Synthesis, characterization and antimicrobial studies of a few novel thiazole derivatives

Article abstract of DOI:10.1007/s00044-013-0629-x

A series of novel N-[4-(substituted)-1,3-thiazol-2-yl]-2-(substituted) acetamide (9a-m) and methyl 2-(2-(2-(substituted)acetamido)thiazol-4-yl)acetate (9n-o) derivatives have been synthesized and compounds were characterised by spectral and analytical studies. All compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumonia by disc diffusion method and for antifungal activity against Penicillium marneffei, Trichophyton mentagrophytes, Aspergillus flavus and Aspergillus fumigatus by serial plate dilution method. Compounds 9b, 9e, 9m and 9o exhibited growth inhibition against all the tested bacterial strains, with MIC values varying from 12.5 to 6.25 μg/ml. Among the compounds tested for antifungal activity, 9a, 9b, 9d, 9j, 9k, 9p and 9n showed wide range of activity against all the tested strains. Most of the newly synthesized compounds were effective against fungal strains rather than bacterial strains. However, some of the compounds like 9a, 9e, 9j, 9k and 9i showed selective sensitivity against some of the bacterial strains whereas they were unable to sustain the growth of other strains.

Full text of DOI:10.1007/s00044-013-0629-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0629-x
ORIGINAL RESEARCH
Synthesis, characterization and antimicrobial studies
of a few novel thiazole derivatives
•
Aletti S. Praveen Hemmige S. Yathirajan
•
•
Badiadka Narayana Balladka K. Sarojini
Received: 26 February 2013 / Accepted: 14 May 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of novel N-[4-(substituted)-1,3-thia-
zol-2-yl]-2-(substituted)acetamide (9a–m) and methyl 2-(2-
(2-(substituted)acetamido)thiazol-4-yl)acetate (9n–o) deriva-
tives have been synthesized and compounds were charac-
terised by spectral and analytical studies. All compounds
were screened for their in vitro antibacterial activity against
Staphylococcus aureus, Escherichia coli, Pseudomonas
aeruginosa and Klebsiella pneumonia by disc diffusion
method and for antifungal activity against Penicillium
marneffei, Trichophyton mentagrophytes, Aspergillus fla-
vus and Aspergillus fumigatus by serial plate dilution
method. Compounds 9b, 9e, 9m and 9o exhibited growth
inhibition against all the tested bacterial strains, with MIC
values varying from 12.5 to 6.25 lg/ml. Among the com-
pounds tested for antifungal activity, 9a, 9b, 9d, 9j, 9k, 9p
and 9n showed wide range of activity against all the tested
strains. Most of the newly synthesized compounds were
effective against fungal strains rather than bacterial strains.
However, some of the compounds like 9a, 9e, 9j, 9k and 9i
showed selective sensitivity against some of the bacterial
strains whereas they were unable to sustain the growth of
other strains.
Keywords Hantzsch thiazoles synthesis Á
Fischer esterification Á T3P Á Antibacterial activity Á
Antifungal activity
Introduction
Heterocycles containing a thiazole ring system are found to
exhibit a wide spectrum of biological activities. Antimi-
crobial activity of thiazole derivatives has been extensively
studied by many researchers (Sarojini et al., 2010; Liaras
et al., 2011). Organic compounds bearing thiazoles of
different pharmacodynamic moieties found to possess anti-
inflammatory activity (Holla et al., 2003). Compounds
containing thiazole ring system were also used as antiviral
agents (Osama et al., 2009). Antitumor activities of thia-
zole derivatives were well known in the literature (Shah-
enda et al., 2012). Many thiazole-containing compounds
were reported as herbicides (Aldo et al., 1996; Tingting
et al., 2010) and fungicides (Narayana et al., 2004). Few
thiazole derivatives were identified as a TRPV1 antagonist
(Ning et al., 2005). Thiazole and thiadiazole analogues
have been recently proposed as a novel promising class of
adenosines A1 and A3 receptor antagonists. (Alice et al.,
2005). Thiazole derivatives were described as inhibitors of
vascular endothelial growth factor receptor I and II
(Alexander et al., 2006). Replacement of carboxyl group of
ethacrynic acid (EA) by a heterocyclic thiazole exhibited
improvement over EA to inhibit GSTpi activity (Ting
et al., 2012). Triazolyl thiazole series were reported as
cdk5/p25 inhibitors, potentially useful for the treatment
of Alzheimer’s disease (Mahendra et al., 2007). The
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0629-x) contains supplementary
material, which is available to authorized users.
