Synthesis of some novel 2,4-disubstituted thiazoles as possible antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2007.03.014

A series of novel 4-aryl/chloroalkyl-2-(2,3,5-trichlorophenyl)-1,3-thiazoles (5a-g and 7a-e) were synthesized by condensing 2,3,5-trichlorobenzenecarbothioamide with phenacyl bromide/dichloroacetone. 2,3,5-Trichlorobenzaldehyde thiosemicarbazone on treatment with phenacyl bromide afforded 4-aryl-2-(2,3,5-trichlorophenylidenehydrazino)-1,3-thiazoles (10a-g) in good yield. The newly synthesized compounds are characterized by IR, ¹H NMR and mass spectral studies. These compounds were also screened for their antibacterial and antifungal activities. Preliminary results reveal that some of the synthesized compounds are showing promising antimicrobial activity.

Full text of DOI:10.1016/j.ejmech.2007.03.014

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 261e267
http://www.elsevier.com/locate/ejmech
Original article
Synthesis of some novel 2,4-disubstituted thiazoles
as possible antimicrobial agents
Prakash Karegoudar a,b, Mari Sithambaram Karthikeyan a,
Dasappa Jagadeesh Prasad a, Manjathuru Mahalinga a,b, Bantwal Shivarama Holla a,
Nalilu Sucheta Kumari c
*
,
a Department of Chemistry, Mangalore University, Mangalagangothri, Konaje, Mangalore, Karnataka 574199, India
b Strides Research and Specialty Chemicals Limited, 120 A & B, Industrial Area, Baikampady, New Mangalore, Karnataka, India
c Department of Biochemistry, K.S. Hegde Medical Academy, Deralakatte 574162, India
Received 2 December 2006; received in revised form 6 March 2007; accepted 8 March 2007
Available online 3 April 2007
Abstract
A series of novel 4-aryl/chloroalkyl-2-(2,3,5-trichlorophenyl)-1,3-thiazoles (5aeg and 7aee) were synthesized by condensing 2,3,5-trichloro-
benzenecarbothioamide with phenacyl bromide/dichloroacetone. 2,3,5-Trichlorobenzaldehyde thiosemicarbazone on treatment with phenacyl
bromide afforded 4-aryl-2-(2,3,5-trichlorophenylidenehydrazino)-1,3-thiazoles (10aeg) in good yield. The newly synthesized compounds are
1
characterized by IR, H NMR and mass spectral studies. These compounds were also screened for their antibacterial and antifungal activities.
Preliminary results reveal that some of the synthesized compounds are showing promising antimicrobial activity.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: 2,3,5-Trichlorobenzenecarbothioamide; 2,4-Disubstitued thiazole; Antibacterial; Antifungal activity
1. Introduction
compounds were tested for their antifungal activity against
three phytopathogenic fungi of rice. One of the tested com-
pound N-[4-(4-chlorophenyl)-2-thiazolyl]salicylamide effec-
tively exhibited inhibitory activities on Helminthosporium
oryza and Piriicularia oryza on rice. Prompted by these inves-
tigations and in continuation of our search for bioactive
molecules [12,13], we considered the synthesis of novel 4-
substituted-2-(2,3,5-trichlorophenyl)-1,3-thiazoles starting from
2,3,5-trichlorobenzenecarbothioamide, 1,3-dichloroacetone and
various substituted phenacyl bromides and tested them for
their antibacterial and antifungal properties.
Thiazoles and their derivatives are found to be associated
with various biological activities such as antibacterial, antifun-
gal and anti-inflammatory activities [1e3]. Different thiazole
bearing compounds possess anti-inflammatory activities [4]
and some are known to be used as pharmaceutical as well as
agrochemical products [5e10]. Among them ritonavir is
a well known anti-HIV drug and imidacloprid is an important
insecticide.
Tripathy and Pradhan [11] have reported the preparation
of N-thiazolyl and halothiazolyl amides of halogenated and
non-halogenated salicylic and naphthoic acids and these
2. Results and discussion
2.1. Chemistry
* Corresponding author. Tel.: þ91 0824 2287262; fax: þ91 0824 2287367/
2287424.
E-mail address: jprasad_2003@yahoo.co.in (B.S. Holla).
The target molecules, 4-aryl-2-(2,3,5-trichlorophenyl)-1,3-
thiazoles (5aeg) were synthesized in good yield by the
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.03.014

262
P. Karegoudar et al. / European Journal of Medicinal Chemistry 43 (2008) 261e267
reaction of 2,3,5-trichlorobenzenecarbothioamide (4) with var-
ious phenacyl bromides in refluxing ethanol. Compound 4 was
prepared by the reaction of 2,3,5-trichlorobenzamide (3) with
phosphorous penta disulfide in tetrahydrofuran at 50 ꢀC.
