Synthesis and evaluation of anti-inflammatory and analgesic activity of some substituted thiazolyl and thaizolidinonyl tetrahydronapthalene derivatives

Article abstract of DOI:10.1007/s00044-014-0926-z

A new series of 1,2,3,4-tetrahydronaphthalen-6-yl-thiazole and thiazolidinone derivatives were synthesized. Twenty four of the newly synthesized compounds were evaluated for their anti-inflammatory and analgesic activity. The study exhibited that the derivatives 7b and 11c produced equipotent anti-inflammatory activity to that of the reference drug indomethacin with faster onset of action. Meanwhile, the compounds 1b, 1d, 6, 10c, 12c, 12e exhibited interesting dual anti-inflammatory and analgesic activity. The thiazolo-coumarin derivative 6 could be identified as the most biologically active member within this study with a significant dual anti-inflammatory and analgesic activity in comparison with indomethacin. The study of ulcerogenic effects proved that all of the tested compounds revealed super GIT safety profile in the experimental rats.

Full text of DOI:10.1007/s00044-014-0926-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-0926-z
ORIGINAL RESEARCH
Synthesis and evaluation of anti-inflammatory and analgesic
activity of some substituted thiazolyl and thaizolidinonyl
tetrahydronapthalene derivatives
•
Mogedda E. Haiba Somaia S. Abd El-Karim
•
•
Rasha S. Gouhar Magdy I. El-Zahar
•
Sally A. El-Awdan
Received: 8 November 2013 / Accepted: 18 January 2014
Ó Springer Science+Business Media New York 2014
Abstract A new series of 1,2,3,4-tetrahydronaphthalen-
6-yl-thiazole and thiazolidinone derivatives were synthe-
sized. Twenty four of the newly synthesized compounds
were evaluated for their anti-inflammatory and analgesic
activity. The study exhibited that the derivatives 7b and
11c produced equipotent anti-inflammatory activity to that
of the reference drug indomethacin with faster onset of
action. Meanwhile, the compounds 1b, 1d, 6, 10c, 12c, 12e
exhibited interesting dual anti-inflammatory and analgesic
activity. The thiazolo-coumarin derivative 6 could be
identified as the most biologically active member within
this study with a significant dual anti-inflammatory and
analgesic activity in comparison with indomethacin. The
study of ulcerogenic effects proved that all of the tested
compounds revealed super GIT safety profile in the
experimental rats.
Introduction
Inflammation is a defensive but exaggerated local tissue
reaction in response to exogenous or endogenous insult. It
is a fundamental physiological process that is not only
essential for survival but also at the same time is one of the
major causes of human morbidity and mortality (O’Neill,
2006, Cheeseright et al., 2009). Non-steroidal anti-
inflammatory drugs (NSAIDs) are used to treat a wide
variety of illnesses and diseases, including inflammation
(Rostom et al., 2009), cancers (Yao et al., 2004), diabetes
(insulin-resistant and related metabolic syndrome) (Hiroki
et al., 2007), and diseases of the peripheral and central
nervous system, e.g., Alzheimer’s and Parkinson’s (Laura
et al., 2004). This versatility is attributed to a wide variety
of effects of these drugs on the cell function. The anti-
inflammatory effect of NSAIDs arises from their ability to
inhibit both COX-1 and COX-2 isoforms of cyclooxygen-
ase (COX) enzyme (Joo et al., 2003). However, long term
clinical usages of NSAIDs are associated with significant
side effects such as severe gastrointestinal ulceration,
bleeding, intolerance, and renal toxicity (Amin et al.,
2010).
Keywords 1,2,3,4-Tetrahydronaphthalene ꢀ Thiazole ꢀ
Thiazolidinone ꢀ Anti-inflammatory ꢀ Analgesic activity
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-0926-z) contains supplementary
material, which is available to authorized users.
Different known anti-inflammatory drugs such as
Naproxen (Harrington and Lodewijk, 1997) and Nabume-
tone (Goudie et al., 1978) are bearing naphthalene moiety,
while Meloxicam has thiazole nucleus (Engelhardt et al.,
1995). Additionally, literature survey exhibited that some
of the synthesized derivatives comprising tetralin ring such
as the compound A (Barker et al., 2006), or comprising
thiazole ring such as the compounds B (Bekhit et al., 2003)
and C (Holla et al., 2003) produced significant anti-
inflammatory and analgesic activity with low ulcerogenic
effects. Thus, in view of the above mentioned facts, we
reported the synthesis, anti-inflammatory, analgesic, and
M. E. Haiba ꢀ S. S. Abd El-Karim (&) ꢀ
R. S. Gouhar ꢀ M. I. El-Zahar
Therapeutical Chemistry Department, National Research Center,
Dokki, Cairo 12622, Egypt
e-mail: somaia_elkarim@hotmail.com
M. E. Haiba
Pharmaceutical Chemistry Department, Faculty of Pharmacy,
King Saud University, Riyadh 11451, Saudi Arabia
S. A. El-Awdan
Pharmacology Department, National Research Center, Dokki,
Cairo 12622, Egypt
123

Med Chem Res
ulcer evaluation of some novel structure hybrids incorpo-
rating both the tetrahydronaphthalene moiety with thiazole
and/or thiazolidinone ring systems through hydrazine
linkage having the general formulae D (Fig. 1). This
combination was suggested in an attempt to investigate the
influence of such hybridization and structure variations on
the anticipated biological activities, hoping to add some
synergistic biological significance to the target molecules.
showed singlet signal at d 2.24 ppm due to the methyl group
protons (CH3–C=N) and singlet signals at d 8.34, 10.14 ppm
(2NH) which exchangeable with D2O. Also, its 13C NMR
spectrum showed signal at d 147.17 ppm referring to (C=N)
groupand atd 177.87 ppmdueto (C=S)group. Treatmentthe
derivatives 1b–d with chloroacetone, phenacyl bromide, and/
or 6-bromoacetyl-1,2,3,4-tetrahydronaphthalene (El-Zahar
et al., 2009) afforded the corresponding thiazole derivatives
2a–i, also the condensation of 1a with phenacyl bromide and/
or 4-bromophenacyl bromide afforded the corresponding
thiazole derivatives 2j, k.
Results and discussion
1H NMR spectra of the derivatives 2a showed proton at
5-position of the thiazole moiety as singlet signal at d
5.69 ppm, while the methyl protons at 4-position appeared
as singlet signal at d 2.13 ppm. IR spectra of the com-
pounds 2j, k showed bands at 3,121, 3,122 cm-1 (NH).
Chemistry
The synthetic strategies adopted to obtain the promising
structures are outlined in (Schemes 1, 2). The key interme-
diates 1-(1-(1,2,3,4-tetrahydronaphthalen-6-yl)ethylidene)
thiosemicarbazide derivatives 1a–e were obtained via the
condensation of 6-acetyl-1,2,3,4-tetrahydronaphthalene with
thiosemicarbazide or with N4-substituted thiosemicarbaz-
ides, namely, methylthiosemicarbazide, ethylthiosemicar-
bazide, phenylthiosemicarbazide, and/or cyclohexylthio-
semicarbazide. The chemical structures of 1a–e were con-
firmed by spectral data. IR spectra showed the absence of
acetyl group band and instead of this the appearance of new
bands at 3,204–3,253, 3,290–3,398 cm-1 (2NH), 1,589–
1
Also H NMR spectrum of compound 2j recorded singlet
signal at d 6.76 ppm referring to the methine proton of the
thiazole moiety. 13C NMR spectrum of the compound 2j
exhibited signals at d 100.43, 142.24 and 168.47 ppm (C5,
C4 and C2-thiazole moiety). The mass spectrum of the
compound 2k showed the molecular ion peaks at 425, 427
which represents the two isotopic peaks of bromine atom.
1-(5-(1,2,3,4-tetrahydronaphthalen-6-yl)thiazol-2-yl)hydra-
zine (3) was obtained from the treatment of 6-bromoacetyl-
1,2,3,4-tetrahydronaphthalene with thiosemicarbazide according
to the reported method (El-Zahar et al., 2009). Upon its
1,613 cm-1 (C=N). H NMR spectrum of compound 1b
1
OH
S
O
N
CH3
OH
S
N
H
N
O
O
O
O
Naproxen
Meloxicam
R1
H2N
O
R2
N
NR
O
N
N
H2N
N
N
R3
S
S
O
R4
Nabumetone
N
N
D
B
OH
F3C
H
O
O
S
N
Cl
N
O
N
N
N
O
H
O
Cl
F
A
C
Fig. 1 Structures of anti-inflammatory naphthalene, thiazole and background for the target compound synthesis
123

Med Chem Res
CH3
CH3
O
R1
N
H
H
N
N
N
X
N
N
R1
R2
X = Cl or B
R2
S
S
r
1a-e
2a-k
1a, R1= H
1d, R1=
1b, R1= CH3
1c, R1= CH2CH3
1e, R1=
H
N
H
N
R1
NH2
Ph
CHO
S
N
N
N
i , Br2
ii , NH2CSNHNH2
COCH3
Ph
S
NHNH2
3
O
CHO
H3CO
O
Ph
CHO
Cl
N
N
N
N
N
Ph
N
S
N
O
H
N
N
S
N
4
H
H3CO
N
O
6
N
N
N
S
N
H
Cl
5
2g
CH3
2a
2e
CH3 CH2CH3
2f
2h
2d
Comp. No
2b
2c
2i
2j
2k
R1
R2
CH3 CH2CH3
CH3
CH2CH3
H
H
CH3
CH3
Br
Scheme 1 Synthesis of ((tetrahydronaphthalen-6-yl)ethylidene)-2-(thiazol-2-yl)hydrazine and ((tetrahydronaphthalen-6yl)thiazol-2-yl)methy-
lene hydrazine derivatives
condensation with different aldehydes, namely, 1,3-diphe-
nyl-1H-pyrazole-4-carboxaldehyde (Prakash et al., 2006),
1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-
carboxaldehyde (Fahmy et al., 2012), and/or 4-oxo-4H-
chromene-3-carboxaldehyde (Nohara et al., 1974) in ethanol
yielded the corresponding Schiff’s bases 4–6, respectively.
IR spectra of the compounds 4–6 showed the absence of
(NH2) group bands and the appearance of strong absorption
bands at 3,140–3,165 cm-1 due to (NH) group. The charac-
teristic signals of 1H NMR spectrum of compound 4 appeared
as singlet signals at d 6.87 ppm (C5H-thiazole moiety),
8.06 ppm (–CH=N), 8.39 ppm (C5H-pyrazole moiety), and
NH proton at d 10.0 ppm. Also, 1H NMR spectrum of Schiff’s
base 5 indicated one singlet signal at d 3.36 ppm, which refers
to the protons of the methoxy group. (Scheme 1).
Furthermore, cyclocondensation of the thiosemicarba-
zone derivatives 1b–d with hydrazonyl chloride yielded the
corresponding 2-phenyldiazeyl thiazole derivatives 7b–
1
d. H NMR spectrum of the compound 7b represented the
methyl protons of C4–CH3-thiazole moiety as a singlet
signal at d 2.71 ppm and 13C NMR spectrum confirmed the
structure by the reveling a signal at d 12.30 ppm due to C4–
CH3-thiazole moiety.
Ethyl 2-(2-(1-(1,2,3,4-tetrahydronaphthalen-6-yl)ethyli-
dene) hydrazono)-2,3-dihydro-3-substituted-4-methylthia-
zole-5-carboxylate derivatives 8b–d were obtaind by
123