A. S. Praveen Á H. S. Yathirajan (&)
Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore 570 006, India
e-mail: yathirajan@hotmail.com
B. Narayana
Department of Studies in Chemistry, Mangalore University,
Mangalagangotri, Mangalore 574 199, India
B. K. Sarojini
Department of Chemistry, P.A. College of Engineering,
Nadupadavu, Mangalore 574153, India
123

Med Chem Res
Biology
thiazole-diamides have been identified as highly potent c-
secretase inhibitors (Yuhpyng et al., 2007).
The evaluation of newly synthesized thiazole derivatives
for their antibacterial activity against Staphylococcus aur-
eus (ATTC-25923), E. coli (ATTC-25922), Pseudomonas
aeruginosa (ATTC 27853), K. pneumonia (recultured)
bacteria and antifungal activity against Pencillium mar-
neffei (recultured), Trichophyton mentagrophytes (recul-
tured), A. flavus (NCIM No.524), Aspergillus fumigatus
(NCIM No.902) was carried out.
According to the literature, thiazole derivatives could be
potent antimicrobials such as antifungal and antibacterial.
This study describes the synthesis of N-[4-(substituted)-
1,3-thiazol-2-yl]-2-(substituted)acetamide, methyl 2-(2-(2-
(substituted)acetamido)thiazol-4-yl)acetate derivatives and
1
characterization by H and 13C NMR, IR, LCMS and ele-
mental analysis. Antibacterial activity against Staphylo-
coccus aureus, Escherichia coli, Pseudomonas aeruginosa,
Klebsiella pneumonia and antifungal activity against Pen-
icillium marneffei, Trichophyton mentagrophytes, Asper-
gillus flavus, Aspergillus fumigatus are evaluated.
Result and discussion
In this study, two thiazole derivatives (3a–b) were synthes-
ised by the reaction of phenacyl bromides with thiourea
using sodium acetate in ethanol. The N-[4-(substituted)-1,
3-thiazol-2-yl]-2-(substituted)acetamide and methyl 2-(2-
(2-(substituted)acetamido)thiazol-4-yl)acetate derivatives
(9a–p) were synthesised by using T3P as a coupling reagent.
The structure of the obtained compounds was elucidated by
spectral data. According to the IR spectroscopic data of the
compounds (9a–p), they exhibited characteristic C=O
Materials and methods
Chemistry
The synthetic route for the synthesis of compounds is out-
lined in Scheme 1. In this study, 2-aminothiazole derivatives
(3a–b and 6) were prepared by modified Hantzsch thiazole
synthesis. (2-Amino-1,3-thiazol-4-yl)acetic acid (7) was
esterified by Fischer esterification to obtain methyl (2-
amino-1,3-thiazol-4-yl)acetate (8). N-[4-(Substituted)-1,
3-thiazol-2-yl]-2-(substituted)acetamide(9a–m). The methyl
2-(2-(2-(substituted)acetamido)thiazol-4-yl)acetate (9n–p)
derivatives were synthesized by reacting substituted 2-ami-
nothiazole and phenylacetic acid derivatives by using 1-pro-
panephosphonic acid cyclic anhydride (T3P) and triethyl
amine in dichloromethane.
1
(amide) stretching bands in 1,690–1,645 cm-1. In the H
NMR spectra of compounds (9a–p), NHCO proton was
observed at 12.38–12.90 ppm as a singlet or broad singlet.
The signal due to COCH2 methylene protons, of all the
compounds, appeared in the region 4.05–4.30 ppm, as sin-
glet. The signal due to –COCH2-OPh was observed
at 4.81 ppm. The signals for other aromatic and aliphatic
protons were observed at expected regions (Aliphatic-
1.95–4.81 ppm, Aromatic-6.06–8.10 ppm). In 13C NMR,
R1
Scheme 1 Reaction scheme
for the synthesis of thiazole
derivatives
O
O
(i)
(ii)
N
Br
NH2
R1
S
R1
(2 a-b)
(v)
(v)
(1)
(3 a-b)
R2
O
S
O
R3
(iii)
N
N
H2N
+
NH
(9 a-p)
NH2
(5)
NH2
S
S
Cl
(4)
(6)
(v)
HO
O
(iv)
O
O
N
N
NH2
NH2
S
S
(7)
(8)
(i) Bromine / acetic acid, (ii) CH 3COONa / Thiourea / Ethanol, (iii) NaOH / water, (iv) Methanol / H + (v) R3-Acid, triethyl amine, T3P/ Dichloromethane
123

Med Chem Res
the –NHCO- carbon peak was observed at
167.42–170.95 ppm. All the other signals in the spectra were
accounted for all the equivalent and nonequivalent carbons
present in the molecule. Mass spectra (LCMS) of compounds
showed either M? peaks in positive mode or M- peak in
negative mode, in agreement with mass calculated for their
molecular formula. The elemental analysis gave satisfactory
percentage of C, H and N present in new compounds. All
compound showed antibacterial and antifungal activity.