Compound 3 was prepared by the reaction of 2,3,5-trichloroben-
zoyl chloride with aqueous ammonia. The 4-(chloromethyl)-2-
(2,3,5-trichlorophenyl)-1,3-thiazole (6) was synthesized in
moderate yield by the condensation of 2,3,5-trichlorobenzene-
carbothioamide with 1,3-dichloroacetone in refluxing methyl
isobutyl ketone. The target molecules 4-substituted-2-(2,3,
5-trichlorophenyl)-1,3-thiazoles (7aee) were prepared by
reaction of 4-(chloromethyl)-2-(2,3,5-trichlorophenyl)-1,3-thi-
azole (6) with various amines and mercaptans in the presence
of a base. 4-Aryl-2-(2,3,5-trichlorophenylidenehydrazino)-
1,3-thiazoles (10aeg) were synthesized in excellent yields
by the reaction of 2,3,5-trichlorobenzaldehyde thiosemicar-
bazone (9) with various phenacyl bromides in ethanol
(Table 1). The starting material 9 was synthesized by con-
densing 2,3,5-trichlorobenzaldehyde (1) with thiosemicarba-
zide (8) in the presence of concentrated sulphuric acid in
ethanol.
2.2. Biological activity
2.2.1. Antibacterial activity
Theinvestigationofantibacterialscreening(Table2)revealed
that all the newly synthesized compounds showed moderate to
good inhibition at 1.56e25 mg/ml in DMSO. Compounds 5b,
5e, 7b, 7e, 10a and 10f exhibited comparatively good activity
against the four tested bacterial stains. Compounds 5f, 5g, and
7d showed good activityagainst Escherichia coli and Pseudomo-
nas aeruginosa. Compounds7c, 10c and 10d showed good activ-
ity against Staphylococcus aureus and Bacillus subtilis.
2.2.2. Antifungal activity
The investigation of antifungal screening (Table 3) revealed
that all the newly synthesized compounds showed moderate to
good inhibition at 1.56e25 mg/ml in DMSO. Compounds 5c,
5d, 7d, 10b and 10c exhibited good activity against all the
four fungal strains. Compounds 5e, 7e and 7b showed good
activity against Aspergillus flavus and Penicillium marneffei.
Compounds 5g, 7b and 10f showed good activity against
Trichophyton mentagrophytes and Aspergillus fumigatus.
Cl
O
Cl
O
Cl
O
Cl
1. KMnO4
Cl
Cl
OH
1. SOCl2
H
NH2
2. HCl
2. Aq. NH3
Cl
Cl
Cl
3
1
2
P2S5
THF
Cl
NH2NHCSNH2
8
O
Cl
Cl
S
Cl
N
Cl
NH2
Cl
Cl
S
MIBK, 50 °C, 2 Hrs
6
Cl
Cl
4
Secondary amines / Mercaptans
ArCOCH2Br
Cl
Cl
Cl
R
Ethanol, reflux
N
Ar
Cl
Cl
Cl
N
S
7a-e
S
5a-g
Ar
Cl
N
Cl
Cl
NH2
1. ArCOCH2Br
Cl
NH
N
NH
Cl
S
N
S
2. Ethanol, reflux, 3 hr
10a-g
Cl
9

P. Karegoudar et al. / European Journal of Medicinal Chemistry 43 (2008) 261e267
263
Table 1
Characterization data of 2-(2,3,5-trichloropheyl)-4-aryl-1,3-thiazoles (5aeg), (7aee) and (10aeg)
Compounds
Ar/R
Molecular formula
MW
M.p. (ꢀC)
Yield (%)
% Analysis of C, H, N found (calculated)
C
H
N
5a
4-OCH3eC6H4
4-SCH3eC6H4
3-Pyridyl
C16H10Cl3NOS
C16H10Cl3NS2
C14H10Cl3N2S
C21H12Cl3NS
369
385
344
415
398
384
373
362
375
360
455
415
444
382
426
415
427
411
95e97
80
85
84
86
82
85
86
81
85
84
83
83
85
86
86
85
82
84
52.00 (52.03)
49.84 (49.87)
48.80 (48.83)
60.45 (60.72)
48.04 (48.24)
46.85 (46.87)
48.20 (48.25)
46.42 (46.40)
48.03 (48.00)
50.03 (50.00)
44.80 (44.83)
46.22 (46.26)
46.19 (45.94)
47.10 (47.12)
45.00 (45.02)
46.22 (46.26)
47.54 (47.77)
49.60 (49.63)
2.73 (2.71)
2.58 (2.59)
2.93 (2.90)
2.86 (2.89)
2.27 (2.26)
1.80 (1.82)
1.85 (1.87)
3.56 (3.59)
3.56 (3.59)
4.22 (4.26)
4.14 (4.16)
2.22 (2.19)
3.16 (3.15)
2.38 (2.35)
2.13 (2.11)
2.14 (2.16)
2.85 (2.81)