Med Chem Res
CH3
R1
N
N
N
CH3
O
CH3
R1
N
S
N
N
8b-d
CH3
CH3
Ph
R1
N
O
S
N
N
O
O
N
N
CH3
S
O
CH3
7b-d
O
Cl
9b-d
Cl
N
NHPh
O
O
O
CH3
H
N
H
N
CH3
N
N
R1
COCH3
Cl
N
S
N
O
O
1a-e
S
O
14
O
Br
O
O
O
Br
CH3
12a
AC2O
O
R1
N
N
N
O
S
CH3
CH3
R1
N
R1
N
N
10b-d
N
N
N
O
O
S
S
O
12a-e
11b-d
OH
H3CO
CHO
R1
H
a
CH3
R1
CH3
CH2CH3
b
c
d
N
N
N
O
S
13b-d
OCH3
e
Scheme 2 Synthesis of (((tetrahydronaphthale-6-yl)ethylidine)hydrazono)thiazole and thiazolidinone derivatives
appling Hantzsch reaction (Er et al., 2008) of thiosemi-
carbazone derivatives 1b–d with ethyl-2-chlor-
oacetoacetate. IR spectra of the derivatives 8b–d indicated
that the disappearance of (2NH) group bands and the
appearance of bands at 1,725–1,736 cm-1 (C=O) ester
protons of the acetyl group as singlet signal at d 2.60 ppm,
in addition to the methyl protons of the thiazole moiety as
singlet signal at d 2.37 ppm and 13C NMR spectrum
showed (C=O) group at d 189.80 ppm. Moreover, the thi-
osemicarbazone derivatives 1b–d were condensed with
ethyl 2-bromopropanoate to afford the corresponding
5-methylthiazolidinones 10b–d. IR spectra of the com-
pounds 10b–d showed bands at 1,715–1,720 cm-1 (C=O)
thiazolidinone moiety. 1H NMR spectrum of compound
10b showed douplet signal at d 1.64 and quartet signal at d
3.98 ppm attributed to the methyl protons of C5–CH3 and
C5–H of the thiazolidinone moiety. Also, 13C NMR spec-
trum showed signals at d 19.51, 41.89, and 175.69 ppm
related to the corresponding 5-methylthiazolidinone
moiety.
1
group. H NMR spectrum of compound 8b exhibited the
ester group signals at d 1.37 and 4.27 ppm, respectively,
and the methyl protons of the thiazole nucleus as singlet
signal at d 2.58 ppm. Also, 13C NMR spectrum of the
compound 8b exhibited signals at d 14.60, 60.74, and
166.30 ppm related to the ester group and another signal at
12.90 ppm referring to the methyl group of the thiazole
nucleus.
In addition, the reaction of thiosemicarbazone deriva-
tives 1b–d with 3-chloro-2,4-pentanedione gave 5-acetyl-
thiazole derivatives 9b–d. IR spectra of the compounds
9b–d showed bands at 1,718–1,721 cm-1 (C=O) acetyl
Thia-Michael reaction of thiosemicarbazone deriva-
tives 1b–d with maleic anhydride as Michael acceptor
(Liesen et al., 2010) in dry toluene led to the formation
1
group. H NMR spectrum of compound 9b exhibited the
123

Med Chem Res
Table 1 Anti-inflammatory effects of the tested compounds on carrageenan-induced rat paw edema (mL)
Group
Paw edema volume (mL)
0 h
1 h
2 h
3 h
4 h
Control
0.30 0.00
0.30 0.00
0.30 0.00
0.29 0.02
0.30 0.00
0.28 0.01
0.30 0.00
0.30 0.00
0.29 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.30 0.00
0.31 0.01
0.30 0.00
0.29 0.01
0.29 0.00
0.28 0.01
0.43 0.02
0.37 0.01
0.38 0.01
0.43 0.03
0.40 0.01
0.42 0.02
0.38 0.02
0.41 0.02
0.35 0.01
0.40 0.02
0.40 0.02
0.33 0.01*
0.32 0.00*
0.33 0.01*
0.35 0.01
0.35 0.01
0.35 0.02
0.36 0.01
0.39 0.02
0.34 0.01
0.33 0.01*
0.39 0.01
0.37 0.02
0.40 0.02
0.35 0.01
0.36 0.02
0.47 0.02
0.38 0.01*
0.39 0.01
0.45 0.02
0.41 0.01
0.43 0.02
0.42 0.02
0.47 0.02
0.40 0.01
0.45 0.01
0.44 0.01
0.36 0.01*
0.34 0.00*
0.35 0.00*
0.42 0.01
0.40 0.01
0.38 0.01*
0.41 0.01
0.46 0.01
0.37 0.01*
0.36 0.01*
0.46 0.02
0.40 0.02*
0.42 0.02
0.40 0.02
0.41 0.02
0.50 0.02
0.38 0.01*
0.40 0.01*
0.45 0.02
0.41 0.01*
0.43 0.02
0.45 0.02
0.52 0.02
0.44 0.01
0.47 0.01
0.46 0.01
0.37 0.01*
0.36 0.01*
0.39 0.00*
0.45 0.01
0.41 0.01*
0.38 0.01*
0.44 0.01
0.51 0.01
0.39 0.01*
0.37 0.01*
0.49 0.03
0.41 0.01*
0.41 0.02*
0.45 0.02
0.43 0.02
0.51 0.02
0.38 0.00*
0.40 0.018
0.44 0.03
0.40 0.01*
0.41 0.02*
0.47 0.01
0.55 0.02
0.45 0.01
0.48 0.01
0.47 0.01
0.41 0.02*
0.36 0.00*
0.39 0.01*
0.47 0.01
0.41 0.01*
0.41 0.01*
0.48 0.01
0.54 0.01
0.41 0.01*
0.38 0.01*
0.53 0.03
0.41 0.01*
0.40 0.02*
0.46 0.02
0.44 0.02
Indomethacin (0.03 mmol/kg)
1b
1c
1d
1e
2a
2e
2g
2h
2j
4
6
7b
8b
8c
9b
9c
10b
10c
11c
12a
12b
12c
12e
13b
The data represents the mean standard error of the mean (n = 6)
Values represent the mean SE of six animals for each groups
p \ 0.05: * Statistically significant from the control using one way Anova followed by Tukey test
of 4-thiazolidinone-acetic acid derivatives 11b–d. IR
spectra of the compounds 11b–d showed broad bands
centered at 3,408–3,427 cm-1 characteristic for (CO2H)
group and bands at 1,707–1,712 cm-1 (C=O) thiazolid-
compound 12b, which exhibited singlet signal at d 3.76 ppm
contributing to the methylene protons of thiazolidinone
moiety and 13C NMR spectra showed signals at d 31.55 and
171.21 ppm due to (CH2 and C = O) groups of thiazolidi-
none moiety.
1
inone moiety. H NMR spectrum of the compound 11c
showed multiplet signals at 2.88–2.91, 2.98–3.01 ppm
(CH2ab), a multiplet signal at 4.32–4.34 (C5–H thiazo-
lidinone), and broad singlet signal at 12.67 ppm (CO2H)
group.
Condensation of 12b–d with 4-methoxybenzaldehyde in
10 % alcoholic sodium hydroxide afforded the corre-
sponding arylidene derivatives 13b–d. IR spectra of the
compounds 13b–d showed bands at 1,692–1,698 cm-1
1
Refluxing of the thiosemicarbazone derivatives 1a–e with
ethyl bromoacetate in the presence of piperidine in absolute
ethanol afforded 2-(2-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-3-substituted-4-thiazolidinones
12a–e. IR spectra of the compounds 12a–e showed bands
at 1,708–1,724 cm-1 (C=O) thiazolidinone moiety. Further
attributed to a,b-unsaturated ketone. H NMR spectrum of
compound 13b represented the methoxy protons as singlet
signal at d 3.86 ppm and no signal derived from the
methylene protons of thiazolidinone derivatives 12b–d was
observed. Furthermore, acylation of the thiazolidinone
derivative 12a with acetic anhydride led to the formation of
2-(2-(1-(1,2,3,4-tetrahydronaphthalen-6-yl)ethylidene)
1
confirmation was obtained from the H NMR spectrum of
123

Med Chem Res
hydrazono)-3-acetylthiazolidin-4-one (14), its IR spectrum
showed a band at 1,647 cm-1 due to (–NCOCH3) group
and in 1H NMR spectrum the acetyl protons were observed
as a singlet signal at 2.41 ppm. (Scheme 2).
Table 2 Percentage of edema inhibition of the tested compounds on
carrageenan-induced rat paw edema
Group no.
% inhibition (potency)
1 h 2 h 3 h
Indomethacin (0.03 mmol/kg) -13.95 -19.14 -24.00 -25.49
4 h
Biological screening
1b
1c
-11.62 -17.02 -20.00 -21.56
0.00 -4.25 -10.00 -13.72
-6.97 -12.76 -18.00 -21.56
-2.32 -8.51 -14.00 -19.60
-11.62 -10.63 -10.00 -7.84
Anti-inflammatory activity
1d
1e
In this study, 24 newly synthesized derivatives were
selected as representative examples to evaluate their anti-
inflammatory activity by applying carrageenan-induced
paw edema bioassay in rats (Winter et al., 1962) using
indomethacin as a reference standard. Results were
expressed as mean SE. The difference between control
and treated groups were tested using one way ANOVA
followed by Tukey test. Methods of statistical analysis
were done according to Armitage (Armitage, 1971). The
evaluated compounds are 1b–e, 2a, 2e, 2g, 2h, 2j, 4, 6, 7b,
8b, c, 9b, c, 10b, c, 11c, 12a, b, c, e, 13b. The anti-
inflammatory activity data (Tables 1, 2) revealed that the
highest anti-inflammatory potency at 4 h was gained by 11
derivatives according to the following order 6 > 11c >
7b > 1d > 12 c > 1e, 4, 8c, 9b, 10c, 12b. It has been
noticed that they exhibited early action showing percent-
ages of edema inhibition higher than or equal to the ref-
erence drug indomethacin. The compound 6 carrying
coumarin-thiazole ring system inhibited the edema volume
by (25.58 %) at the 1st h post administration, and the
activity was enhanced up to the 4th h giving edema volume
inhibition by (29.41 %) higher than that produced by
indomethacin (13.95 and 25.49 %, respectively). Also,
significant edema inhibition at the first hour post com-
pounds administration (20.93–23.25 %) was observed by
the derivatives carrying pyrazolothiazole, 5-phenyldiazeyl-
thiazole, 3-ethyl-5-methylthiazolidinone, and 3-ethyl-thia-
zolidinone-5-acetic acid nuclei (4, 7b, 10c, 11c). A sub-
stantial reduction in the activity, but still higher than that of
indomethacin, was detected by the derivatives: thiazole-5-
carboxylates 8b,c, 5-acetylthiazoles 9b,c, 3-methyl/cyclo-
hexylthiazolidinones 12b,e, and 5-methoxybenzylidine-
thiazolidinone conjugate 13b. Regarding to the duration of
actions of the tested derivatives demonstrated that the
highest potency obtained at 4 h post after derivatives
administration was also produced by the coumarin-thiazole
compound 6, which exhibited edema inhibition (29.41 %)
higher than that of indomethacin (25.49 %). Equipotency
to the reference drug indomethacin was observed by the
acetic acid derivative 11c. Slight reduction in the activity at
4 h after compounds administration (21.56–23.52 %) was
noticed by the derivatives 1b, 1d, 7b, and 12c. A note-
worthy decrease in the activity was obtained by the other
tested derivatives.
2a
2e
-4.65
0.00
4.00
7.84
2g
-18.60 -14.89 -12.00 -11.76
-6.97 -4.25 -6.00 -5.88
-6.97 -6.38 -8.00 -7.84
-23.25 -23.40 -26.00 -19.60
-25.58 -27.65 -28.00 -29.41
-23.25 -25.53 -22.00 -23.52
-18.60 -10.63 -10.00 -7.84
-18.60 -14.89 -18.00 -19.60
-18.60 -19.14 -24.00 -19.60
-16.27 -12.76 -12.00 -5.88
2h
2j
4
6
7b
8b
8c
9b
9c
10b
10c
11c
12a
12b
12c
12e
13b
-9.30 -2.12
2.00
5.88
-20.93 -21.27 -22.00 -19.60
-23.25 -23.40 -26.00 -25.49
-9.30 -2.12 -2.00
3.92
-13.95 -14.89 -18.00 -19.60
-6.97 -10.63 -18.00 -21.56
-18.60 -14.89 -10.00 -9.80
-16.27 -12.76 -14.00 -13.72
Analgesic activity
The analgesic activity of the above mentioned derivatives
was also evaluated in comparison with indomethacin as a
standard reference drug (10 mg/kg) by applying hot plate
test (Tzschentke et al., 2007). The results were expressed
as mean SE. The difference between vehicle control and
treatment groups was tested using one way ANOVA fol-
lowed by Tukey. Methods of statistical analysis were done
according to Armitage (Armitage, 1971). The analgesic
activity expressed in (Table 3) showed that the longest
duration of actions up to 90 min post derivatives admin-
istration was gained by the compounds bearing thiosemi-
carbazide, 3-methyl-4-tetralylthiazole, coumarin-thiazole,
3-ethyl-5-methylthiazolidinone, 3-methylthiazolidinone,
cyclohexylthiazolidinone, 3-ethyl-4-tetralylthiazole, and
4-phenyllthiazole ring systems (1d, 2g, 6, 10c, 12b, 12e,
2h, 2j). They exhibited equipotent analgesia to that
obtained by indomethacin. A noteworthy drop in the pro-
duced analgesia was got by the other tested derivatives.
123