(4-methylthiazol-2-yl)acetamide 9e, N-(4-(3-chlorophenyl)
thiazol-2-yl)-2-(3,4-dimethylphenoxy)acetamide 9m were
found to be active against both E. coli and K. pneumonia
with MIC 6.25 lg/ml. Antifungal activity showed that
N-(4-methylthiazol-2-yl)-2-phenylacetamide 9d is active
against Trichophyton mentagrophytes and A. flavus, N-(4-
(3-chlorophenyl)thiazol-2-yl)-2-p-tolylacetamide 9j against
P. marneffei and A. flavus, N-(4-(3-chlorophenyl)thiazol-2-
yl)-2-m-tolylacetamide 9k against A. flavus and Aspergillus
fumigates and methyl 2-(2-(2-(3-methoxyphenyl)acetam-
ido)thiazol-4-yl)acetate 9p against P. marneffei and A. fumi-
gates with MIC 6.25 lg/ml. It is difficult to arrive at the
structure activity relationship with respect to their antimi-
crobial activities. However, the compounds with either p-tolyl
or m-tolyl substitution at the amide end exhibited better
activity than the rest.
Antibacterial activity
Among the tested compounds, N-(4-methylthiazol-2-yl)-2-
p-tolylacetamide 9a, N-(4-methylthiazol-2-yl)-2-m-toly-
lacetamide 9b, 2-(3-methoxyphenyl)-N-(4-methylthiazol-
2-yl)acetamide 9c, 2-(3,4-dimethylphenoxy)-N-(4-(3-fluo-
rophenyl)thiazol-2-yl)acetamide 9i, N-(4-(3-chlorophenyl)
thiazol-2-yl)-2-p-tolylacetamide 9j, N-(4-(3-chlorophenyl)
thiazol-2-yl)-2-m-tolylacetamide 9k and N-(4-(3-chloro-
phenyl)thiazol-2-yl)-2-(3,4-dimethylphenoxy)acetamide 9m,
were found to be active and the minimum inhibitory con-
centration (MIC) was 6.25 lg/ml. These compounds were
active against all the tested microorganisms. It is noteworthy
that all the active compounds contain either m-tolyl or p-tolyl
groups at the amide end as one of the substituent.
Experimental
All reagents were used as received. All chemistry was
performed under a nitrogen atmosphere using standard
techniques. Completion of the reaction was monitored by
TLC. Melting points were determined by Buchi B-545
apparatus. All the NMR spectra were measured using
Bruker AMX 400 instrument with 5 mm PABBO BB-1H
Antifungal activity
1
tubes. H NMR spectra were measured for approximately
0.03 M solutions in d6-DMSO at 400 MHz with TMS as
internal reference. 13C NMR spectra were measured for
approximately 0.05 M solutions in d6-DMSO at 100 MHz
with TMS as internal reference. LCMS were obtained
using Agilent 1200 series LC and Micromass zQ spec-
trometer. Column chromatography was performed using a
silica gel (230–400 mesh), pet ether and ethyl acetate or
pet ether and diethyl ether as eluent.
In the antifungal assay, the compounds 9d, 9g, 9j, 9k, 9l,
9m, 9n and 9p were found to be more active against all the
tested strains with MIC values ranging from 6.25 lg/ml.
Compounds 9a, 9b, 9e, 9f and 9o were moderately active
with MIC 12.5 lg/ml for all the tested strains. Other
compounds were active against some of the tested strains
and inactive against some of them. The active compounds
possessed either m-tolyl or p-tolyl groups at the amide end
as one of the substituent.
However, for the standard compounds, MIC was below
6.25 lg/ml. But, this is a promising preliminary result.