2.95 (2.91)
3.80 (3.79)
5b
5c
119e121
199e200
162e164
210e212
190e192
162e164
104e106
280e282
256e258
220e222
242e244
256e258
208e210
256e258
238e40
3.65 (3.63)
8.15 (8.13)
3.34 (3.37)
7.05 (7.03)
7.26 (7.29)
3.73 (3.75)
7.71 (7.73)
7.71 (7.73)
5d
5e
Biphenyl
4-OH-3-CONH2eC6H3
4-NO2eC6H4
4-CleC6H4
Morpholino
N-Methylpiperazino
Piperidino
C16H9Cl3N2O2S
C15H7Cl3N2O2S
C15H7Cl4NS
5f
5g
7a
C14H13Cl3N2OS
C15H16Cl3N3S
7b
7c
C15H15Cl3N2S
C17H10Cl3N5S2
C16H12Cl3N3S2
C17H14Cl3N4O2S
C15H9Cl3N4S
11.275 (11.20)
7.73 (7.77)
7d
7e
4-Mercaptopyrazolopyrimidine
4,6-(CH3)2-2-Mercaptopyrimidine
4-OH-3-CONH2eC6H3
3-Pyridyl
15.35 (15.38)
12.63 (12.61)
14.63 (14.65)
13.00 (13.14)
10.15 (10.12)
9.80 (9.83)
10a
10b
10d
10e
10f
10g
4-NO2eC6H4
4-NO2eC6H4
C16H9Cl3N4O2S
C16H9Cl4N3
4-SCH3eC6H4
4-OCH3eC6H4
C17H12Cl3N3S2
C17H12Cl3N3OS
134e135
228e230
10.19 (10.2)
3. Conclusion
structurally resemble a known antifungal agent N-[4-(4-chloro-
phenyl)-2-thiazolyl]salicylamide [11].
We have synthesized several thiazole derivatives containing
2,3,5-trichlorophenyl moiety and studied their antibacterial
and antifungal properties. In particular the thiazoles 5b and
10f carrying 4-(methylthio)phenyl, 5e and 10a carrying salicy-
lamide, 7b carrying N-methylpiparazino and 7e carrying 4,6-
dimethyl-2-mercaptopyrimidine substituents appear to exhibit
the highest antibacterial activity. Also thiazoles 5c, 10b carry-
ing 3-pyridyl, 5d, 10c carrying biphenyl and 7d carrying
4-mercaptopyrazolopyrimidine substituents appear to exhibit
the highest antifungal activity. Compounds 5e and 10a
4. Experimental
Melting points were determined by the open capillary
method and are uncorrected. The IR spectra (in KBr pellets)
were recorded on a NICOLET AVATAR 330-FTIR spectrom-
eter. PMR spectra were recorded (CDCl3/DMSO-d6) on
a Bruker-AC 300F (300 MHz) NMR spectrometer using
TMS as an internal standard. Chemical shift values are given
in d scales. The FAB mass spectra were recorded on a VG
Table 2
Antibacterial activity data of prepared compounds (5aeg), (7aee) and (10aeg)
Compounds
MIC in mg/ml (zone of inhibition in mm)
Escherichia
coli
Staphylococcus
aureus
Pseudomonas
aeruginosa
Bacillus
subtilis
5a
5b
6.25 (16e20)
6.25 (16e20)
12.5 (11e15)
25 (<10)
12.5 (11e15)
6.25 (16e20)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
12.5 (11e15)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
25 (<10)
12.5 (11e15)
6.25 (16e20)
25 (<10)
12.5 (11e15)
6.25 (16e20)
12.5 (11e15)
12.5 (11e15)
6.25 (16e20)
25 (<10)
5c
5d
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
5e
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
12.5 (11e15)
6.25 (16e20)
25 (<10)
5f
5g
25 (<10)
7a
7b
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
12.5 (10e15)
25 (<10)
7c
7d
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
12.5 (11e15)
25 (<10)
7e
10a
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
12.5 (10e15)
6.25 (16e20)
6.25 (16e20)
25 (<10)
10b
10c
6.25 (16e20)
6.25 (16e20)
25 (<10)
10d
10e
25 (<10)
25 (<10)
25 (<10)
12.5 (11e15)
6.25 (16e20)
25 (<10)
10f
10g
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
25 (<10)
1.56 (21)
Ciprofloxacin
6.25 (16e20)
Note: the MIC values were evaluated at concentration range 1.56e25 mg/ml. The values in the table show the MIC values and the corresponding zone of inhibition
(in mm).