Med Chem Res
Ulcerogenic activity
GC MS-Qp1000EX Shimadzu, Cairo University, Cairo,
Egypt. Follow up of the reactions and checking the purity
of the compounds were made by TLC on silica gel-pre-
coated aluminum sheets (Type 60, F 254, Merck, Darms-
tadt, Germany) using chloroform/pet.ether 40–60 (5:1,
v/v), and the spots were detected by exposure to UV lamp
at k254 nm for few seconds and by iodine vapor.
The chemical names given for the prepared compounds
are according to the IUPAC system. 1-(5-(1,2,3,4-tetra-
hydronaphthalen-6-yl)thiazol-2-yl)hydrazine (3) (El-Zahar
et al., 2009), 1,3-diphenyl-1H-pyrazole-4-carboxaldehyde
(Prakash et al., 2006), 1-(3-chlorophenyl)-3-(4-methoxy-
phenyl)-1H-pyrazole-4-carboxaldehyde (Fahmy et al., 2012),
and 4-oxo-4H-chromene-3-carboxaldehyde (Nohara et al.,
1974) were prepared according to the reported method.
The ulcerogenic potential of the tested compounds was
evaluated in rats (Abouzid et al., 2012, El-Araby et al.,
2012). Interestingly, all the tested derivatives showed
superior GIT safety profile and exhibited no ulcerogenic
effects in comparison to indomethacin which exhibited
ulcer severity 22.40 – 1.24 the same experimental condi-
tions. These data represented the potential medicinal value
of these compounds as anti-inflammatory and analgesic
agents, since they have better safety margin than indo-
methacin on gastric mucosa.
Conclusions
This study deals with synthesis of novel derivatives of tet-
rahydronaphthalene nucleus incorporated with substituted
thiazole moiety via hydrazine linkage. Biological evaluation
of many of the derivatives as anti-inflammatory and analgesic
agents showed that some of them produced higher potency
than the reference drug indomethacin. Also, it is noticeable
that dual anti-inflammatory and analgesic activities were
obtained by thiosemicarbazide, coumarin-thiazole, 3-ethyl-
5-methylthiazolidinone, and 3-methyl/cyclohexylthiazolidinone
derivatives (1d, 6, 10c, 12b, 12e). It is noteworthy that the
coumarin-thiazole compound 6 produced the highest anti-
inflammatory and analgesic potency with superior GIT safety,
and this result comes in agreement with the literature report
(Kalkhambkar et al., 2007, Kashyap et al., 2012) that
indicated the valuability of coumarin and tetralin nuclei in
producing anti-inflammatory efficiency.
General procedure for the synthesis of 1-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)
thiosemicarbazide derivatives 1a–e
A
mixture of 6-acetyl-1,2,3,4-tetrahydronaphthalene
(3.48 g, 0.02 mol) and thiosemicarbazide or the appropriate
thiosemicarbazide derivatives, namely; methylthiosemicar-
bazide, ethylthiosemicarbazide, phenylthiosemicarbazide,
and/or cyclohexylthiosemicarbazide (0.02 mol) in absolute
ethanol (15 mL) containing a few drops of conc. hydro-
chloric acid was refluxed for 3 h. The formed precipitate on
cooling was filtered, dried, and recrystallized from ethanol to
give the title compounds 1a–e.
1-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)ethylidene)
thiosemicarbazide (1a)
Yield 71 %, mp. 177–178 °C; IR (KBr, cm-1): 3398, 3233,
3142 (NH, NH2), 2929, 2853 (CH2-tetrahydronaphthalene),
Experimental
1
1589 (C=N); H NMR (DMSO-d6): d 1.67–1.74 (4H, m,
Chemistry
2(CH2)-tetrahydronaphthalene protons), 2.24 (3H, s, CH3–
C=N), 2.68–2.74 (4H, m, 2(CH2)-tetrahydronaphthalene
protons), 7.00 (1H, d, CH=, J = 9.00 Hz), 7.61 (1H, d, CH=,
J = 9.00 Hz), 7.87 (1H, s, CH =), 8.27, 10.16 (3H, 2 s, NH,
NH2, D2O exchangeable); 13C NMR (DMSO-d6): d 13.32,
22.10, 28.03, 28.24, 123.09, 126.43, 128.14, 134.20, 135.85,
137.42, 147.55, 178.12; MS, m/z (%): 246.9 [M?] (70), 248.0
[M? ? 1] (12), 231.9 [M?-NH] (100). Anal. For C13H17N3S
(247.36): Calcd. C, 63.12; H, 6.93; N, 16.99; S, 12.96;
Found: C, 63.25; H, 7.03; N, 16.81; S, 12.78.
All melting points are uncorrected and were taken in open
capillary tubes using Electrothermal apparatus 9100. Ele-
mental microanalyses were carried out at Microanalytical
Unit, Central Services Laboratory, National Research
Centre, Dokki, Cairo, Egypt, using Vario Elementar and
were found within 0.4 % of the theoretical values.
Infrared spectra were recorded on a Jasco FT/IR-6100,
Fourier transform, Infrared spectrometer at cm-1 scale
using KBr disk technique at Central Services Laboratory,
1
National Research Centre, Dokki, Cairo, Egypt. H NMR
1-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)ethylidene)-4-
and 13C NMR spectra were determined by using a JEOL
AS-500 NMR spectrometer at Central Services Laboratory,
National Research Centre, Dokki, Cairo, Egypt, chemical
shifts are expressed in d (ppm) downfield from TMS as an
internal standard. The mass spectra were measured with a
methylthiosemicarbazide (1b)
Yield 77 %, mp. 114–115 °C; IR (KBr, cm-1): 3319, 3211
(2 NH), 2933, 2855 (CH2-tetrahydronaphthalene), 1609
(C=N); 1H NMR (DMSO-d6): d 1.69–1.72 (4H, m, 2(CH2)-
123

Med Chem Res
Table 3 Analgesic activity of the tested compounds by hot plate method
Group
Reaction time/min
0 min
30 min
60 min
90 min
Control
4.06 0.68
5.56 0.23
3.52 0.40
3.96 0.39
4.12 0.57
3.92 0.59
2.67 0.40
2.72 0.32
3.44 0.55
4.06 0.18
3.54 0.54
2.82 0.23
3.48 0.22
2.94 0.43
2.64 0.25
3.08 0.34
3.08 0.39
3.00 0.46
2.48 0.43
3.38 0.60
3.18 0.42
3.64 0.53
3.48 0.31
4.12 0.57
3.36 0.63
3.36 0.62
4.98 0.25
8.04 0.55*
5.34 0.26
4.40 0.43
5.62 0.67
5.16 0.49
4.00 0.31
4.00 0.22
6.00 0.54
5.80 0.43
6.06 0.50
4.00 0.26
4.74 0.35
4.12 0.26
3.76 0.22
4.34 0.246
4.48 0.42
5.06 0.61
3.86 0.20
5.20 0.48
4.46 0.46
4.60 0.43
5.92 0.75
5.16 0.62
5.14 0.60
5.70 0.63
5.78 0.44
10.86 0.57*
6.12 0.61
5.50 0.43
7.54 0.73
6.12 0.61
4.34 0.18
6.30 0.59
6.90 0.57
6.88 0.38
7.92 0.41
4.88 0.36
5.38 0.53
6.04 6.04
5.02 0.38
6.18 0.48
6.26 0.50
5.96 0.69
7.80 0.53
6.36 0.55
5.96 0.20
5.40 0.36
7.58 0.68
5.76 0.52
6.28 0.57
6.58 0.80
5.56 0.64
9.86 1.07*
7.90 0.49
6.86 0.56
10.18 1.14*
7.36 0.81
4.60 0.28
7.72 1.08
10.12 0.57*
9.82 0.75*
9.82 0.37*
6.30 0.49
10.20 0.37*
7.94 0.56
5.48 0.30
6.80 0.51
7.56 0.91
6.98 0.78
6.88 0.77
10.40 0.81*
6.64 0.45
6.16 0.60
10.78 1.02*
6.32 0.34
10.18 0.36*
7.92 0.83
Indomethacin (0.03 mmol/kg)
1b
1c
1d
1e
2a
2e
2g
2h
2j
4
6
7b
8b
8c
9b
9c
10b
10c
11c
12a
12b
12c
12e
13b
Values represent the mean SE of six animals for each group
p \ 0.05: * Statistically significant from control using one way Anova followed by Tukey test
tetrahydronaphthalene protons), 2.24 (3H, s, CH3–C=N),
2.69–2.73 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
3.06 (3H, s, N–CH3), 7.02 (1H, d, CH=, J = 8.10 Hz), 7.54
(1H, s, CH =), 7.65 (1H, d, CH=, J = 8.10 Hz), 8.37,
10.14 (2H, 2 s, 2NH, D2O exchangeable); 13C NMR
(DMSO-d6): d 13.24, 21.97, 27.93, 28.21, 30.37, 122.95,
126.33, 128.01, 134.17, 135.71, 137.23, 147.17, 177.87;
MS, m/z (%): 261.0 [M?] (36), 262.0 [M??1] (12), 246.0
[M?-CH3] (60), 107.2 [C8H11] (100). Anal. For C14H19N3S
(261.39): Calcd. C, 64.33; H, 7.33; N, 16.08; S, 12.27;
Found: C, 64.64; H, 7.25; N, 16.21; S, 12.35.
J = 6.90 Hz), 1.80–1.82 (4H, m, 2(CH2)-tetrahydronaph-
thalene protons), 2.29 (3H, s, CH3–C=N), 2.77–2.79 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 3.76 (2H, q, N–
CH2CH3, J = 6.90 Hz), 7.09 (1H, d, CH=, J = 7.50 Hz),
7.35 (1H, s, CH =), 7.40 (1H, d, CH=, J = 7.50 Hz), 7.58,
8.56 (2H, 2 s, 2NH, D2O exchangeable); 13C NMR (CDCl3):
d 13.95, 14.66, 23.13, 29.36, 29.59, 39.40, 123.51, 127.12,
129.39, 134.80, 137.32, 139.23, 147.63, 177.64; MS,
m/z (%): 275.2 [M?] (47), 260.2 [M?-CH3] (18), 187.2
[M?-C3H6NS] (19), 174.2 [M?-C3H5N2S] (100). Anal. For
C15H21N3S (275.41): Calcd. C, 65.41; H, 7.69; N, 15.26; S,
11.64; Found: C, 65.39; H, 7.81; N, 15.44; S, 11.78.
4-Ethyl-1-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene) thiosemicarbazide (1c)
1-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)ethylidene)-4-
phenylthiosemicarbazide (1d)
Yield 80 %, mp. 107–108 °C; IR (KBr, cm-1): 3366, 3253
(2 NH), 2927, 2860 (CH2-tetrahydronaphthalene), 1600
(C=N); 1H NMR (CDCl3): d 1.30 (3H, t, N–CH2CH3,
Yield 82 %, mp. 167–168 °C; IR (KBr, cm-1): 3290, 3250
(2 NH), 2931, 2852 (CH2-tetrahydronaphthalene), 1590
123

