Synthesis and pharmacological evaluation of a novel series of 3-aryl-2-(2-substituted-4-methylthiazole-5-yl)thiazolidin-4-one as possible anti-inflammatory and antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2012.08.073

A new series of 3-aryl-2-(2-aryl/benzyl-4-methylthiazole-5-yl)thiazolidin- 4-one was synthesized by condensation of 2-aryl/benzyl-4-methylthiazole-5- carbaldehyde, aromatic amines and thioglycolic acid in toluene. All the synthesized compounds are characterized by IR, NMR and elemental or mass analysis. Sixteen out of the newly synthesized compounds were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema method. Some of the synthesized compounds exhibited good anti-inflammatory activity compared with indomethacin. The synthesized compounds were also evaluated for their in vitro antimicrobial activity. Some of the compounds showed mild antibacterial activity while most of the compounds showed good antifungal activity.

Full text of DOI:10.1016/j.bmcl.2012.08.073

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6373–6376
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and pharmacological evaluation of a novel series of
3-aryl-2-(2-substituted-4-methylthiazole-5-yl)thiazolidin-4-one as possible
anti-inflammatory and antimicrobial agents
Shivaji H. Shelke a, Pravin C. Mhaske b, Mukesh Nandave c, Sachin Narkhade c, Namdeo M. Walhekar b,
Vivek D. Bobade a,
⇑
a Department of Chemistry, H.P.T. Arts and R.Y.K. Science College, College Road, Vidyanagari, Nashik 422005, India
b Department of Chemistry, Sir Parshurambhau College, Tilak Road, Pune 411030, India
c SPP School of Pharmacy & Technology Management, SVKM’s NMIMS, Vile Parle (w), Mumbai 400056, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of 3-aryl-2-(2-aryl/benzyl-4-methylthiazole-5-yl)thiazolidin-4-one was synthesized by con-
densation of 2-aryl/benzyl-4-methylthiazole-5-carbaldehyde, aromatic amines and thioglycolic acid in
toluene. All the synthesized compounds are characterized by IR, NMR and elemental or mass analysis.
Sixteen out of the newly synthesized compounds were screened for in vivo anti-inflammatory activity
using carrageenan-induced rat paw edema method. Some of the synthesized compounds exhibited good
anti-inflammatory activity compared with indomethacin. The synthesized compounds were also evalu-
ated for their in vitro antimicrobial activity. Some of the compounds showed mild antibacterial activity
while most of the compounds showed good antifungal activity.
Received 12 June 2012
Revised 7 August 2012
Accepted 20 August 2012
Available online 25 August 2012
Keywords:
Thiazoles
Thiazolidinone
Cyclocondensation reactions
Antimicrobial activityl
Anti-inflammatory activity
Ó 2012 Elsevier Ltd. All rights reserved.
The development of new synthetic methods leading to struc-
tures, which incorporates various biologically active moieties in a
single molecule, has attracted much attention in organic chemistry.
In particular, heterocyclic compounds hold a special place among
pharmaceutically active products, and the development of simple
and efficient synthesis of compounds incorporating multi heterocy-
clic rings has given a new dimension to the drug discovery.
Thiazole compounds have attracted continuing interest over the
years because of their varied biological activities.1–11 Thiazolidi-
nones in particular have been investigated in great detail because
of its biological importance.12 Thiazolidinone nucleus containing
compounds shows anti-inflammatory,13–20 anticonvulsant,21–24
hypnotic,25–27 antitubercular,25–27 antibacterial, antifungal and
anticancer28–35 activities.
Concurring with previous reports, thiazolyl/formazanyl ind-
ols,36 admantane derivatives of thiazolyl-N-substituted amide,37
2-amino-5-thiazolyl motif,38 2-(2,4-disubstituted thiazol-5-yl)-
3-aryl-3Hquinazoline-4-one39 and thiazolyl derivatives of 1-H pyr-
azole40 have shown anti-inflammatory and antimicrobial activities.
Literature also revealed that thiazolidinone nucleus at 2-position of
thiazole showed good antifungal41 and antiviral42 activities.
3-hydroxy-2-(substituted thiazolyl)-4-thiazolidinones in which
the thiazolidinone nucleus is at 5-position of thiazole ring showed
antimicrobial activity.43 Similarly, thiazolyl-thiazolidine-2,4-dione
derivatives44 and 2-thiazolylimino-5-arylidene-4-thiazolidinon-
es45 showed antimicrobial activity. In view of these observations,
it was thought to synthesize some new thiazole based 1,3-thiazo-
lidinone-4-one by the condensation of 2-aryl/substitutedbenzyl-4-
methylthiazole-5-carbaldehyde with aromatic amine and thiogly-
colic acid.
The synthetic strategies adopted for the synthesis of title
compounds 6a–r are depicted in Schemes 1 and 2. The key starting
material 2-aryl/benzyl-4-methylthiazole-5-carbaldehyde 3a–c
was prepared by oxidation of corresponding alcohols 2a–c using
IBX.46–48 The alcohols in turn were obtained by reduction of esters
1a–c by LiAlH4. These esters 1a–c were synthesized by reaction of
aryl/benzyl thioamide with ethyl 2-chloro-3-oxobutanoate in dry
ethanol in good yield.49
Thiazolidinone derivatives 6a–r were obtained by one pot reac-
tion of aldehydes 3a–c with different substituted aromatic amines
4a–f in toluene, with azeotropic separation of water, followed by
cyclo-condensation with thioglycolic acid.
The anti-inflammatory screening of the selected synthesized
compounds was carried out using carrageenan-induced paw ede-
ma method of inflammation in rats.50 The results of anti-inflamma-
tory analysis is reported in Table 1. From the anti-inflammatory
⇑
Corresponding author. Tel.: +91 253 2572153; fax: +91 253 2573097.
E-mail address: v_bobade31@rediffmail.com (V.D. Bobade).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.073