264
P. Karegoudar et al. / European Journal of Medicinal Chemistry 43 (2008) 261e267
Table 3
Antifungal activity data of prepared compounds (5aeg), (7aee) and (10aeg)
Compounds
MIC in mg/ml (zone of inhibition in mm)
Aspergillus
flavus
Trichophyton
mentagrophytes
Aspergillus
fumigatus
Penicillium
marneffei
5a
5b
25 (<10)
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
12.5 (11e15)
25 (<10)
25 (<10)
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
25 (<10)
25 (<10)
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
25 (<10)
25 (<10)
25 (<10)
5c
5d
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
25 (<10)
5e
5f
5g
25 (<10)
6.25 (16e20)
25 (<10)
12.5 (11e15)
6.25 (16e20)
25 (<10)
25 (<10)
7a
7b
25 (<10)
25 (<10)
25 (<10)
12.5 (11e15)
25 (<10)
25 (<10)
6.25 (16e20)
25 (<10)
6.25 (16e20)
25 (<10)
7c
7d
6.25 (16e20)
6.25 (16e20)
12.5 (11e15)
6.25 (16e20)
6.25(16e20)
25 (<10)
6.25 (16e20)
25 (<10)
6.25 (16e20)
25 (<10)
6.25 (16e20)
6.25 (16e20)
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
25 (<10)
7e
10a
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
25 (<10)
12.5 (11e15)
6.25 (16e20)
6.25 (16e20)
25 (<10)
10b
10c
10d
10e
12.5 (11e15)
25 (<10)
25 (<10)
12.5 (11e15)
6.25 (16e20)
12.5 (11e15)
6.25 (16e20)
12.5 (11e15)
6.25 (16e20)
25 (<10)
12.5 (11e15)
25 (<10)
25 (<10)
10f
10g
Ciclopiroxolamine
6.25 (16e20)
6.25 (16e20)
6.25 (16e20)
Note: the MIC values were evaluated at concentration range 1.56e25 mg/ml. The values in the table show the MIC values and the corresponding zone of inhibition
(in mm).
Micro mass spectrometer operating at 70 eV. Elemental anal-
ysis was carried out using Flash EA 1112 elementar analyzer.
The completion of the reaction was checked by thin layer
chromatography (TLC) on silica gel coated aluminium sheets
(silica gel 60 F254) using a mixture of ethylacetate and hexane
(1:4 v/v). Commercial grade solvents and reagents were used
without further purification.
30 min, the resulting solid mass was filtered, washed with water
and dried. The crude product was recrystallized from methanol.
Yield 73%, m.p. 198e200 ꢀC.
1H NMR (DMSO-d6): d 7.54 (d, 1H, J ¼ 2.1 Hz, 2,3,5-tri-
chlorophenyl), 7.81 (s, 1H, CONH2), 7.91 (d, 1H, J ¼ 2.4 Hz,
2,3,5-trichlorophenyl), 8.04 (s, 1H, CONH2); FAB MS (m/z,
%): 231 (2, M þ 6), 229 (5, M þ 4), 227 (4, M þ 2), 225 (90,
Mþ), 207 (5), 165 (7), 120 (10), 107 (35), 89 (20).
4.1. Procedure for the synthesis of 2,3,5-
trichlorobenzoic acid (2)
4.3. Procedure for the synthesis of 2,3,5-
trichlorobenzenecarbothioamide (4)
To
a solution of 2,3,5-trichlorobenzaldehyde (37 g,
0.176 mol) in 30 ml water a solution of potassium permanga-
nate (30 g, 0.191 mol) in 60 ml water was added at 70e80 ꢀC
over a period of 2 h. The reaction mass was stirred at the same
temperature for 2 h. After filtration of reaction mass, the fil-
trate was acidified using conc. hydrochloric acid at 0e5 ꢀC.
The product obtained was filtered, washed with water and
dried. The crude product was recrystallized from methanol.
Yield 75%, m.p. 167e168 ꢀC [20].
To a solution of 2,3,5-trichlorobenzamide (20 g, 0.089 mol)
in tetrahydrofuran (50 ml) phosphorous penta disulfide (40 g,
0.18 mol) was slowly added at 50 ꢀC over a period of 2 h.
The resulting mass was stirred at 50e55 ꢀC for 2 h and the re-
action mass was poured into ice-cold water. The precipitated
solid was filtered, washed with water and dried. The product
was recrystallized from ethylacetate. Yield 74%, m.p. 218e
220 ꢀC.
1H NMR (DMSO-d6): 6.99 (s, 1H, CSNH2), 7.01 (d, 1H,
J ¼ 2.1 Hz, 2,3,5-trichloro phenyl), 7.52 (d, 1H, J ¼ 2.1 Hz,
2,3,5-trichlorophenyl), 7.72(s, 1H, CSNH2); FAB MS (m/z,
%): 425 (6, M þ 6), 245 (10, M þ 4), 243 (60, M þ 2), 241
(95, Mþ), 224 (70), 206 (30), 167 (20), 107 (35), 89 (20).