General procedure for the synthesis of 2-bromo-1-(3-
substituted phenyl)ethanone (2)
To
a stirred solution of substituted acetophenone
Conclusion
(0.01 mol) in acetic acid (10 vol), bromine (0.011 mol)
was added at 0–5 °C. Reaction mixture was stirred at room
temperature for 3–5 h. After the completion of the reaction,
the mixture was quenched to ice and extracted to methyl
tert-butyl ether (50 ml). Organic layer was washed with
aq.10 % NaHCO3 solution, water (50 ml 91), brine (50 ml
91), dried over Na2SO4, filtered and concentrated under
vacuum to afford the crude product which was purified by
column chromatography using a silica gel (230–400 mesh)
pet ether and diethyl ether as eluent.
A series of novel N-[4-(substituted)-1,3-thiazol-2-yl]-2-
(substituted)acetamide (9a–m) and methyl 2-(2-(2-(substi-
tuted)acetamido)thiazol-4-yl)acetate (9n–o) derivatives
were synthesised. The structures of the obtained com-
pounds were elucidated by H and 13C NMR, IR, LCMS
1
and elemental analysis. In the preliminary evaluation for
the antimicrobial activity, compounds N-(4-methylthiazol-
2-yl)-2-m-tolylacetamide 9b, 2-(3,4-dimethylphenoxy)-N-
123

Med Chem Res
General procedure for the synthesis of 4-(3-substituted
vacuum to afford the crude solid which was washed with
phenyl)-1,3-thiazol-2-amine (3)
cold ethanol to obtain the pure product (9) in good yield.
To a solution of 2-bromo-1-(3-substituted phenyl)ethanone
(2) in ethanol thiourea and sodium acetate was added and
stirred at room temperature for 2–3 h. After the completion
of the reaction, reaction mass was poured to ice and pre-
cipitated solid was filtered to afford the crude product
which was purified either by washing with cold ethanol or
by column chromatography using a silica gel (230–400
mesh) pet ether and ethyl acetate as eluent to obtain the
pure product.
4-(3-Chlorophenyl)-1,3-thiazol-2-amine (3a)
Purified by column chromatography (Pet. ether:ethyl ace-
tate, 4:1), isolated yield 88 %, (pale yellow solid), 1H NMR
(400 MHz, DMSO-d6) d (ppm): 7.13 (s, 2H), 7.17 (s, 1H),
7.29–7.32 (m, 1H), 7.39 (t, J = 7.80 Hz, 1H), 7.75 (d,
J = 7.76 Hz, 1H), 7.84 (s, 1H). 13C NMR (100 MHz,
DMSO-d6) d (ppm):103.58(C-5), 124.44(C-12), 125.65(C-
8), 127.30(C-10), 130.81(C-11), 133.77(C-7), 137.30(C-9),
148.55(C-4), 168.78(C-2). MS calcd. For C9H7ClN2S:
210.6. Found: 211.2 (M?). Anal. Calc. for C9H7ClN2S: C,
51.31; H, 3.35; Cl, 16.83; N, 13.30; S, 15.22. Found: C,
51.30; H, 3.32; S, 15.22.
General procedure for the synthesis of 4-methylthiazol-
2-amine (6)
To a suspension of thiourea (0.01 mol) in water (10 vol),
chloroacetone was added under stirring. Resulting solution
was refluxed for 4 h. Reaction mass was cooled basified
with NaOH (pH *14) and extracted to ethyl acetate.
Organic layer was washed with water (100 ml 91), brine
(100 ml 91), dried over Na2SO4, filtered and concentrated
under vacuum to afford the crude product which was
purified by column chromatography using a silica gel
(230–400 mesh) pet ether and ethyl acetate as eluent to
obtain the pure product (6).
4-(3-Fluorophenyl)thiazol-2-amine (3b)
Purified by column chromatography (Pet. ether:ethyl ace-
1
tate, 4:1), isolated yield 82 %, (yellow solid), H NMR
(400 MHz, DMSO-d6) d (ppm): d 7.05–7.10 (m, 1H), 7.12
(br s, 2H), 7.14 (s, 1H), 7.37–7.42 (m, 1H), 7.55–7.59 (m,
1H), 7.64 (d, J = 7.88 Hz, 1H). 13C NMR (400 MHz,
DMSO-d6) d (ppm):103.06 (C-5), 112.15(C-10), 113.92(C-
8), 121.53(C-12), 130.50(C-11), 137.28(C-7), 148.50(C-4),
161.30(C-9), 168.32(C-2). MS calcd. for C9H7FN2S: 194.2.
Found: 195.2 (M?). Anal. Calc. for C9H7FN2S: C, 55.65;
H, 3.63; F, 9.78; N, 14.42; S, 16.51. Found: C, 55.62; H,
3.62; S, 16.50.