6374
S. H. Shelke et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6373–6376
O
O
H3C
OH
OEt
H
H3C
H3C
IBX, DMSO
LiAlH4, Et2O
N
S
S
S
N
N
0 oC, 3 h
82-90%
0 oC, 0.5 h
86-95%
Ar
2a-c
Ar
1a-c
Ar
3a-c
Scheme 1.
O
O
R1
H
H
+
NH2
H3C
N
N
R1
H3C
S
CH3COOH
Toluene, reflux
HSCH2COOH
H3C
R1
S
N
H
S
N
Toluene, reflux
S
N
64-76%
Ar
Ar
Ar
3a-c
4a-f
5a-r
6a-r
Compd. Ar
R1
Compd. Ar
R1
Compd. Ar
R1
6a
6b
6c
6d
6e
6f
C6H5
H
6g
6h
6i
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
H
6m
6n
6o
6p
6q
6r
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
H
C6H5
C6H5
C6H5
C6H5
C6H5
4-Cl
3-Cl-4-F
4-F
4-OMe
4-Me
4-Cl
3-Cl-4-F
4-F
4-OMe
4-Me
4-Cl
3-Cl-4-F
4-F
4-OMe
4-Me
6j
6k
6l
Scheme 2.
activity result analysis, it was observed that compounds 6b, 6d, 6f,
6j, 6k, 6l and 6r showed good activity with 53.99% to 85.33% inhi-
bition of edema. The data also revealed that maximum protection
was shown in the tested compounds 6b, 6d, 6f, having phenyl
group at 2-position of thiazole nucleus (Ar = C6H5–) and phenyl
group of thiazolidinone ring having 4-methyl, 4-chloro or 4-fluoro
substituent (R1 = 4-CH3, 4-Cl, 4-F). The % inhibition is retained for
compounds 6j and 6l in which phenyl group on thiazole nucleus
is replaced by 4-chloro phenyl group (Ar = 4-Cl-C6H4–) and phenyl
ring on thiazolidinone nucleus having 4-methyl or 4-fluoro
substituent (R1 = 4-CH3, 4-F). It was also seen that when the
4-chlorophenyl group of thiazole ring was replaced by 4-chloro-
benzyl group (Ar = 4-Cl-C6H4-CH2–), only compound 6r in which
the phenyl group of thiazolidinone ring has 4-methyl substituent
(R1 = CH3) showed anti-inflammatory activity. In general, it is con-
cluded that 2-phenyl thiazole show better inhibition as compared
to 2-(4-chlorophenyl)thiazole or 2-(4-chlorobenzyl)thiazole. The
synthesized compounds 6a–r were also evaluated for their antimi-
crobial activity against Escherichia coli (ATCC 25922) representing
Gram-negative bacteria, Staphylococcus aureus (ATCC 25923) repre-
senting Gram-positive bacteria and Candida albicans (ATCC 10231)
and Aspergillus niger (ATCC 9029) representing fungi. The in vitro
minimal inhibitory concentrations (MIC) screening51 results of
tested compounds are listed in Table 2.
Table 1
In vivo anti-inflammatory effect of the compounds against carrageenan-induced rat paw model
Test sample
1 h
2 h
4 h
Swelling
% Inhibition
Swelling
% Inhibition
Swelling
% Inhibition
Control
6a
6b
6c
6d
6e
6f
6h
6i
6j
6k
6l
3.10 0.09
2.95 0.09
2.47 0.05*
3.16 0.23
2.68 0.07*
2.92 0.04
2.60 0.06*
3.87 0.16
2.93 0.09
2.71 0.11*
2.48 0.04*
2.59 0.09*
NA
—
3.88 0.10
4.00 0.09
2.64 0.06*
3.51 0.08
2.71 0.11*
3.72 0.05
2.79 0.06*
3.32 0.08
3.69 0.06
2.71 0.16*
2.13 0.04*
2.40 0.08*
NA
—
4.83 0.11
4.72 0.08
2.14 0.05*
3.75 0.04
2.13 0.11*
4.15 0.08
2.32 0.07*
2.87 0.07
4.29 0.11
2.41 0.08*
2.63 0.06*
2.72 0.16*
NA
—
44.40
54.76
55.92
63.90
52.30
58.14
69.28
53.41
63.36
53.99
38.30
NA
50.61
59.07
20.87
63.36
48.15
60.10
45.70
45.15
63.87
80.74
37.60
NA
63.68
80.75
28.64
85.33
67.14
80.56
43.15
65.11
67.61
59.06
63.86
NA
6m
6n
6o
6q
6r
2.30 0.10*
2.92 0.10
3.51 0.08
2.61 0.09*
2.48 0.18*
48.90
40.74
20.87
59.90
70.2
3.09 0.11
3.15 0.12
3.75 0.04
2.69 0.10*
2.42 0.15*
40.07
45.07
28.64
61.39
78.30
3.20 0.29
2.71 0.07*
3.16 0.23
2.19 0.13*
2.29 0.15*
53.89
68.89
55.92
81.32
87.26
Indomethacin
Values are expressed mean SEM in carrageenan-induced rat model of paw edema.
Indomethacin and test compounds were administered orally at the dose of 40 mg/kg. NA: non-active.
*
P < 0.05 versus saline control; n = 6.