4.2. Procedure for the synthesis of 2,3,5-
trichlorobenzamide (3)
In a four-necked round-bottomed flask mixture of 2,3,5-tri-
chlorobenzoic acid (30 g, 0.133 mol) and thionyl chloride
(100 ml) were refluxed for 2 h. After completion of the reaction
excess thionyl chloride was distilled off under reduced pressure.
To the cooled residue in acetone (50 ml) a solution of aqueous
ammonia (200 ml) in acetone (50 ml) was added at 0e5 ꢀC.
The reaction temperature was maintained at 10e15 ꢀC for
4.4. General procedure for the synthesis of 4-substituted-
2-(2,3,5-trichlorophenyl)thiazoles (5aeg)
An equimolar mixture of the appropriate 2,3,5-trichloroben-
zenecarbothioamide (4) (0.01 mol) and substituted phenacyl

P. Karegoudar et al. / European Journal of Medicinal Chemistry 43 (2008) 261e267
265
bromide (0.01 mol) in methanol was refluxed for 4 h, after
4.5. Procedure for the synthesis of 4-(chloromethyl)-2-
(2,3,5-trichlorophenyl)-1,3-thiazole (6)
completion of the reaction. The mass was cooled to room tem-
perature. The solid obtained was filtered and recrystallized
from chloroform.
An equimolar mixture of the appropriate 2,3,5-trichloro-
benzenecarbothioamide (4) (16 g, 0.066 mol) and 1,3-dichlor-
oacetone (12.5 g, 0.099 mol) in methylisobutylketone (MIBK)
was refluxed for 3 h. The reaction mass was poured into cold
water, the separated organic layer was washed with water,
dried over anhydrous sodium sulphate and concentrated under
reduced pressure. The obtained product was recystallized us-
ing chloroform. Yield 76%, m.p. 118e120 ꢀC.
1H NMR (CDCl3): d 4.76 (s, 2H, CH2), 7.55 (s, 1H,
J ¼ 2.2 Hz, 2,3,5-trichlorophenyl), 7.59 (s, 1H, J ¼ 2.2 Hz,
2,3,5-trichlorophenyl), 8.22 (s, 1H, thiazole H); FAB MS (m/
z, %): 319 (4, M þ 6), 317 (10, M þ 4), 315 (15, M þ 2),
313 (20, Mþ), 281 (20), 267 (10), 224 (15), 207 (20), 167
(10), 120 (20), 107 (30).
4.4.1. 4-(4-Methoxyphenyl)-2-(2,3,5-trichlorophenyl)-1,3-
thiazole (5a)
IR (KBr, nmax cmꢁ1): 1529 (C]C), 1598 (C]N), 1078
1
(C]S), 708, 830, 990 (CeCl); H NMR (DMSO-d6): d 3.87
(s, 3H, OCH3), 7.00 (d, 2H, J ¼ 8.4 Hz, p-anisyl), 7.55 (d,
1H, J ¼ 2 Hz, 2,3,5-trichlorophenyl), 7.57 (s, 1H, thiazole
H), 7.92 (d, 2H, J ¼ 8.4 Hz, p-anisyl), 8.36 (d, 1H, J ¼ 2 Hz,
2,3,5-trichlorophenyl); FAB MS (m/z, %): 375 (5, M þ 6),
373 (30, M þ 4), 371 (75, M þ 2), 369 (80, Mþ), 273 (5),
245 (5), 165 (5), 120 (10), 107 (25), 88 (20).
4.4.2. 4-[4-(Methylthio)phenyl]-2-(2,3,5-trichlorophenyl)-
1,3-thiazole (5b)
IR (KBr, nmax cmꢁ1): 1540 (C]C), 1580 (C]N), 1068
(C]S), 707, 820, 1005 (CeCl); 1H NMR (DMSO-d6):
d 2.52 (s 3H, SCH3), 7.12 (d, 1H, J ¼ 8.7 Hz, p-thioanisyl),
7.52 (s, 1H, thiazole H), 7.75 (d, 1H, J ¼ 2 Hz, 2,3,5-trichlor-
ophenyl), 7.91 (d, 2H, J ¼ 4.8 Hz, p-thioanisyl), 8.38 (d, 2H,
J ¼ 4.8 Hz, 2,3,5-trichlorophenyl).