Med Chem Res
(C=N); 1H NMR (DMSO-d6): d 1.72–1.74 (4H, m, 2(CH2)-
tetrahydronaphthalene protons), 2.33 (3H, s, CH3–C=N),
2.72–2.75 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
7.05–7.75 (8H, m, CH-tetrahydronaphthalene protons and
tetrahydronaphthalene protons), 3.44 (3H, s, N–CH3), 5.69
(1H, s, C5H-thiazole proton), 7.04 (1H, d, CH=,
J = 8.00 Hz), 7.53 (1H, s, CH =), 7.59 (1H, d, CH=,
J=8.00 Hz); 13C NMR (CDCl3): d 14.44, 23.43, 29.44,
29.75, 31.37, 96.48, 123.52, 126.93, 129.03, 135.33,
136.80, 137.83, 155.34, 169.49; MS, m/z (%): 299.0 [M?]
(100), 300.0 [M??1] (23), 298.0 [M?-1] (86); Anal. For
C17H21N3S (299.43): Calcd. C, 68.19; H, 7.07; N, 14.03; S,
10.71; Found: C, 68.33; H, 7.27; N, 14.26; S, 10.65.
Ar–H), 9.97, 10.52 (2H, 2 s, 2NH, D2O exchangeable); 13
C
NMR (DMSO-d6): d 13.90, 22.15, 28.16, 28.38, 123.47,
124.82, 125.33, 126.83, 127.57, 128.30, 134.18, 136.00,
137.81, 138.68, 148.91, 176.34; MS, m/z (%): 323.0 [M?]
(25), 308.0 [M?-CH3] (40), 230.0 [M?-C6H7N] (31), 93.0
[C6H7N] (100). Anal. For C19H21N3S (323.46): Calcd. C,
70.55; H, 6.54; N, 12.99; S, 9.91; Found: C, 70.46; H, 6.77;
N, 12.79; S, 9.68.
2-(3-Ethyl-4-methylthiazol-2(3H)-ylidene)-1-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)hydrazine (2b)
4-Cyclohexyl-1-(1-(1,2,3,4-tetrahydronaphthalen-6-
Yield 77 %, mp. 114–115 °C; IR (KBr, cm-1): 2934, 2856
(CH2-tetrahydronaphthalene), 1595, 1563 (C=N); 1H NMR
(CDCl3): d 1.32 (3H, t, N–CH2CH3, J = 6.90 Hz)
1.79–1.83 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
2.14 (3H, s, C4–CH3–thiazole protons), 2.37 (3H, s, CH3–
C=N), 2.76–2.80 (4H, m, 2(CH2)-tetrahydronaphthalene
protons), 3.94 (2H, q, N–CH2CH3, J = 6.90 Hz), 5.65 (1H,
s, C5H-thiazole proton), 7.03 (1H, d, CH=, J = 8.00 Hz),
7.53 (1H, s, CH =), 7.59 (1H, d, CH=, J = 8.00 Hz); MS,
m/z (%): 312.9 [M?] (33), 314 [M??1] (22), 299.6
[M?-CH] (31), 158.2 [C12H15] (40), 59.6 [C3H10N] (100);
Anal. For C18H23N3S (313.46): Calcd. C, 68.97; H, 7.40; N,
13.41; S, 10.23; Found: C, 69.12; H, 7.72; N, 13.68; S,
10.44.
yl)ethylidene)thiosemicarbazide (1e)
Yield 52 %, mp. 160–161 °C; IR (KBr, cm-1): 3330, 3204
(2 NH), 2927, 2847 (CH2-tetrahydronaphthalene and
cyclohexyl moieties), 1613 (C=N); 1H NMR (DMSO-d6): d
1.13–1.60 (10H, m, 5(CH2)-cyclohexyl protons), 1.66–1.76
(4H, m, 2(CH2)-tetrahydronaphthalene protons), 2.25 (3H,
s, CH3–C=N), 2.68–2.76 (4H, m, 2(CH2)-tetrahydronaph-
thalene protons), 4.17–4.24 (1H, m, –NCH-cyclohexyl
moiety), 7.04 (1H, d, CH=, J = 7.70 Hz), 7.44 (1H, s,
CH =), 7.56 (1H, d, CH=, J = 7.70 Hz), 7.93, 10.15 (2H,
2 s, 2NH, D2O exchangeable); 13C NMR (DMSO-d6): d
13.90, 22.31, 24.35, 24.72, 28.30, 28.51, 31.33, 51.98,
123.18, 126.81, 128.63, 134.59, 136.22, 137.70, 147.96,
176.23; MS, m/z (%): 328.8 [M?] (14), 174.0 [C12H16N]
(100), 98 [C6H12N] (97). Anal. For C19H27N3S (329.50):
Calcd. C, 69.26; H, 8.26; N, 12.75; S, 9.73; Found: C,
69.44; H, 8.11; N, 12.42; S, 9.88.
1-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)ethylidene)-2-(4-
methyl-3-phenylthiazol-2(3H)-ylidene)hydrazine (2c)
Yield 85 %, mp. 130-131 °C; IR (KBr, cm-1): 2942, 2835
(CH2-tetrahydronaphthalene), 1594, 1563 (C=N); 1H NMR
(CDCl3): d 1.79–1.82 (4H, m, 2(CH2)-tetrahydronaphtha-
lene protons), 1.89 (3H, s, C4–CH3-thiazole protons), 2.20
(3H, s, CH3–C=N), 2.77–2.79 (4H, m, 2(CH2)-tetrahydro-
naphthalene protons), 5.81 (1H, s, C5H-thiazole proton),
7.10–7.60 (8H, m, CH-tetrahydronaphthalene protons and
Ar–H); MS, m/z (%): 361.0 [M?] (100), 362.0 [M??1]
(33), 130.0 [C10H10] (48), 77.0 [C6H5] (75); Anal. For
C22H23N3S (361.50): Calcd. C, 73.09; H, 6.41; N, 11.62; S,
8.87; Found: C, 73.28; H, 6.11; N, 11.81; S, 8.64.
General procedure for the synthesis of 1-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)-2-(3,4-
disubstituted thiazol-2(3H)-ylidene)hydrazine 2a–f
A mixture of the thiosemicarbazone derivatives 1b–d
(0.002 mol), chloroacetone and/or phenacyl bromide
(0.002 mol), and anhydrous sodium acetate (0.17 g,
0.002 mol) in absolute ethanol (15 mL) was heated under
reflux for 6 h. The formed precipitate on cooling was fil-
tered, washed several times with water, dried, and recrys-
tallized from ethanol to give the title compounds 2a–f.
1-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)ethylidene)-2-(3-
methyl-4-phenylthiazol-2(3H)-ylidene)hydrazine (2d)
1-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)ethylidene)-2-
(3,4-dimethylthiazol-2(3H)-ylidene)hydrazine (2a)
Yield 73 %, mp. 141–142 °C; IR (KBr, cm-1): 2921, 2842
(CH2-tetrahydronaphthalene), 1590, 1564 (C=N); 1H NMR
(CDCl3): d 1.80–1.82 (4H, m, 2(CH2)-tetrahydronaphtha-
lene protons), 2.46 (3H, s, CH3–C=N), 2.78–2.82 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 3.38 (3H, s, N–
CH3), 5.95 (1H, s, C5H-thiazole proton), 7.36–7.65 (8H, m,
CH-tetrahydronaphthalene protons and Ar–H); 13C NMR
Yield 75 %, mp. 153–154 °C; IR (KBr, cm-1): 2926, 2842
(CH2-tetrahydronaphthalene), 1597, 1566 (C=N); 1H NMR
(CDCl3): d 1.79–1.83 (4H, m, 2(CH2)-tetrahydronaphtha-
lene protons), 2.13 (3H, s, C4–CH3-thiazole protons), 2.44
(3H, s, CH3–C=N), 2.76–2.80 (4H, m, 2(CH2)-
123

Med Chem Res
2-(4-(1,2,3,4-Tetrahydronaphthalen-6-yl)-3-methylthiazol-
2(3H)-ylidene)-1-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene) hydrazine (2g)
(CDCl3): d 13.33, 22.06, 28.15, 28.44, 32.49, 98.62,
122.31, 124.24, 125.75, 127.55, 127.76, 127.85, 128.04,
128.13, 130.07, 135.56, 136.74, 139.67, 154.78, 168.24;
MS, m/z (%): 361.0 [M?] (100), 362 [M??1] (29), 175.8
[C12H18N] (43); Anal. For C22H23N3S (361.50): Calcd. C,
73.09; H, 6.41; N, 11.62; S, 8.87; Found: C, 73.34; H, 6.56;
N, 11.43; S, 8.91.
Yield 80 %, mp. 139–140 °C; IR (KBr, cm-1): 2927, 2847
(CH2-tetrahydronaphthalene), 1593, 1566 (C = N); 1H
NMR (CDCl3): d 1.81–1.83 (8H, m, 4(CH2)-tetrahydro-
naphthalene protons), 2.51 (3H, s, CH3–C = N), 2.78–2.82
(8H, m, 4(CH2)-tetrahydronaphthalene protons), 3.48 (3H,
s, N–CH3), 5.99 (1H, s, C5H-thiazole proton), 7.06–7.65
(6H, m, CH-tetrahydronaphthalene protons); 13C NMR
(CDCl3): d 15.09, 23.12, 23.39, 29.48, 29.74, 34.45,
100.12, 123.66, 125.91, 127.12, 128.03, 129.09, 129.59,
136.39, 136.89, 137.90, 138.32, 138.73, 141.65, 156.43,
169.81; MS, m/z (%): 415.0 [M?] (100), 416.0 [M??1]
(32), 414.0 [M?-1] (35); Anal. For C26H29N3S (415.59):
Calcd. C, 75.14; H, 7.03; N, 10.11; S, 7.72; Found: C,
75.23; H, 6.85; N, 10.24; S, 7.91.
2-(3-Ethyl-4-phenylthiazol-2(3H)-ylidene)-1-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)hydrazine (2e)
Yield 68 %, mp. 83–84 °C; IR (KBr, cm-1): 2924, 2840
(CH2-tetrahydronaphthalene), 1597, 1565 (C=N); 1H NMR
(CDCl3): d 1.24 (3H, t, N–CH2CH3, J = 6.90 Hz),
1.79–1.81 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
2.46 (3H, s, CH3–C=N), 2.78–2.81 (4H, m, 2(CH2)-tetra-
hydronaphthalene protons), 3.89 (2H, q, N–CH2CH3,
J = 6.90 Hz), 5.91 (1H, s, C5H-thiazole proton), 7.38–7.63
(8H, m, CH-tetrahydronaphthalene protons and Ar–H);
MS, m/z (%): 361.0 [M?-CH2] (23), 362 [M?-CH] (23),
56.9 [C4H9] (100); Anal. For C23H25N3S (375.53): Calcd.
C, 73.56; H, 6.71; N, 11.19; S, 8.54; Found: C, 73.74; H,
6.86; N, 11.28; S, 8.32.
2-(3-Ethyl-4-(1,2,3,4-tetrahydronaphthalen-6-yl)thiazol-
2(3H)-ylidene)-1-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene)hydrazine (2h)
Yield 78 %, mp. 119–120 °C; IR (KBr, cm-1): 2927, 2855
(CH2-tetrahydronaphthalene), 1595, 1560 (C=N); 1H NMR
(CDCl3): d 1.28 (3H, t, N–CH2CH3, J = 6.90 Hz),
1.81–1.83 (8H, m, 4(CH2)-tetrahydronaphthalene protons),
2.48 (3H, s, CH3–C=N), 2.78–2.82 (8H, m, 4(CH2)-tetra-
hydronaphthalene protons), 3.39 (2H, q, N–CH2CH3,
J = 6.90 Hz), 5.90 (1H, s, C5H-thiazole proton), 7.05–7.67
(6H, m, CH-tetrahydronaphthalene protons); MS, m/z (%):
429.0 [M?] (50), 430.0 [M??1] (16), 428 [M?-1] (9), 257
[M?-C12H14N] (32), 115 [C9H7] (100); Anal. For
C27H31N3S (429.62): Calcd. C, 75.48; H, 7.27; N, 9.78; S,
7.46; Found: C, 75.66; H, 7.31; N, 9.67; S, 7.51.
1-(1-(1,2,3,4–tetrahydronaphthalen–6–yl)ethylidene)-2-
(3,4-diphenylthiazol-2(3H)-ylidene)hydrazine (2f)
Yield 59 %, mp. 140-141 °C; IR (KBr, cm-1): 2927, 2839
(CH2-tetrahydronaphthalene), 1591, 1569 (C=N); 1H NMR
(CDCl3): d 1.78–1.80 (4H, m, 2(CH2)-tetrahydronaphtha-
lene protons), 2.35 (3H, s, CH3–C=N), 2.77–2.81 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 6.16 (1H, s, C5H-
thiazole proton), 7.12–7.70 (13H, m, CH-tetrahydronaph-
thalene protons and Ar–H); MS, m/z (%): 423.0 [M?]
(100), 424.0 [M??1] (35), 422.4 [M?-1] (48); Anal. For
C27H25N3S (423.57): Calcd. C, 76.56; H, 5.95; N, 9.92; S,
7.57; Found: C, 76.38; H, 6.21; N, 9.74; S, 7.36.
2-(4-(1,2,3,4-Tetrahydronaphthalen-6-yl)-3-phenylthiazol-
2(3H)-ylidene)-1-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene) hydrazine (2i)
General procedure for the synthesis of 2-(4-(1,2,3,4-
tetrahydronaphthalen-6-yl)-3-substituted thiazol-2(3H)-
ylidene)-1-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene)hydrazine 2g–i
Yield 61 %, mp. 114–115 °C; IR (KBr, cm-1): 2924, 2856
(CH2-tetrahydronaphthalene), 1598, 1562 (C=N); 1H NMR
(CDCl3): d 1.72–1.81 (8H, m, 4(CH2)-tetrahydronaphtha-
lene protons), 2.30 (3H, s, CH3–C=N), 2.67–2.80 (8H, m,
4(CH2)-tetrahydronaphthalene protons), 6.11 (1H, s, C5H-
thiazole proton), 7.17–7.65 (11H, m, CH-tetrahydronaph-
thalene protons and Ar–H); MS, m/z (%): 476.9 [M?] (62),
478.0 [M??1] (30), 476.4 [M?-1] (34); 60.0 [C2H4S]
(100); Anal. For C31H31N3S (477.66): Calcd. C, 77.95; H,
6.54; N, 8.80; S, 6.71; Found: C, 77.74; H, 6.41; N, 8.62; S,
6.84.
A mixture of the thiosemicarbazone derivatives 1b–
d (0.002 mol) and 6-bromoacetyl-1,2,3,4-tetrahydronaph-
thalene (0.51 g, 0.002 mol) in absolute ethanol (15 mL)
containing few drops of piperidine was heated under reflux
for 4 h. After cooling, the mixture was poured onto ice/
cold water, the formed precipitate was filtered, washed
several times with water, dried, and recrystallized from
ethylacetate/pet.ether to give the title compounds 2g–i.
123