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6375
Table 2
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Compound
MW
MIC
l
g/mL (
lM)
E. coli
S. aureus
C. albicans
A. Niger
ATCC 25922 ATCC 25923 ATCC 10231 ATCC 9029
6a
6b
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386.92 25(64.61)
404.91 25(61.74)
370.46 12.5(33.74) 25(67.48)
381.49 25(65.53)
365.49 25(60.40)
386.92 12.5(32.30) 12.5(32.30) 50(129.22) 50(129.22)
421.36 12.5(29.66) 25(59.33)
439.35 25(56.90) 25(56.90)
404.91 6.25(15.43) 12.5(30.87) 12.5(30.87) 25(61.74)
416.94 12.5(29.98) 12.5(29.98) 12.5(29.98) 12.5(29.98)
400.94 12.5(31.17) 12.5(31.17) 6.25(15.58) 12.5(31.17)
368.88 25(67.77)
435.39 25(57.42)
453.38 25(55.14)
418.94 25(59.67)
430.97 25(58.00)
414.97 25(60.24)
25(70.92)
50(141.85) 50(141.85)
50(129.23) 50(129.23) 50(129.23)
25(61.74)
50(123.48) 50(123.48)
12.5(33.74) 12.5(33.74)
12.5(32.76) 12.5(32.76)
25(65.53)
50(120.80) 12.5(30.20) 12.5(30.20)
50(118.66) 50(118.66)
50(113.80) 50(113.80)
25(67.77)
12.5(33.88) 12.5(33.88)
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.08.
073.

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