well as calcu-
lated theoretically log P values are given in Table 2. Poor
correlation was obtained between RM and clog P values.
• (1) a substituted aromatic heterocyclic group (thiazolyl–
/benzothiazolyl–);
• (2) a 4-phenyl-substituted piperazine;
• (3) a central ligand consisting of a NHCO amide group;
• (4) a methylenic linkage (CH2)n.
The nature of the moieties (1) and (4) seems to have a
major effect on the activity.
We tried to delineate the contribution of the 4-phenyl-
substituted piperazine in the biological activity, since from
previous results a 4-CH3–piperazinyl group leads to 72.1%
inhibition of carrageenin paw oedema [9]. The insertion of
the benzothiazolyl group does not increase the activity. Com-
pounds 8–11 present higher lipophilicity values and may be
this is the reason for the decrease of activity. Comparing com-
pounds 1–4, with our previous findings [9] it seems that the
new compounds inhibit more the carrageenin induced mice
paw oedema at the same dose level (0.2 mmol kg). On the
contrary our new compounds 6 and 7 present lower efficacy
with the exception of compound 5, which was found to be the
most potent within the series. It contains the 4-phenyl-
substituted piperazinyl group and a (CH2)2. The tested com-
pounds did not present any side effects from the gastrointes-
tinal route (results not shown). On the contrary indomethacin,
the standard drug, was responsible for side effects in some
animals.
3.2. Biological studies
Basic anti-inflammatory agents are gaining interest because
they possess better pharmacokinetic properties and cause less
gastric irritation compared to acidic agents. The in vivo anti-
inflammatory effects of the synthesised amides were assessed
by using the functional model of carrageenin induced mouse
paw oedema the most frequently used model for anti-
inflammatory activity (Table 2), as percentage of weight
increase at the right hind paw in comparison to the unin-
jected left hind paw. We have previously reported that
thiazolyl-amides demonstrated good anti inflammatory as well
as local anaesthetic properties [9]. Thus, with modifications
performed with the synthesis of more compounds presented
herein we further elucidated the relative significance of struc-
tural features for activity.
Regression analysis was performed to find out whether any
correlation exists between the % in vivo anti-inflammatory
activity (expressed as log % CPE, carrageenin induced paw
The main chemical features of the synthesised amides can
be divided into four basic parts:
Table 2
Lipophilicity values a) experimentally performed RM values; b) theoretically calculated lipophilicity values using: i) Suzuki–Kudo’s method ii) the clog P
program from Biobyte. In vivo carrageenin rat paw oedema % inhibition after 3.5 h (CPE %).
Compounds
R
N
1
1
1
1
2
2
2
1
1
1
2
RM
Clog P
3.02
3.52
5.11
5.13
3.21
5.31
5.33
4.61
4.75
5.43
4.81
logPsk
–1.429
0.980
–0.011
0.033
0.086
1.740
1.548
0.017
0.265
0.310
1.532
CPE a
51
%
1
2
3
4
5
6
7
8
H
0.618 0.06
Nt
CH3
C6H5
p-OmePh
H
49
0.115 0.011
0.094 0.005
0.419 0.019
Nt
49
44
74
C6H5
p-OmePh
H
44
–0.468 0.028
–0.204 0.020
Nt
45
44
9
10
11
F
46
OC2H5
H
–0403 (0.024)
Nt
36
44
Nt—non tested
a Indomethacin as standard drug for comparison reasons (0.1 mmol/kg–1) 56%.

C. Papadopoulou et al. / Il Farmaco 60 (2005) 969–973
973
oedema) of the examined amides and several physicochemi-
cal parameters (lipophilicity, steric and electronic param-
eters). The % inhibition of CPE of the tested compounds and
their lipophilicity as clog P values, calculated using the
C-QSAR program [14], were correlated (Eq. (1)) in a linear
model with the presence of an indicator variable I1 which
takes the value = 1 for the congeners where N = 1:
substituents R was not well defined, since the numbers of the
data were low.
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(1)
log % CPE = − 0.072 0.035 clog P − 0.085
͑
͒
͑
͒
0.068 I1+2.052 0.170
͒
͑
͒
͑
n = 9, r = 0.918, r2 = 0.842, q2 = 0.480, s = 0.039, F2,6 = 16
, ␣ = 0.01
Equation includes: 95% confidence limits for each term in
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significant with a significant F-value. Both the intercept and
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benzothiazolyl substituted groups and the amide group are
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