General procedure for the synthesis of methyl
(2-amino-1,3-thiazol-4-yl)acetate (8)
(2-Amino-1,3-thiazol-4-yl)acetic acid was refluxed in
methanol in the presence of catalytic amount of Conc.
H2SO4 for 3 h. Excess of methanol was removed under
vacuum. Residue was dissolved in ethyl acetate and
washed with aq.10 % NaHCO3 solution, water (50 ml 91),
brine (50 ml 91), dried over Na2SO4, filtered and con-
centrated under vacuum to afford the title compound (8).
4-Methylthiazol-2-amine (6)
Purified by column chromatography (Pet. ether:ethyl ace-
tate, 1:1), isolated yield 66 %, (pale brown solid), 1H NMR
(400 MHz, DMSO-d6) d (ppm): 2.06 (s, 3H), 6.07 (s, 1H),
6.80 (br s, 2H). 13C NMR (400 MHz, DMSO-d6) d
(ppm):17.53(C-6), 100.80(C-5), 148.00(C-4), 168.45(C-2).
MS calcd. for C4H6N2S:114.1. Found: 115.2 (M?). Anal.
Calc. for C4H6N2S: C, 42.08; H, 5.30; N, 24.54; S, 28.09.
Found: C, 42.06; H, 5.28 S, 28.07.
General procedure for the synthesis of N-(4-methyl-1,3-
thiazol-2-yl)-2-phenoxy or phenyl acetamide or acetate
(9)
N-(4-Methylthiazol-2-yl)-2-p-tolylacetamide (9a)
To a solution of ethyl (2-amino-1,3-thiazol-4-yl)acetate (8)
or 4-(substituted)-1,3-thiazol-2-amine (3 or 6) (0.01 mol)
in dichloromethane (10 vol) substituted phenyl acetic acid
(0.011 mol) triethylamine (0.015 mol) and T3P (0.01 mol)
was added at 0 °C. Reaction mixture was stirred at room
temperature for 1 h. After the completion of the reaction,
water was added and the layers were separated. Organic
layer was washed with aq.10 % NaHCO3 solution, aq.10 %
citric acid solution (10 ml), water (10 ml 91), brine (10 ml
91), dried over Na2SO4, filtered and concentrated under
Isolated yield 87 %, (pale yellow solid) m.p. 98–100 °C,
1H NMR (400 MHz, DMSO-d6) d (ppm): 2.25 (s, 3H), 2.27
(s, 3H), 3.68 (s, 2H), 6.72 (s, 1H), 7.12 (d, J = 7.56 Hz,
2H), 7.20 (d, J = 7.32 Hz, 2H), 12.25 (br s, 1H). 13C NMR
(400 MHz, DMSO-d6) d (ppm): 17.31(C-9), 21.09(C-17),
41.82(C-10), 108.09(C-5), 129.41(C-12, C-13, C-15,
C-16), 132.43(C-11), 136.30(C-14), 147.07(C-4), 157.73
(C-2), 169.62(C-7). IR(KBr, cm-1): 3,230 (N–H), 1,689
(C=O), 1,307 (C–N), MS calcd. for C13H14N2OS:246.3.
123

Med Chem Res
Found: 247.0 (M?). Anal. Calc. for C13H14N2OS: C, 63.39;
H, 5.73; N, 11.37; O, 6.50; S, 13.02. Found: C, 63.38; H,
5.71; S, 13.01.
2-(3,4-Dimethylphenoxy)-N-(4-methylthiazol-2-
yl)acetamide (9e)