4.6. General procedure for the synthesis of 4-substituted-
2-(2,3,5-trichlorophenyl)thiazoles (7aee)
An equimolar mixture of 6 (0.02 mol) and amines/mercap-
tans (0.02 mol) was refluxed in methylisobutylketone (MIBK)
(25 ml) in presence of potassium carbonate/sodium hydroxide
for 2e3 h. After completion of the reaction, the mass was
poured into water; the organic layer was separated, washed
with water and dried over anhydrous sodium sulphate. The or-
ganic layer was concentrated under reduced pressure and the
solid obtained after cooling was filtered and recrystallized
from chloroform.
4.4.3. 4-(1,10-Biphenyl-4-yl)-2-(2,3,5-trichlorophenyl)-1,3-
thiazole (5d)
FAB MS (m/z, %): 422 (10, M þ 6), 420 (30, M þ 4), 418
(75, M þ 2), 416 (70, Mþ), 273 (10), 242 (5), 210 (10), 178
(10), 165 (15), 107 (20), 89 (10), 77 (10).
4.6.1. 4-{[2-(2,3,5-Trichlorophenyl)-1,3-thiazol-4-yl]-
methyl}morpholine (7a)
4.4.4. 2-[Amino(hydroxy)methyl]-4-[2-(2,3,5-
trichlorophenyl)-1,3-thiazol-4-yl]phenol (5e)
IR (KBr, nmax cmꢁ1): 3260 (NH), 1525 (C]C), 1598
IR (KBr, nmax cmꢁ1): 1530 (C]C), 1600 (C]N), 70
(C]S), 710, 815,1010 (CeCl); 1H NMR (DMSO-d6):
d 7.02 (d, 1H, J ¼ 8.7 Hz, salicylamide), 8.14 (d, 1H,
J ¼ 8.7 Hz, salicylamide), 8.25 (s, 1H, thiazole H), 8.00 (d,
1H, J ¼ 2.1 Hz, 2,3,5-trichlorophenyl), 8.03 (s, 1H, NH am-
ide), 8.47 (s, 1H, NH amide), 8.56 (d, 1H, J ¼ 2.1 Hz, 2,3,5-
trichlorophenyl), 8.62 (s, 1H, J ¼ 8.7, salicylamide), 13.2 (s,
1H, OH); FAB MS (m/z, %): 405 (10, M þ 6), 403 (30,
M þ 4), 401 (70, M þ 2), 399 (75, Mþ), 391 (60), 383 (30),
329 (5), 215 (50), 176 (10), 120 (20), 107 (40), 95 (20).
1
(C]N), 1068 (C]S), 990, 830 and 708 (CeCl); H NMR
(DMSO-d6): d 2.48e2.45 (t, 4H, morpholine ring protons),
3.609e3.579 (t, 4H, morpholine ring protons), 3.7 (s, 2H,
CH2), 7.81 (s, 1H, thiazole H), 8.00 (d, 1H, J ¼ 2.4 Hz,
2,3,5-trichlorophenyl), 8.16 (d, 1H, J ¼ 2.4 Hz, 2,3,5-trichlor-
ophenyl); FAB MS (m/z, %): 368 (10, M þ 6), 366 (30,
M þ 4), 364 (80, M þ 2), 362 (90, Mþ), 277 (20), 155 (40),
120 (10), 107 (20).
4.6.2. 1-Methyl-4-{[2-(2,3,5-trichlorophenyl)-1,3-thiazol-4-yl]-
methyl}piperazine (7b)
IR (KBr, nmax cmꢁ1): 3360 (NH), 1527 (C]C), 1590
4.4.5. 4-(4-Nitrophenyl)-2-(2,3,5-trichlorophenyl)-
1,3-thiazole (5f)
1
(C]N), 1053 (C]S), 998, 840 and 718 (CeCl); H NMR
FAB MS (m/z, %): 401 (5, M þ 6), 389 (10, M þ 4), 387
(40, M þ 2), 385 (25, Mþ), 371 (5), 273 (5), 197 (10), 165
(15), 120 (20), 107 (30), 89 (20), 77 (10).
(DMSO-d6): d 3.5 (s, 3H, NeCH3), 2.30e2.33 (t, 4H, N-meth-
ylpiperidine protons), 3.63e3.60 (t, 4H, N-methylpiperidine
protons), 3.72 (s, 2H, CH2), 7.85 (s, 1H, thiazole H), 8.1 (d,
1H, J ¼ 2.4 Hz, 2,3,5-trichlorophenyl), 8.26 (d, 1H,
J ¼ 2.4 Hz, 2,3,5-trichlorophenyl).
4.4.6. 4-(4-Chlorophenyl)-2-(2,3,5-trichlorophenyl)-
1,3-thiazole (5g)
1H NMR (DMSO-d6): d 7.5 (s, 1H, thiazole H), 7.67 (d, 1H,
J ¼ 2.2 Hz, 2,3,5-trichlorophenyl), 7.34 (d, 2H, J ¼ 4.8 Hz, p-
chlorophenyl), 7.36 (d, 1H, J ¼ 2.2 Hz, 2,3,5-trichlorophenyl),
7.83 (d, 2H, J ¼ 4.8 Hz, p-chlorophenyl).