Med Chem Res
General procedure for the synthesis of 1-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)-2-(4-phenyl/(4
bromophenyl)thiazol-2-yl)hydrazine 2j, k
carboxaldehyde, 1-(3-chlorophenyl)-3-(4-methoxyphenyl)-
1H-pyrazole-4-carboxaldehyde, and/or 4-oxo-4H-chro-
mene-3-carboxaldehyde (0.002 mol) in absolute ethanol
(15 mL) was heated under reflux for 10 h. The formed
precipitate on cooling was filtered, dried, and recrystallized
from ethanol to give the title compounds 4–6.
A mixture of the thiosemicarbazone derivative 1a (0.5 g,
0.002 mol) and a-haloketone namely; phenacyl bromide
and/or 4-bromophenacyl bromide (0.002 mol) in absolute
ethanol (15 mL) was heated under reflux for 6 h. The
formed precipitate on cooling was filtered, washed with
sodium carbonate solution (5 %) and then with water,
dried, and recrystallized from ethanol to give the title
compounds 2j, k.
1-(5-(1,2,3,4-Tetrahydronaphthalen-6-yl)thiazol-2-yl)-2-
((1,3-diphenyl-1H-pyrazol-4-yl)methylene)hydrazine (4)
Yield 56 %, mp. 185–186 °C; IR (KBr, cm-1): 3165 (NH),
2923, 2851 (CH2-tetrahydronaphthalene), 1595 (C=N); H
1
NMR (CDCl3): d 1.80–1.82 (4H, m, 2(CH2)-tetrahydro-
naphthalene protons), 2.78–2.80 (4H, m, 2(CH2)-tetrahy-
dronaphthalene protons), 6.87 (1H, s, C5H-thiazole proton),
7.25–7.81 (13H, m, CH-tetrahydronaphthalene protons,
and Ar–H), 8.06 (1H, s, –CH=N–), 8.39 (1H, s, CH-pyra-
zole proton), 10.0 (1H, s, NH, D2O exchangeable); MS,
m/z (%): 475.1 [M?] (12), 245.9 [C13H16N3S] (90), 230.2
[C13H14N2S] (90), 77 [C6H5] (100); Anal. For C29H25N5S
(475.61): Calcd. C, 73.23; H, 5.30; N, 14.73; S, 6.74;
Found: C, 73.42; H, 5.51; N, 14.63; S, 6.81.
1-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)ethylidene)-2-(4-
phenylthiazol-2-yl)hydrazine (2j)
Yield 71 %, mp. 215–216 °C; IR (KBr, cm-1): 3122 (NH),
2922, 2855 (CH2-tetrahydronaphthalene), 1613 (C=N); H
1
NMR (CDCl3): d 1.80–1.82 (4H, m, 2(CH2)-tetrahydro-
naphthalene protons), 2.44 (3H, s, CH3–C=N), 2.79–2.81
(4H, m, 2(CH2)-tetrahydronaphthalene protons), 6.76 (1H,
s, C5H-thiazole proton), 7.07–7.74 (8H, m, CH-tetrahy-
dronaphthalene protons and Ar–H), 8.48 (1H, s, NH, D2O
exchangeable); 13C NMR (CDCl3): d 14.16, 21.84, 28.14,
28.33, 100.43, 122.40, 124.46, 126.06, 127.94,128.16,
128.55, 132.45, 136.21, 138.80, 142.24, 153.07, 168.47;
MS, m/z (%): 347.0 [M?] (73), 348.0 [M??1] (18), 172.0
[C12H14N] (72), 91 [C7H7] (100), 77 [C7H5] (52); Anal. For
C21H21N3S (347.48): Calcd. C, 72.59; H, 6.09; N, 12.09; S,
9.23; Found: C, 72.74; H, 6.41; N, 12.13; S, 9.38.
2-((1-(3-Chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-
4-yl)methylene)-1-(5-(1,2,3,4-tetrahydronaphthalen-6-
yl)thiazol-2-yl)hydrazin (5)
Yield 59 %, mp. 133–134 °C; IR (KBr, cm-1): 3150 (NH),
2927, 2851 (CH2-tetrahydronaphthalene), 1593 (C=N); H
1
NMR (CDCl3): d 1.79–1.83 (4H, m, 2(CH2)-tetrahydro-
naphthalene protons), 2.77–2.81 (4H, m, 2(CH2)-tetrahy-
dronaphthalene protons), 3.36 (3H, s, OCH3), 6.65 (1H, s,
C5H-thiazole proton), 7.19–7.83 (11H, m, CH-tetrahydro-
naphthalene protons, and Ar–H), 8.01 (1H, s, –CH=N–),
8.41 (1H, s, CH-pyrazole proton), 9.80 (1H, s, NH, D2O
exchangeable); MS, m/z (%): 539.0, 540.0 [M?] (61, 20),
230.2 [C13H14N2S] (28), 64 [C5H4] (100); Anal. For
C30H26ClN5OS (540.08): Calcd. C, 66.72; H, 4.85; N,
12.97; S, 5.94; Found: C, 66.41; H, 5.02; N, 12.71; S, 5.77.
2-(4-(4-Bromophenyl)thiazol-2-yl)-1-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)hydrazine (2 k)
Yield 80 %, mp. 246–247 °C; IR (KBr, cm-1): 3121 (NH),
2917, 2850 (CH2-tetrahydronaphthalene), 1613 (C=N); H
1
NMR (CDCl3): d 1.80–1.82 (4H, m, 2(CH2)-tetrahydro-
naphthalene protons), 2.52 (3H, s, CH3–C=N), 2.79–2.80
(4H, m, 2(CH2)-tetrahydronaphthalene protons), 6.77 (1H,
s, C5H-thiazole proton), 7.09–7.60 (7H, m, CH-tetrahy-
dronaphthalene protons and Ar–H); MS, m/z (%): 425.0,
427.0 [M?] (38, 42), 426.0, 428.0 [M??1] (18, 13), 254.0,
256 [M?-C12H14N] (20, 25), 172 [C12H14N] (100); Anal.
For C21H20BrN3S (426.37): Calcd. C, 59.16; H, 4.73; N,
9.86; S, 7.52; Found: C, 59.32; H, 4.42; N, 9.74; S, 7.71.
1-(5-(1,2,3,4-Tetrahydronaphthalen-6-yl)thiazol-2-yl)-2-
((4H-chromen-4-one-3-yl)methylene)hydrazine (6)
Yield 62 %, mp. 187–188 °C; IR (KBr, cm-1): 3140 (NH),
2923, 2854 (CH2-tetrahydronaphthalene), 1665 (C=O),
1607 (C=N); 1H NMR (CDCl3): d 1.75–1.81 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 2.71–2.79 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 6.95 (1H, s, C5H-
thiazole proton), 7.01–7.80 (8H, m, CH-tetrahydronaph-
thalene protons, CH-chromone and Ar–H), 8.21 (1H, s,
–CH=N–), 10.39 (1H, s, NH, D2O exchangeable); MS,
m/z (%): 401.2 [M?] (14), 245.9 [C13H16N3S] (90), 230.2
[C13H14N2S] (90), 94 [C6H6O] (100); Anal. For
General procedure for the synthesis of 1-(5-(1,2,3,4-
tetrahydronaphthalen-6-yl)thiazol-2-yl)-
2((substituted)methylene) hydrazine 4–6
A mixture of 1-(5-(1,2,3,4-tetrahydronaphthalen-6-yl)thia-
zol-2-yl)hydrazine (3) (0.49 g, 0.002 mol) and different
aromatic aldehydes, namely, 1,3-diphenyl-1H-pyrazole-4-
123