Isolated yield 73 %, (off white solid), m.p. 106–108 °C. 1H
NMR (400 MHz, DMSO-d6) d (ppm): 2.13 (s, 3H), 2.17 (s,
3H), 2.26 (s, 3H), 4.76 (s, 2H), 6.65 (d, J = 2.64 Hz, 1H),
6.68 (d, J = 14.80 Hz, 1H), 6.78 (s, 1H), 7.02 (t,
J = 8.28 Hz, 1H). 13C NMR (400 MHz, DMSO-d6) d
(ppm): 16.88(C-9), 18.46(C-19), 19.68(C-18), 66.10(C-10),
108.05(C-5), 111.35(C-13), 116.02(C-17), 128.77(C-15),
130.19(C-14), 137.36(C-16), 146.71(C-4), 155.91(C-12),
166.91(C-12), 170.47(C-7). IR(KBr, cm-1): 3,398 (N–H),
1,689 (C=O), 1,309 (C–N), 1,251(C–O–C). MS calcd. for
C14H16N2O2S:276.35. Found: 277.2 (M?). Anal. Calc. for
C14H16N2O2S: C, 60.85; H, 5.84; N, 10.14; O, 11.58; S,
11.60. Found: C, 60.83; H, 5.83; S, 11.58.
N-(4-Methylthiazol-2-yl)-2-m-tolylacetamide (9b)
Isolated yield 85 %, (off white solid), m.p. 130–132 °C, 1H
NMR (400 MHz, DMSO-d6) d (ppm): d 2,254.00 (s, 3H),
2.29 (s, 3H), 3.69 (s, 2H), 6.73 (s, 1H), 7.06 (d,
J = 7.44 Hz, 1H), 7.11 (d, J = 7.68 Hz, 1H), 7.13 (s, 1H),
7.21 (t, J = 7.48 Hz, 1H), 12.26 (br s, 1H). 13C NMR
(400 MHz, DMSO-d6) d (ppm): 17.31(C-9), 21.42(C-17),
42.16(C-10), 108.12(C-5), 126.71(C-16), 127.87(C-14),
128.75(C-15), 130.25(C-12), 135.37(C-11), 137.93(C-13),
147.07(C-4), 157.70(C-2), 169.50(C-7). IR(KBr, cm-1):
3,227(N–H), 1,653 (C=O), 1317 (C–N). MS calcd. for
C13H14N2OS:246.3. Found: 247.0 (M?). Anal. Calc. for
C13H14N2OS: C, 63.39; H, 5.73; N, 11.37; O, 6.50; S,
13.02. Found: C, 63.37; H, 5.72S, 13.00.
N-(4-Methylthiazol-2-yl)-2-(2-nitrophenyl)acetamide (9f)
1
Isolated yield 76 %, (brown solid), m.p. 160–162 °C, H
2-(3-Methoxyphenyl)-N-(4-methylthiazol-2-yl)acetamide
(9c)
NMR (400 MHz, DMSO-d6) d (ppm): 2.26 (s, 3H), 4.20 (s,
2H), 6.73 (s, 1H), 7.57–7.60 (m, 2H), 7.71–7.75 (m, 1H),
8.08–8.09 (m, 1H), 12.31 (s, 1H). 13C NMR (100 MHz,
DMSO-d6) d (ppm):17.32(C-9), 39.32(C-10), 108.10(C-5),
125.19(C-13), 129.17(C-11), 130.34(C-16), 134.25(C-15),
147.12(C-4), 149.11(C-12), 157.63(C-2), 168.30(C-7).
IR(KBr, cm-1): 3,404 (N–H), 1,656 (C=O), 1,595 (N–O),
1,327 (C-NO2), 1,259 (C–N). MS calcd. For C12H11N3
O3S:277.3 Found: 278.2 (M?). Anal. Calc. for
C12H11N3O3S: C, 51.98; H, 4.00; N, 15.15; O, 17.31; S,
11.56. Found: C, 51.95; H, 3.097; S, 11.53.
Isolated yield 79 %, (pale yellow solid), m.p. 104–106 °C,
1H NMR (400 MHz, DMSO-d6) d (ppm): 2.25 (s, 3H), 3.70
(s, 2H), 3.74 (s, 3H), 6.73 (s, 1H), 6.82 (d, J = 2.16 Hz,
1H), 6.86 (d, J = 14.96 Hz, 1H), 6.91 (s, 1H), 7.23 (t,
J = 8.12 Hz, 1H), 12.26 (br s, 1H).). 13C NMR (400 MHz,
DMSO-d6) d (ppm): 17.31(C-9), 42.26(C-10), 55.45(C-18),
108.14(C-5), 112.62(C-16), 115.48(C-12), 121.84(C-14),
129.87(C-15), 136.89(C-11), 147.10(C-14), 157.69(C-13),
159.72(C-2), 169.32(C-7). IR(KBr, cm-1): 3,232 (N–H),
1,655 (C=0), 1,315 (C–N). MS calcd. for C13H14N2O2S:
262.33. Found: 263.0 (M?). Anal. Calc. for C13H14N2O2S:
C, 59.52; H, 5.38; N, 10.68; O, 12.20; S, 12.22. Found: C,
59.50; H, 5.36; S, 12.20.