4.6.3. 1-{[2-(2,3,5-Trichlorophenyl)-1,3-
thiazol-4-yl] methyl}piperidine (7c)
1H NMR (DMSO-d6): d 1.80e2.43 (m, 6H, piperidine pro-
tons), 3.53e3.50 (t, 4H, piperidine protons), 3.62 (s, 2H, CH2),

266
P. Karegoudar et al. / European Journal of Medicinal Chemistry 43 (2008) 261e267
7.8 (s, 1H, thiazole H), 8.0 (d, 1H, J ¼ 2.4 Hz, 2,3,5-trichloro-
phenyl), 8.25 (d, 1H, J ¼ 2.4 Hz, 2,3,5-trichlorophenyl).
4.8.3. 4-(4-Chlorophenyl)-2-[(E )-(2,3,5-
trichlorobenzyl)diazenyl]-1,3-thiazole (10e)
1H NMR (DMSO-d6): d 7.46 (d, 2H, J ¼ 4.8 Hz, p-chloro-
phenyl), d 7.58 (d, 2H, J ¼ 4.8 Hz, p-chlorophenyl), 7.69 (d,
1H, J ¼ 2.2 Hz, 2,3,5-trichlorophenyl), 7.57 (s, 1H, thiazole
H), 8.12 (d, 1H, J ¼ 2.2 Hz, 2,3,5-trichlorophenyl), 8.23 (s,
1H, NH), 11.88 (s, 1H, eN]CH); FAB MS (m/z, %): 421
(7, M þ 6), 419 (15, M þ 4), 417 (40, M þ 2), 415 (60, Mþ),
391 (40), 374 (10), 273 (10), 210 (25), 165 (10), 120 (20),
107 (40).
4.6.4. 4,6-Dimethyl-2-({[2-(2,3,5-trichlorophenyl)-
1,3-thiazol-4-yl]methyl}thio)pyrimidine (7e)
1H NMR (CDCl3): d 2.42 (s, 6H, dimethylpyrimidine), 4.62
(s, 2H, CH2), 6.72 (s, 1H, dimethylpyrimidine ring proton),
7.48 (s, 1H, thiazole H), 7.52 (d, 1H, J ¼ 2.4 Hz, 2,3,5-tri-
chlorophenyl), 8.21 (d, 1H, J ¼ 2.4 Hz, 2,3,5-trichlorophenyl);
FAB MS (m/z, %): 421 (3, M þ 6), 419 (10, M þ 4), 417 (30,
M þ 2), 415 (40, Mþ), 401 (20), 355 (5), 327 (20), 278 (50),
267 (30), 221 (20), 207 (25) 147 (60), 107 (10), 95(10).
4.8.4. 4-[4-(Methylthio)phenyl]-2-[(E)-(2,3,5-trichlorobenzyl)-
diazenyl]-1,3-thiazole (10f)
4.7. Procedure for the synthesis of 2,3,5-
trichlorobezaldehyde thiasemicarbazone (9)
1H NMR (DMSO-d6): d 2.52 (s, 3H, SCH3), 7.23 (d, 1H,
J ¼ 4.8 Hz, p-thioanisyl), 7.71 (s, 1H, thiazole H), 7.61 (d,
1H, J ¼ 2.1 Hz, 2,3,5-trichlorophenyl), 7.91 (d, 2H,
J ¼ 4.8 Hz, p-thioanisyl), 8.12 (d, 2H, J ¼ 2.2 Hz, 2,3,5-tri-
chlorophenyl), 7.95 (s, 1H, NH), 11.91 (s, 1H, eN]CH).
An equimolar mixture of 2,3,5-trichlorobenzaldehyde
(30 g, 0.143 mol) and thiosemicarbazide (15 g, 0.164 mol) in
methanol (25 ml) and catalytic amount of concentrated sul-
phuric acid was refluxed for 3 h. The solid separated was fil-
tered, dried and recrystallized using methanol/DMF mixture.
Yield 77%, m.p. 260e262 ꢀC.
FAB MS (m/z, %): 279 (6, M þ 6), 275 (12, M þ 4), 273
(30, M þ 2), 271 (5, Mþ), 242 (15), 209 (20), 176 (10), 165
(40), 120 (70), 107 (90), 89 (75).