Med Chem Res
(2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
C23H19N3O2S (401.48): Calcd. C, 68.81; H, 4.77; N, 10.47;
S, 7.99; Found: C, 68.93; H, 4.85; N, 10.62; S, 7.75.
yl)ethylidene)hydrazono))-4-methyl-3-phenyl-5-(2-
phenyldiazenyl)thiazole (7d)
Yield 77 %, mp. 204–205 °C; IR (KBr, cm-1): 2925, 2849
(CH2-tetrahydronaphthalene), 1597, 1562 (C=N); 1H NMR
(CDCl3): d 1.78–1.82 (4H, m, 2(CH2)-tetrahydronaphtha-
lene protons), 2.44 (3H, s, CH3–C=N), 2.56 (3H, s, C4–
CH3-thiazole protons), 2.77–2.81 (4H, m, 2(CH2)-tetrahy-
dronaphthalene protons), 7.24–7.82 (13H, m, CH-tetrahy-
dronaphthalene protons and Ar–H); MS, m/z (%): 465.0
[M?] (59), 466.0 [M??1] (19), 464.0 [M?-1] (25), 118.0
[C8H8N] (100); Anal. For C28H27N5S (465.61): Calcd. C,
72.23; H, 5.84; N, 15.04; S, 6.89; Found: C, 72.44; H, 5.91;
N, 15.13; S, 6.62.
General procedure for the synthesis of (2-(2-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)hydrazono))-
3-substituted-4-methyl-5-(2-phenyldiazenyl)thiazole
7b–d
A mixture of the thiosemicarbazone derivatives 1b–d
(0.002 mol), hydrazonyl chloride (0.40 g, 0.002 mol), and
anhydrous sodium acetate (0.17 g, 0.002 mol) in absolute
ethanol (20 mL) was heated under reflux for 3 h and then
left to cool. The formed precipitate was filtered, washed
several times with water, dried, and recrystallized from
ethanol to give the title compounds 7b–d.
General procedure for the synthesis of ethyl 2-(2-(1-
(1,2,3,4-tetrahydronaphthalen-6-yl)ethylidene)
hydrazono)-2,3-dihydro-3-substituted-4-
methylthiazole-5-carboxylate 8b–d
(2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono))-3,4-dimethyl-5-(2-
phenyldiazenyl)thiazole (7b)
Yield 81 %, mp. 163–164 °C; IR (KBr, cm-1): 2927, 2851
(CH2-tetrahydronaphthalene), 1593, 1561 (C=N); 1H NMR
(CDCl3): d 1.79–1.81 (4H, m, 2(CH2)-tetrahydronaphtha-
lene protons), 2.47 (3H, s, CH3–C=N), 2.71 (3H, s, C4–
CH3-thiazole protons), 2.79–2.83 (4H, m, 2(CH2)-tetrahy-
dronaphthalene protons), 3.72 (3H, s, N–CH3) 7.09–7.78
A mixture of the thiosemicarbazone derivatives 1b–d
(0.002 mol), ethyl-2-chloroacetoacetate (0.42 mL, 0.003
mol), and anhydrous sodium acetate (0.25 g, 0.003 mol) in
absolute ethanol (15 mL) was heated under reflux for
12 h. The formed precipitate on cooling was filtered,
washed several times with water, dried, and recrys-
tallized from ethanol to give the title compounds
8b–d.
(8H, m, CH-tetrahydronaphthalene protons and Ar–H); 13
C
NMR (CDCl3): d 12.30, 14.70, 23.39, 29.51, 29.75, 31.48,
122.11, 123.90, 127.33, 128.84, 129.03, 134.21, 135.99,
136.98, 138.84, 145.43, 152.98, 159.17, 164.50; MS,
m/z (%): 403.0 [M?] (38), 404.0 [M??1] (11), 402.0 [M?-1]
(15), 56.0 [C3H6N] (100); Anal. For C23H25N5S (403.54):
Calcd. C, 68.46; H, 6.24; N, 17.35; S, 7.95; Found: C, 68.62;
H, 6.41; N, 17.50; S, 8.11.
Ethyl 2-(2-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene) hydrazono)-2,3-dihydro-3,4-
dimethylthiazole-5-carboxylate (8b)
Yield 79 %, mp. 148–149 °C; IR (KBr, cm-1): 2925, 2856
(CH2-tetrahydronaphthalene), 1735 (C=O, ester), 1595,
(2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono))-3-ethyl-4-methyl-5-(2-
phenyldiazenyl)thiazole (7c)
1564 (C=N); 1H NMR (CDCl3):
d 1.37 (3H, t,
CO2CH2CH3, J = 7.00 Hz), 1.79–1.81 (4H, m, 2(CH2)-
tetrahydronaphthalene protons), 2.46 (3H, s, CH3–C=N),
2.58 (3H, s, C4–CH3-thiazole protons), 2.77–2.81 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 3.55 (3H, s, N–
CH3), 4.27 (2H, q, CO2CH2CH3, J = 7.00 Hz), 7.07(1H, d,
CH=, J = 8.00 Hz), 7.54 (1H, s, CH =), 7.63 (1H, d, CH=,
J = 8.00 Hz); 13C NMR (CDCl3): d 12.90, 14.60, 23.37,
29.47, 29.72, 31.56, 60.74, 103.30, 123.70, 127.16, 129.09,
136.21, 136.90, 138.46, 146.98, 157.93, 162.56, 166.30;
MS, m/z (%): 345.0 [M?-C2H2] (12), 344.0 [M?-C2H3]
(20), 299.0 [M?-C3H4O2] (14), 244.0 [M?-C7H11O2]
(100); Anal. For C20H25N3O2S (371.50): Calcd. C, 64.66;
H, 6.78; N, 11.31; S, 8.63; Found: C, 64.85; H, 6.81; N,
11.21; S, 8.34.
Yield 79 %, mp. 137–138 °C; IR (KBr, cm-1): 2928, 2854
(CH2-tetrahydronaphthalene), 1594, 1567 (C=N); 1H NMR
(CDCl3): d 1.24 (3H, t, N–CH2CH3, J = 6.90 Hz),
1.79–1.81 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
2.48 (3H, s, CH3–C=N), 2.67 (3H, s, C4–CH3-thiazole
protons), 2.80–2.83 (4H, m, 2(CH2)-tetrahydronaphthalene
protons), 3.70 (2H, q, N–CH2CH3, J = 6.90 Hz),
7.25–7.66 (8H, m, CH-tetrahydronaphthalene protons and
Ar–H); MS, m/z (%): 417.2 [M?] (32), 418.2[M??1] (23),
386.6 [M?-C2H3] (26), 68.9 [C4H7N] (100); Anal. For
C24H27N5S (417.57): Calcd. C, 69.03; H, 6.52; N, 16.77; S,
7.68; Found: C, 69.11; H, 6.71; N, 16.58; S, 7.53.
123

Med Chem Res
Ethyl 2-(2-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene) hydrazono)-2,3-dihydro-3-ethyl-4-
methylthiazole-5-carboxylate (8c)
tetrahydronaphthalene protons), 2.37 (3H, s, C4–CH3-thia-
zole protons), 2.45(3H, s, CH3–C=N), 2.60(3H, s, –COCH3),
2.78–2.82 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
3.53 (3H, s, N–CH3), 7.07 (1H, d, CH=, J = 8.00 Hz), 7.54
(1H, s, CH =), 7.63 (1H, d, CH=, J = 8.00 Hz); 13C NMR
(CDCl3): d 13.55, 14.74, 23.33, 29.45, 29.72, 30.26, 31.56,
113.00, 123.71, 127.19, 129.15, 136.06, 137.00, 138.67,
146.43, 158.65, 165.28, 189.80; MS, m/z (%): 341.3 [M?]
(38), 342.0 [M?1] (38), 54.6 [C3H5N] (100); Anal. For
C19H23N3OS (341.47): Calcd. C, 66.83; H, 6.79; N, 12.31; S,
9.39; Found: C, 66.59; H, 6.60; N, 12.41; S, 9.45.
Yield 85 %, mp. 136–137 °C; IR (KBr, cm-1): 2934, 2865
(CH2-tetrahydronaphthalene), 1732 (C=O, ester), 1592,
1561 (C=N); 1H NMR (CDCl3): d 1.33–1.36 (6H, m,
–CO2CH2CH3, N–CH2CH3), 1.80–1.84 (4H, m, 2(CH2)-
tetrahydronaphthalene protons), 2.41(3H, s, CH3–C=N),
2.62 (3H, s, C4–CH3-thiazole protons), 2.77–2.81 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 4.03 (2H, q, N–
CH2CH3, J = 6.90 Hz), 4.27 (2H, q, CO2CH2CH3,
J = 7.00 Hz), 7.06 (1H, d, CH=, J = 8.40 Hz), 7.54 (1H,
s, CH =), 7.63 (1H, d, CH=, J = 8.40 Hz); MS, m/z (%):
384.9 [M?] (100), 385.8 [M??1] (24); Anal. For
C21H27N3O2S (385.52): Calcd. C, 65.42; H, 7.06; N, 10.90;
S, 8.32; Found: C, 65.23; H, 7.21; N, 10.87; S, 8.41.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-5-acetyl-2,3-dihydro-3-ethyl-
4-methylthiazole (9c)
Yield 82 %, mp. 148–149 °C; IR (KBr, cm-1): 2920, 2854
(CH2-tetrahydronaphthalene), 1720 (C=O), 1590, 1542
(C=N); 1H NMR (CDCl3): d 1.35 (3H, t, N–CH2CH3,
J = 6.90 Hz), 1.80–1.85 (4H, m, 2(CH2)-tetrahydronaph-
thalene protons), 2.35 (3H, s, C4–CH3-thiazole protons),
2.42 (3H, s, CH3–C=N), 2.60 (3H, s, –COCH3), 2.77–2.81
(4H, m, 2(CH2)-tetrahydronaphthalene protons), 4.06 (2H,
q, N–CH2CH3, J = 6.90 Hz), 7.06 (1H, d, CH=,
J = 8.50 Hz), 7.54 (1H, s, CH =), 7.61 (1H, d, CH=,
J = 8.50 Hz); MS, m/z (%): 355.0 [M?] (100), 356.0
[M??1] (24), 353.9 [M?-1] (14); Anal. For C20H25N3OS
(355.50): Calcd. C, 67.57; H, 7.09; N, 11.82; S, 9.02;
Found: C, 67.38; H, 7.22; N, 11.67; S 9.31.
Ethyl 2-(2-(1-(1,2,3,4-tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-2,3-dihydro-4-methyl-3-
phenylthiazole-5-carboxylate (8d)
Yield 70 %, mp. 122–123 °C; IR (KBr, cm-1): 2927, 2857
(CH2-tetrahydronaphthalene), 1730 (C=O, ester), 1600,
1554 (C=N); 1H NMR (CDCl3):
d 1.35 (3H, t,
CO2CH2CH3, J = 7.00 Hz), 1.78–1.80 (4H, m, 2(CH2)-
tetrahydronaphthalene protons), 2.15 (3H, s, CH3–C=N),
2.28 (3H, s, C4–CH3-thiazole protons), 2.79–2.79 (4H, m,
2(CH2) tetrahydronaphthalene protons), 4.29 (2H, q,
CO2CH2CH3, J = 7.00 Hz), 7.07–7.59 (8H, m, CH-tetra-
hydronaphthalene protons and Ar–H); MS, m/z (%): 433.0
[M?] (100), 434.0 [M??1] (31), 363.0 [M?-C3H2O2] (96);
Anal. For C25H27N3O2S (433.57): Calcd. C, 69.26; H, 6.28;
N, 9.69; S, 7.40; Found: C, 69.38; H, 6.44; N, 9.81; S, 7.61.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-5-acetyl-2,3-dihydro-
4-methyl-3-phenylthiazole (9d)
Yield 76 %, mp. 65–66. IR (KBr, cm-1): 2926, 2850 (CH2-
tetrahydronaphthalene), 1718 (C=O), 1594, 1546 (C=N);
1H NMR (CDCl3): d 1.78–1.81 (4H, m, 2(CH2)-tetrahy-
dronaphthalene protons), 2.18 (3H, s, C4–CH3-thiazole
protons), 2.35 (3H, s, CH3–C=N), 2.43 (3H, s, –COCH3),
2.75–2.79 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
7.01–7.68 (8H, CH-tetrahydronaphthalene protons and Ar–
H); MS, m/z (%): 403.0 [M?] (67), 404.0 [M??1] (20),
402.0 [M?-1] (35), 360.0 [M?-COCH3] (40), 361.0 [M?-
COCH2] (93), 77.0 [C6H5] (100); Anal. For C24H25N3OS
(403.54): Calcd. C, 71.43; H, 6.24; N, 10.41; S, 7.95;
Found: C, 71.25; H, 6.51; N, 10.22; S 8.04.
General procedure for the synthesis of 2-(2-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)hydrazono)-5-
acetyl-2,3-dihydro-3-substituted-4-methylthiazole 9b–d
A mixture of the thiosemicarbazone derivatives 1b–d
(0.002 mol), 3-chloro-2,4-pentanedione (0.36 mL, 0.003
mol), and anhydrous sodium acetate (0.25 g, 0.003 mol) in
absolute ethanol (20 mL) was heated under reflux for 10 h.
The formed precipitate on cooling was filtered, washed
several times with water, dried, and recrystallized from
ethanol to give the title compounds 9b–d.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)ethylidene)
General procedure for the synthesis of 2-(2-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)hydrazono)-3-
substituted-5-methylthiazolidin-4-one 10b–d
hydrazono)-5-acetyl-2,3-dihydro-3,4-dimethylthiazole (9b)
Yield 75 %, mp. 139–140 °C; IR (KBr, cm-1): 2932, 2874
(CH2-tetrahydronaphthalene), 1721 (C=O), 1595, 1548
A mixture of the thiosemicarbazone derivatives 1b–d
(0.002 mol), ethyl 2-bromopropanoate (0.27 mL, 0.002 mol),
1
(C=N); H NMR (CDCl3): d 1.79–1.81 (4H, m, 2(CH2)-
123