N-(4-(3-Fluorophenyl)thiazol-2-yl)-2-m-tolylacetamide
(9g)
1
Isolated yield 83 %, (yellow solid), m.p. 173–175 °C, H
N-(4-Methylthiazol-2-yl)-2-phenylacetamide (9d)
NMR (400 MHz, DMSO-d6) d (ppm): 2.28 (s, 3H), 3.75 (s,
2H), 7.07 (d, J = 7.40 Hz, 1H), 7.12–7.17 (m, 3H), 7.21 (t,
J = 7.44 Hz, 1H), 7.44–7.49 (m, 1H), 7.67–7.70 (m, 1H),
7.74 (s, 1H), 7.76 (s, 1H), 12.51 (bs, 1H 13C NMR
(100 MHz, DMSO-d6) d (ppm): 21.00(C-23), 41.68(C-15),
109.55(C-5), 114.39(C-10), 121.71(C-4), 126.36(C-21),
127.52(C-19), 128.37(C-20), 129.90(C-13), 130.78(C-17),
134.80(C-9), 136.66(C-16), 137.55(C-18), 147.45(C-4),
161.42(C-11), 163.83(C-2), 169.65(C-7). IR(KBr, cm-1):
1,552 (C=O), 1,325 (C–N). MS calcd. For C18H15FN2OS:
326.3. Found: 327.0 (M?). Anal. Calc. for C18H15FN2OS:
C, 66.24; H, 4.63; F, 5.82; N, 8.58; O, 4.90; S, 9.82. Found:
C, 66.22; H, 4.61; S, 9.81.
Isolated yield 75 %, (pale yellow solid), m.p. 103–105 °C,
1H NMR (400 MHz, DMSO-d6) d (ppm): 2.26 (s, 3H), 3.74
(s, 2H), 6.73 (s, 1H), 7.32–7.37 (m, 5H), 12.29 (br s, 1H).).
13C NMR (400 MHz, DMSO-d6) d (ppm): 17.32(C-9),
42.21(C-10), 108.13(C-5), 127.24(C-14, 129.01(C-13,
C-15), 129.65(C-12, C-16), 135.50(C-11), 147.10(C-4),
157.70(C-2), 169.47(C-7). IR(KBr, cm-1): 3,238(N–H),
1,653 (C=O), 1,319 (C–N). MS calcd. for C12H12N2
OS:232.3. Found: 233.0 (M?). Anal. Calc. for C12H12N2
OS: C, 62.04; H, 5.21; N, 12.06; O, 6.89; S, 13.80. Found
C, 62.01; H, 5.20; S, 13.80.
123

Med Chem Res
N-(4-(3-Fluorophenyl)thiazol-2-yl)-2-p-tolylacetamide
(9h)
4.41; Cl, 10.34; N, 8.17; O, 4.67; S, 9.35. Found: C, 63.04;
H, 4.40; S, 9.32.
Isolated yield 80 %, (off white solid), m.p. 160–162 °C, 1H
NMR (400 MHz, DMSO-d6) d (ppm): 2.27 (s, 3H), 3.73 (s,
2H), 7.12–7.23 (m, 5H), 7.46–7.49 (m, 1H), 7.68 (d,
J = 10.40 Hz, 1H), 7.73 (s, 1H), 7.75 (s, 1H), 12.50 (s,
1H). 13C NMR (100 MHz, DMSO-d6) d (ppm): 21.11(C-
23), 41.76(C-15), 109.96(C-5), 114.81(C-12), 115.01(C-
10), 122.13(C-14), 129.44(C-17, C-18, C-20, C-21),
131.20(C-13), 132.28(C-16), 136.38(C-9), 137.10(C-19),
147.95(C-4), 161.84(C-11), 164.25(C-2), 170.20(C-7).
IR(KBr, cm-1): 3,228 (N–H) 1,649 (C=O), 1,257 (C–N).
MS calcd. For C18H15FN2OS:326.3. Found: 327.0 (M?).
Anal. Calc. for C18H15FN2OS: C, 66.24; H, 4.63; F, 5.82;
N, 8.58; O, 4.90; S, 9.82. Found: C, 66.21; H, 4.60; S, 9.80.