4.8.5. 4-(4-Methoxyphenyl)-2-[(E )-(2,3,5-trichlorobenzyl)-
diazenyl]-1,3-thiazole (10g)
1H NMR (DMSO-d6): d 3.86 (s, 3H, OCH3), 7.02 (d, 2H,
J ¼ 8.4 Hz, p-anisyl), 7.58 (d, 1H, J ¼ 2.1 Hz, 2,3,5-trichloro-
phenyl), 7.6 (s, 1H, thiazole H), 7.93 (d, 2H, J ¼ 8.4 Hz, p-ani-
syl), 8.38 (d, 1H, J ¼ 2.1 Hz, 2,3,5-trichlorophenyl), 7.95 (s,
1H, NH), 11.91 (s, 1H, eN]CH).
4.8. General procedure for the synthesis of 4-substituted-
2-(2,3,5-trichlorophenyl)thiazoles (10aeg)
An equimolar mixture of 2,3,5-trichlorobezaldehyde thiase-
micarbazone (9) (0.01 mol) and substituted phenacyl bromide
(0.01 mol) in methanol was refluxed for 4 h. After completion
of the reaction, the resulting reaction mixture was allowed to
cool. The solid thus separated was collected by filtration and
recrystallized using chloroform.
4.9. Experimental procedure for antibacterial testing
The newly synthesized compounds were screened for their
antibacterial activity against E. coli (ATTC-25922), S. aureus
(ATTC-25923), P. aeruginosa (ATTC-27853) and B. subtilis
(recultured) bacterial stains by serial plate dilution method
[14,15]. Serial dilutions of the drug in MullereHinton broth
were taken in tubes and their pH was adjusted to 5.0 using
phosphate buffer. A standardized suspension of the test bacte-
rium was inoculated and incubated for 16e18 h at 37 ꢀC. The
minimum inhibitory concentration (MIC) was noted by seeing
the lowest concentration of the drug at which there was no vis-
ible growth. A number of antimicrobial discs are placed on the
agar for the sole purpose of producing zones of inhibition in
the bacterial lawn. Twenty milliliters of agar media was
poured into each petri dish. Excess of suspension was dec-
anted and the dishes were placed in an incubator at 37 ꢀC
for 1 h. Using an agar punch, wells were made on these seeded
agar plates and minimum inhibitory concentrations of the test
compounds in dimethylsulfoxide (DMSO) were added into
each well labeled. A control was also prepared for the plates
in the same way using DMSO. The petri dishes were prepared
in triplicate and maintained at 37 ꢀC for 3e4 days. Antibacte-
rial activity was determined by measuring the diameter of in-
hibition zone. Activity of each compound was compared with
ciprofloxacin as standard [18,19]. Zones of inhibition were de-
termined for (5aeg), (7aee) and (10aeg) and the results of
such studies are summarized in Table 2.
4.8.1. 2-[Amino(hydroxy)methyl]-4-{2-[(E )-
(2,3,5-trichlorobenzyl)diazenyl]-1,3-
thiazol-4-yl}phenol (10a)
IR (KBr, nmax cmꢁ1): 1529 (C]C), 1598 (C]N), 1078
1
(C]S), 708.830.990 (CeCl); H NMR (DMSO-d6): d 7.82
(d, 1H, J ¼ 8.3 Hz, salicylamide), 7.84 (s, 1H, thiazole H),
7.86 (d, 1H, J ¼ 2.2 Hz, 2,3,5-trichlorophenyl), 7.87 (s, 1H,
salicylamide), 7.92 (d, 1H, J ¼ 8.7 Hz, salicylamide), 7.95
(s, 1H, NH amide), 8.34 (d, 1H, J ¼ 2.2 Hz, 2,3,5-trichloro-
phenyl), 8.36 (s, 1H, NH), 8.48 (s, 1H, NH amide), 12.62 (s,
1H, eN]CH), 12.95 (s, 1H, OH); FAB MS (m/z, %): 450
(40, M þ 6), 448 (5, M þ 4), 446 (20, M þ 2), 444 (10, Mþ),
400 (50), 391(30), 354 (20), 324 (30), 281 (50), 232 (20),
207 (30), 176 (60), 147 (80), 120 (60), 107 (80), 95 (40).
4.8.2. 4-(4-Nitrophenyl)-2-[(E )-
(2,3,5-trichlorobenzyl)diazenyl]-1,3-thiazole (10d)
FAB MS (m/z, %): 434 (2, M þ 6), 432 (5, M þ 4), 430 (10,
M þ 2), 428 (20, Mþ), 317 (20), 397 (20), 377 (20), 366 (20),
355 (30), 307 (10), 279 (10), 197 (20), 176 (40), 165 (40), 115
(30), 107 (50), 97 (50), 77 (40), 75 (5).

P. Karegoudar et al. / European Journal of Medicinal Chemistry 43 (2008) 261e267
267
4.10. Experimental procedure for antifungal testing
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Acknowledgments
We are grateful to the Strides Research and Specialty Chem-
ical Limited, New Mangalore for providing laboratory facilities.
The authors are also thankful to Head, SAIF, CDRI, Lucknow
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