Med Chem Res
and anhydrous sodium acetate (0.17 g, 0.002 mol) in absolute
ethanol (15 mL) was heated under reflux for 6 h. The formed
precipitate on cooling was filtered, washed several times with
water, dried, and recrystallized from ethanol to give the title
compounds 10b–d.
thiazolidinone protons, J = 7.00 Hz), 1.80–1.83 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 2.20 (3H, s, CH3–
C=N), 2.79–2.81 (4H, m, 2(CH2)-tetrahydronaphthalene
protons), 4.15 (1H, q, C5H-thiazolidinone proton, J =
7.00 Hz), 7.07–7.70 (8H, m, CH-tetrahydronaphthalene
protons and Ar–H); MS, m/z (%): 377.0 [M?] (100), 377.9
[M??1] (36), 376.1 [M?-1] (28), 130.0 [C10H10] (75);
Anal. For C22H23N3OS (377.50): Calcd. C, 70.00; H, 6.14;
N, 11.13; S, 8.49; Found: C, 70.23; H, 6.28; N, 11.22; S,
8.56.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-3,5-dimethylthiazolidin-
4-one (10b)
Yield 66 %, mp. 69–70 °C; IR (KBr, cm-1): 2926, 2858
(CH2 tetrahydronaphthalene), 1715 (C=O), 1605, 1559
General procedure for the synthesis of 2-(2-(2-(1-
(1,2,3,4-tetrahydronaphthalen-6-yl) ethylidene)
hydrazono)-4-oxo-3-substituted thiazolidin-5-yl)acetic
acid 11b–d
1
(C=N); H NMR (CDCl3): d 1.63 (3H, d, C5–CH3-thiazo-
lidinone protons, J = 7.00 Hz), 1.80–1.82 (4H, m, 2(CH2)-
tetrahydronaphthalene protons), 2.43 (3H, s, CH3–C=N),
2.78–2.80 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
3.33 (3H, s, N-CH3), 3.98 (1H, q, C5H-thiazolidinone
proton, J = 7.00 Hz), 7.07 (1H, d, CH=, J = 8.00 Hz),
7.55 (1H, s, CH =), 7.59 (1H, d, CH=, J = 8.00 Hz);
13CNMR (CDCl3): d 14.97, 19.51, 23.28, 29.48, 29.67,
29.98, 41.89, 123.95, 127.54, 129.20, 135.43, 137.09,
139.55, 160.90, 163.07, 175.69; MS, m/z (%): 315.0 [M?]
(100), 316.0 [M??1] (22), 314.0 [M?-1] (23), 300.0 [M?-
CH3] (71); Anal. For C17H21N3OS (315.43): Calcd. C,
64.73; H, 6.71; N, 13.32; S, 10.17; Found: C, 64.38; H,
6.44; N, 13.50; S, 10.31.
A mixture of the thiosemicarbazone derivatives 1b–
d (0.002 mol) and maleic anhydride (0.40 g, 0.004 mol) in
dry toluene (15 mL) was heated under reflux for 8 h. The
solvent was evaporated under reduced pressure and the
crude product was treated with pet.ether. The formed pre-
cipitate was filtered, dried, and recrystallized from acetic
acid to give the title compounds 11b–d.
2-(2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-4-oxo-3-methylthiazolidin-5-
yl)acetic acid (11b)
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-3-ethyl-5-methylthiazolidin-
4-one (10c)
Yield 85 %, mp. 119–120 °C; IR (KBr, cm-1): Broad band
centered at 3421 (CO2H), 2921, 2855 (CH2-tetrahydro-
1
naphthalene), 1712 (C=O), 1607, 1582 (C=N); H NMR
Yield 77 %, mp. 75–76 °C; IR (KBr, cm-1): 2927, 2850
(CH2-tetrahydronaphthalene), 1717 (C=O), 1605, 1565
(C=N); 1H NMR (CDCl3): d 1.31 (3H, t, –NCH2CH3,
J = 6.90 Hz) 1.64 (3H, d, C5–CH3-thiazolidinone protons,
J = 7.00 Hz), 1.79–1.81 (4H, m, 2(CH2)-tetrahydronaph-
thalene protons), 2.42 (3H, s, CH3–C=N), 2.78–2.80 (4H,
m, 2(CH2)-tetrahydronaphthalene protons), 3.90 (2H, q,
–NCH2CH3, J = 6.90 Hz), 3.98 (1H, q, C5H-thiazolidinone
proton, J = 7.00 Hz), 7.09 (1H, d, CH=, J = 9.10 Hz), 7.56
(1H, s, CH =), 7.61 (1H, d, CH=, J = 9.10 Hz); MS,
m/z (%): 329.0 [M?] (84), 330 [M??1] (30), 328.0 [M?-1]
(51), 158.0 [C12H14] (100); Anal. For C18H23N3OS (329.46):
Calcd. C, 65.62; H, 7.04; N, 12.75; S, 9.73; Found: C, 65.72;
H, 6.95; N, 12.46; S, 9.82.
(DMSO-d6): d 1.70–1.71 (4H, m, 2(CH2)-tetrahydronaph-
thalene protons), 2.36 (3H, s, CH3–C=N), 2.69–2.72 (4H,
m, 2(CH2)-tetrahydronaphthalene protons), 2.85–2.89 (1H,
m, CH2a), 2.99–3.04 (1H, m, CH2b), 3.16 (3H, s, N–CH3),
4.32–4.34 (1H, m, C5H-thiazolidinone proton), 7.07 (1H, d,
CH=, J = 8.40 Hz), 7.48 (1H, s, CH =), 7.54 (1H, d, CH=,
J = 8.40 Hz), 12.92 (1H, br s, CO2H, D2O exchangeable);
MS, m/z (%): 359.0 [M?] (100), 360.0 [M??1] (23), 358.0
[M?-1] (19), 344 [M?-CH3] (56); Anal. For C18H21N3O3S
(359.44): Calcd. C, 60.15; H, 5.89; N, 11.69; S, 8.92;
Found: C, 60.32; H, 5.71; N, 11.48; S, 8.75.
2-(2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-4-oxo-3-ethylthiazolidin-5-
yl)acetic acid (11c)
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-5-methyl-3-phenylthiazolidin-4-
one (10d)
Yield 78 %, mp. 151-152 °C; IR (KBr, cm-1): Broad band
centered at 3408 (CO2H), 2932, 2858 (CH2-tetrahydro-
1
naphthalene), 1707 (C=O), 1602, 1580 (C=N); H NMR
Yield 62 %, mp. 128–129 °C; IR (KBr, cm-1): 2927, 2850
(CH2-tetrahydronaphthalene), 1720 (C=O), 1611, 1568
(C=N); 1H NMR (CDCl3): d 1.75 (3H, d, C5–CH3-
(DMSO-d6): d 1.17 (3H, t, N–CH2CH3, J = 6.90 Hz),
1.70–1.74 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
2.33 (3H, s, CH3–C=N), 2.70–2.72 (4H, m, 2(CH2)-
123

Med Chem Res
tetrahydronaphthalene protons), 2.88–2.91 (1H, m, CH2a),
2.98–3.01 (1H, m, CH2b), 3.74 (2H, q, N–CH2CH3,
J = 6.90 Hz), 4.32–4.34 (1H, m, C5H-thiazolidinone pro-
ton), 7.06 (1H, d, CH=, J = 8.40 Hz), 7.48 (1H, s, CH =),
7.54 (1H, d, CH=, J = 8.40 Hz), 12.67 (1H, br s, CO2H,
D2O exchangeable); MS, m/z (%): 373.0 [M?] (65), 374.0
[M?1] (15), 358.0 [M?-CH3] (54), 327.0 [M?-HCO2H]
(22); 158.0 [C11H12N] (100); Anal. For C19H23N3O3S
(373.47): Calcd. C, 61.10; H, 6.21; N, 11.25; S, 8.59;
Found: C, 61.34; H, 6.38; N, 11.34; S, 8.64.
29.24, 29.47, 33.60, 124.01, 127.55, 129.43, 135.60, 136.9,
139.22, 160.85, 163.97, 174.41; MS, m/z (%): 287.0 [M?]
(99), 288.0[M??1] (22), 286 [M?-1] (55), 158.0 [C12H14]
(100); Anal. For C15H17N3OS (287.38): Calcd. C, 62.69; H,
5.96; N, 14.62; S, 11.16; Found: C, 62.73; H, 5.81; N,
14.47; S, 11.22.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-3-methylthiazolidin-4-one (12b)
Yield 81 %, mp. 161–162 °C; IR (KBr, cm-1): 2928, 2854
(CH2-tetrahydronaphthalene), 1722 (C=O), 1602, 1576
2-(2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-4-oxo-3-phenylthiazolidin-5-
yl)acetic acid (11d)
1
(C=N); H NMR (CDCl3): d 1.79–1.81 (4H, m, 2(CH2)-
tetrahydronaphthalene protons), 2.42 (3H, s, CH3–C=N),
2.78–2.80 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
3.31 (3H, s, N–CH3), 3.76 (2H, s, CH2-thiazolidinone
protons) 7.07 (1H, d, CH=, J = 8.07 Hz), 7.56 (1H, s,
CH =), 7.62 (1H, d, CH=, J = 8.07 Hz); 13C NMR
(CDCl3): d 13.98, 22.15, 28.43, 28.59, 28.86, 31.55,
122.96, 126.56, 128.17, 134.18, 136.09, 138.69, 161.01,
162.35, 171.21; MS, m/z (%): 301.0 [M?] (81),
301.9[M??1] (16), 285.9 [M?-CH3] (66), 129.1 [C10H9]
(100); Anal. For C16H19N3OS (301.41): Calcd. C, 63.76; H,
6.35; N, 13.94; S, 10.64; Found: C, 63.58; H, 6.46; N,
14.08; S, 10.71.
Yield 87 %, mp. 206–207 °C; IR (KBr, cm-1): Broad band
centered at 3427 (CO2H), 2924, 2851 (CH2-tetrahydro-
1
naphthalene), 1712 (C=O), 1613, 1587 (C=N); H NMR
(DMSO-d6): d 1.70–1.74 (4H, m, 2(CH2)-tetrahydronaph-
thalene protons), 2.13 (3H, s, CH3–C=N), 2.67–2.70 (4H,
m, 2(CH2)-tetrahydronaphthalene protons), 2.74–2.78 (1H,
m, CH2a), 3.06–3.11 (1H, m, CH2b), 4.48–4.50 (1H, m,
C5H-thiazolidinone proton), 7.05–7.60 (8H, m, CH-tetra-
hydronaphthalene protons and Ar–H), 12.79 (1H, br s,
CO2H, D2O exchangeable); MS, m/z (%): 374.9
[M?-HCO2H] (36); 158.0 [C11H12N] (26); 59.7 [C4H12] (100);
Anal. For C23H23N3O3S (421.51): Calcd. C, 65.54; H, 5.50; N,
9.97; S, 7.61; Found: C, 65.67; H, 5.41; N, 9.82; S, 7.33.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-3-ethylthiazolidin-4-one (12c)
General procedure for the synthesis of 2-(2-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)hydrazono)-3-
substituted thiazolidin-4-one 12a–e
Yield 84 %, mp. 132–133 °C; IR (KBr, cm-1): 2935, 2848
(CH2-tetrahydronaphthalene), 1718 (C=O), 1598, 1572
(C=N); 1H NMR (CDCl3): d 1.30 (3H, t, –NCH2CH3,
J = 6.96 Hz), 1.79–1.82 (4H, m, 2(CH2)-tetrahydronaph-
thalene protons), 2.43 (3H, s, CH3–C=N), 2.78–2.80 (4H,
m, 2(CH2)-tetrahydronaphthalene protons), 3.74 (2H, s,
CH2-thiazolidinone protons), 3.90 (2H, q, –NCH2CH3,
J = 6.96 Hz), 7.07 (1H, d, CH=, J = 8.07 Hz), 7.55 (1H,
s, CH =), 7.59 (1H, d, CH=, J = 8.07 Hz); 13C NMR
(CDCl3): d 11.57, 14.06, 22.24, 28.50, 28.68, 31.71, 37.78,
122.98, 126.57, 128.24, 134.44, 136.14, 138.59,160.13,
162.10, 171.04; MS, m/z (%): 314.9 [M?] (100), 316.0
[M??1] (22), 157.8 [C12H14] (86); Anal. For C17H21N3OS
(315.43): Calcd. C, 64.73; H, 6.71; N, 13.32; S, 10.17;
Found: C, 64.81; H, 6.53; N, 13.23; S, 10.31.
A mixture of the thiosemicarbazone derivatives 1a–e
(0.002 mol) and ethyl bromoacetate (0.23 mL, 0.002 mol)
in absolute ethanol (10 mL) containing few drops of
piperidine was heated under reflux for 3 h. The formed
precipitate on cooling was filtered, washed several times
with cyclohexane, dried, and recrystallized from ethanol to
give the title compounds 12a–e.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)thiazolidin-4-one (12a)
Yield 69 %, mp. 208-209 °C; IR (KBr, cm-1): 3110 (NH),
2926, 2850 (CH2-tetrahydronaphthalene), 1708 (C=O),
1618, 1561 (C=N); 1H NMR (DMSO-d6): d 1.69–1.71 (4H,
m, 2(CH2)-tetrahydronaphthalene protons), 2.31 (3H, s,
CH3–C=N), 2.69–2.71 (4H, m, 2(CH2)-tetrahydronaphtha-
lene protons), 3.82 (2H, s, CH2-thiazolidinone protons)
7.06 (1H, d, CH=, J = 8.40 Hz), 7.46 (1H, s, CH =), 7.53
(1H, d, CH=, J = 8.40 Hz), 11.76 (1H, s, NH, D2O
exchangeable); 13C NMR (DMSO-d6): d 15.10, 23.23,
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-yl)
ethylidene)hydrazono)-3-phenylthiazolidin-4-one (12d)
Yield 85 %, mp. 171–172 °C; IR (KBr, cm-1): 2930, 2853
(CH2-tetrahydronaphthalene), 1724 (C=O), 1601, 1573
1
(C=N); H NMR (CDCl3): d 1.79–1.81 (4H, m, 2(CH2)-
tetrahydronaphthalene protons), 2.22 (3H, s, CH3–C=N),
2.78–2.79 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
123

Med Chem Res
3.94 (2H, s, CH2-thiazolidinone protons), 7.06–7.60 (8H,
m, CH-tetrahydronaphthalene protons and Ar–H); 13C
NMR (CDCl3): d 14.30, 22.23, 28.61, 31.76, 123.08,
126.76, 127.90, 128.27, 134.04, 136.19, 138.89, 160.82,
162.97, 170.82; MS, m/z (%): 362.9 [M?] (49), 363.9
[M??1] (12), 77.0 [C6H5] (100); Anal. For C21H21N3OS
(363.48): Calcd. C, 69.39; H, 5.82; N, 11.56; S, 8.82;
Found: C, 69.45; H, 5.93; N, 11.44; S, 8.74.
protons), 3.46 (3H, s, N–CH3), 3.86 (3H, s, OCH3), 6.97–7.68
(8H, m, CH-tetrahydronaphthalene protons, Ar–H and CH-
olifinic); MS, m/z (%): 418.8 [M?] (100), 419.8 [M??1] (28),
404.0 [M?-CH3] (41); Anal. For C24H25N3O2S (419.54):
Calcd. C, 68.71; H, 6.01;N, 10.02; S, 7.64; Found:C, 68.66; H,
6.21; N, 10.18; S, 7.78.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-5-(4-methoxybenzylidene)-3-
ethylthiazolidin-4-one (13c)
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-3-cyclohexylthiazolidin-4-one
(12e)
Yield 82 %, mp. 144–145 °C; IR (KBr, cm-1): 2929, 2844
(CH2-tetrahydronaphthalene), 1692 (a,b unsaturateded
ketone), 1599, 1557 (C=N); 1H NMR (CDCl3): d 1.36 (3H, t,
–NCH2CH3, J = 6.90 Hz), 1.80–1.82 (4H, m, 2(CH2)-tetra-
hydronaphthalene protons), 2.48 (3H, s, CH3–C=N),
2.80–2.84 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
3.85 (3H, s, OCH3), 4.08 (2H, q, –NCH2CH3, J = 6.90 Hz),
6.97–7.70 (8H, m, CH-tetrahydronaphthalene protons, Ar–H
and CH-olifinic); MS, m/z (%): 432.7 [M?] (98), 433.8
[M??1] (33), 418.0 [M?-CH3] (43), 164.1 [C10H12O2] (100);
Anal. For C25H27N3O2S (433.57):Calcd. C, 69.26;H, 6.28; N,
9.69; S, 7.40; Found: C, 69.31; H, 6.38; N, 9.57; S, 7.23.
Yield 88 %, mp. 171–172 °C; IR (KBr, cm-1): 2928, 2852
(CH2-tetrahydronaphthalene), 1714 (C=O), 1599, 1565
(C=N); 1H NMR (CDCl3): d 1.20–1.26, 1.33–1.40,
1.67–1.70 (10H, m, cyclohexyl protons), 1.81–1.85 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 2.45 (3H, s, CH3–
C=N), 2.78–2.80 (4H, m, 2(CH2)-tetrahydronaphthalene
protons), 3.71 (2H, s, CH2-thiazolidinone protons),
4.40–4.45 (1H, m, N-CH cyclohexyl proton), 7.09 (1H, d,
CH=, J = 8.50 Hz), 7.55(1H, s, CH =), 7.61(1H, d, CH=,
J = 8.50 Hz); 13C NMR (CDCl3): d 15.41, 23.27, 25.44,
26.58, 28.86, 29.49, 29.65, 32.61, 56.58, 123.98, 129.23,
131.07, 135.39, 137.12, 139.55, 161.76, 162.74, 172.34;
MS, m/z (%): 369.0 [M?] (23), 370.0 [M??1] (8), 354.0
[M?-CH3] (58), 288.0 [M?-C6H9] (78), 172.0 [C12H14N]
(100); Anal. For C21H27N3OS (369.52): Calcd. C, 68.26; H,
7.36; N, 11.37; S, 8.68; Found: C, 68.34; H, 7.25; N, 11.42;
S, 8.50.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-5-(4-methoxybenzylidene)-3-
phenylthiazolidin-4-one (13d)
Yield 79 %, mp. 177–178 °C; IR (KBr, cm-1): 2928, 2856
(CH2-tetrahydronaphthalene), 1694 (a,b unsaturateded
ketone), 1610, 1565 (C=N); 1H NMR (CDCl3): d 1.79–1.82
(4H, m, 2(CH2)-tetrahydronaphthalene protons), 2.43 (3H,
s, CH3–C=N), 2.81–2.83 (4H, m, 2(CH2)-tetrahydronaph-
thalene protons), 3.82 (3H, s, –OCH3), 6.95– 7.72 (13H, m,
CH-tetrahydronaphthalene protons, Ar–H and CH-olifinic);
MS, m/z (%): 481.0 [M?] (21), 481.9 [M??1] (19), 466.0
[M?-CH3] (41), 77 [C6H5] (100); Anal. For C29H27N3O2S
(481.61): Calcd. C, 72.32; H, 5.65; N, 8.72; S, 6.66; Found:
C, 72.54; H, 5.47; N, 8.52; S, 6.42.
General procedure for the synthesis of 2-(2-(1-(1,2,3,4-
tetrahydronaphthalen-6-yl)ethylidene)hydrazono)-5-(4-
methoxybenzylidene)-3-substituted thiazolidin-4-one
(13b–d)
A
mixture of the thiazolidinone derivatives 12b–
d (0.002 mol) and 4-methoxybenzaldehyde (0.25 mL,
0.002 mol) in 10 % alcoholic sodium hydroxide (15 mL)
was stirred at room temperature overnight. The reaction
mixture was filtered, washed several times with water,
dried, and recrystallized from absolute ethanol to give the
title compounds 13b–d.
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-3-acetylthiazolidin-4-one (14)
A mixture of thiazolidinone derivative 12a (0.57 g,
0.002 mol) and acetic anhydride (10 mL) was refluxed for
1 h and then poured onto ice/cold water. The formed pre-
cipitate was filtered, washed several times with water,
dried, and recrystallized from ethanol to give the title
compounds 14.
Yield 64 %, mp. 159–160 °C; IR (KBr, cm-1): 2927,
2862 (CH2-tetrahydronaphthalene), 1723 (C=O), 1647
(–NCOCH3), 1611, 1569 (C=N); 1H NMR (CDCl3): d
1.72–1.75 (4H, m, 2(CH2)-tetrahydronaphthalene protons),
2-(2-(1-(1,2,3,4-Tetrahydronaphthalen-6-
yl)ethylidene)hydrazono)-5-(4-methoxybenzylidene)-3-
methylthiazolidin-4-one (13b)
Yield 87 %, mp. 189–190 °C; IR (KBr, cm-1): 2924, 2859
(CH2-tetrahydronaphthalene), 1698 (a,b unsaturated ketone),
1
1613, 1561 (C=N); H NMR (CDCl3): d 1.80–1.83 (4H, m,
2(CH2)-tetrahydronaphthalene protons), 2.48 (3H, s, CH3–
C=N), 2.80–2.84 (4H, m, 2(CH2)-tetrahydronaphthalene
123

Med Chem Res
2.21 (3H, s, CH3–C=N), 2.72–2.80 (4H, m, 2(CH2)-tetra-
hydronaphthalene protons), 2.41 (3H, s, –NCOCH3), 3.48
(2H, s, CH2-thiazolidinone protons) 7.04 (1H, d, CH=,
J = 8.40 Hz), 7.15 (1H, s, CH =), 7.25 (1H, d, CH=,
J = 8.40 Hz); MS, m/z (%): 329.0 [M?] (17), 330.0
[M??1] (14), 286.2 [M?-COCH3] (20), 59.7 [C2H6NO]
(100); Anal. For C17H19N3O2S (329.42): Calcd. C, 61.98;
H, 5.81; N, 12.76; S, 9.73; Found: C, 61.83; H, 5.94; N,
12.59; S, 9.90.
The percent edema inhibition was calculated from the
mean effect in the control and treated animals according to
the following equation:
% edema inhibition ¼ ðvtꢁ vcÞ = vc ꢂ 100:
Where vt represents the mean increase in paw volume in
rats treated with tested compounds and vc represents the
mean increase in paw volume in the control group of rats
(Armitage, 1971).
Analgesic assay
Biological screening
The apparatus consists of a hot plate on which the rat was
placed for testing (7280 Ugo Basile Biological Research
Apparatus Company, Comerio, Italy). It consists of a
20 cm diameter metal hot plate surface set at 50 °C, a
plexiglass cage that fits the hot metal surface and a timer
operated by a foot-switch (Laviola and Alleva, 1990).
For three consecutive days preceding the experiment, rats
were adapted on the hot plate by placing them on a plate
maintained at room temperature for 15 min each day. All
groups were given vehicle and/or the different compounds
and the last group received indomethacin (10 mg/Kg) 60 min
prior to testing. Each animal was then placed gently onto a
50 °C hot plate to perform the test. Latency to exhibit noci-
ceptive responses, such as licking paws or jumping off the hot
plate was determined 30, 60, and 90 min after administration
of test substances or the saline (Tzschentke et al., 2007).
Anti-inflammatory assay
Male Wistar rats weighing (120–150 g) were used
throughout the assay. Animals were housed under stan-
dardized conditions for light and temperature and received
standard rat chow and tap water ad libitum. Animals were
randomly assigned to different experimental groups, each
of six rats and kept in separate cages. One group of six rats
was kept as a control and another group received the
standard drug indomethacin. All animal procedures were
performed after approval from the Ethics Committee of the
National Research Centre and in accordance with the rec-
ommendations for the proper care and use of laboratory
animals (NIH publication No. 85-23, revised 1985).
Carrageenan lambda from Sigma Aldrich Chemical Co.
(USA), indomethacin from Khahira Pharmaceutical, and
Chemical Co. (Cairo, Egypt).
Ulcerogenic assay
Paw edema was induced by subplantar injection of
100 lL of 1 % sterile carrageenan in saline into the right
hind paw (1 % suspension of carrageenan in sterile saline
was prepared, the suspension was placed in a refrigerator
(4 °C) overnight to allow complete hydration of the car-
rageenan (Winter et al., 1962).
Groups of male Wistar rats with a weight between 120 and
150 g were used. They were starved 18 h prior to drug
administration. The test compounds were administered
orally in 100 mg/kg as aqueous suspension. The animals
were sacrificed after 5 h. Stomachs were removed and
examined. A longitudinal incision along the greater cur-
vature was made with fine scissor. The presence of a single
or multiple lesions (erosion, ulcer or perforation) was
evaluated (Manivannan and Chaturvedi, 2011). The num-
ber of ulcers and the occurrence of hyperemia were noted.
Twenty six groups of rats, each of six animals, were
used. One group received saline and served as control.
Indomethacin (0.03 mmol/kg) was administered to a group
of rats that served as a positive control. Tested groups
received the compounds in a dose of (0.3 mmol/kg). All
the tested compounds and indomethacin were orally
administered 1 h before induction of inflammation.
The hind paw volume was measured immediately before
carrageenan injection and at selected times (1, 2, 3, and
4 h) thereafter by water displacement method using 7410,
Ugo Basile, plythesmometer, Comerio, Italy (Chattopad-
hyay et al., 2002). The apparatus depends on measurement
of the volume of an electrolyte solution displaced by the
animal paw. The increased water level in the cell com-
partment increases the immersed portion of two parallel
platinum electrodes, thus increasing conductivity between
the two electrodes. The increased conductivity is converted
to volume by a transducer (7153 Conductance Transducer).
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