N-(4-(3-Chlorophenyl)thiazol-2-yl)-2-m-tolylacetamide
(9k)
1
Isolated yield 74 %, (white solid), m.p. 186–188 °C, H
NMR (400 MHz, DMSO-d6) d (ppm): 2.30 (s, 3H), 3.75 (s,
2H), 7.08 (d, J = 7.48 Hz, 1H), 7.14 (d, J = 7.72 Hz, 1H),
7.16 (s, 1H), 7.22 (t, J = 7.44 Hz, 1H), 7.37–7.40 (m, 1H),
7.47 (t, J = 7.84 Hz, 1H), 7.78 (s, 1H), 7.86–7.88 (m, 1H),
7.96 (t, J = 1.80 Hz, 1H).). 13C NMR (100 MHz, DMSO-
d6) d (ppm):21.43(C-23), 42.12(C-15), 110.06(C-5), 124.64
(C-14), 125.84(C-21), 126.78(C-10), 127.94(C-19),
127.97(C-12), 128.79(C-20), 130.31(C-13), 131.14(C-17),
134.05(C-9), 135.21(C-11), 136.75(C-16), 137.97(C-18),
147.67(C-4), 158.55(C-2), 170.06(C-7). IR(KBr, cm-1):
3,404 (N–H), 1,647 (C=O), 1,321 (C–N). MS calcd. For
C18H15ClN2OS 342.84. Found: 343.0. Anal. Calc. for
C18H15ClN2OS C, 63.06; H, 4.41; Cl, 10.34; N, 8.17; O,
4.67; S, 9.35. Found: C, 63.03; H, 4.39; S, 9.34.
2-(3,4-Dimethylphenoxy)-N-(4-(3-fluorophenyl)thiazol-2-
yl)acetamide (9i)
1
Isolated yield 79 %, (yellow solid), m.p. 158–159 °C, H
NMR (400 MHz, DMSO-d6) d (ppm): 2.12 (s, 3H), 2.17 (s,
3H), 4.81 (s, 2H), 6.66–0.00 (m, 1H), 6.79 (d, J = 2.48 Hz,
1H), 7.03 (d, J = 8.32 Hz, 1H), 7.14–7.19 (m, 1H),
7.45–7.50 (m, 1H), 7.69–7.72 (m, 1H), 7.76 (d,
J = 7.84 Hz, 1H), 7.79 (s, 1H), 12.50 (s, 1H). 13C NMR
(100 MHz, DMSO-d6) d (ppm):18.87(C-25), 20.09(C-24),
66.54(C-15), 110.22(C-5), 111.81(C-18), 112.59(C-12),
112.82(C-22) 115.08(C-10), 122.18(C-14), 129.25(C-20),
130.64(C-19), 131.22(C-13), 137.01(C-9), 137.09(C-21),
148.08(C-4), 157.92(C-17), 161.84(C-11), 164.26(C-2),
167.83(C-7). IR(KBr, cm-1): 3,469 (N–H) 1,697 (C=O),
1,352 (C–O–C), 1,249 (C–N). MS calcd. For
C19H17FN2O2S 356.41 Found: 357.0 (M?). Anal. Calc. for
C19H17FN2O2S C, 64.03; H, 4.81; F, 5.33; N, 7.86; O, 8.98;
S, 9.00. Found: C, 64.01; H, 4.79; S, 9.01.
N-(4-(3-Chlorophenyl)thiazol-2-yl)-2-(3-
methoxyphenyl)acetamide (9l)
1
Isolated yield 81 %, (white solid), m.p. 166–168 °C, H
NMR (400 MHz, DMSO-d6) d (ppm): 3.75 (s, 3H), 3.77 (s,
2H), 6.83–6.86 (m, 1H), 6.91 (s, 1H), 6.92–6.93 (m, 1H),
7.25 (t, J = 7.96 Hz, 1H), 7.37–7.39 (m, 1H), 7.47 (t,
J = 7.80 Hz, 1H), 7.78 (s, 1H), 7.85–7.88 (m, 1H), 7.96 (t,
J = 1.76 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) d
(ppm):42.20(C-15), 55.48(C-24), 110.08(C-5), 112.70(C-
17, C-19), 115.56(C-21), 121.91(C-14), 124.64(C-10),
125.84(C-12), 127.97(C-20), 129.91(C-13), 131.14(C-9),
134.05(C-11), 136.74(C-16), 147.68(C-4), 158.53(C-17),
158.73(C-2), 169.91(C-7). IR(KBr, cm-1): 3,406 (N–H),
1,651 (C=O), 1,321 (C–N). MS calcd. For C18H15ClN2O2S
358.84. Found: 359.0 (M?). Anal. Calc. for C18H15ClN2
O2S C, 60.25; H, 4.21; Cl, 9.88; N, 7.81; O, 8.92; S, 8.94.
Found: C, 60.23; H, 4.20; S, 8.91.
N-(4-(3-Chlorophenyl)thiazol-2-yl)-2-p-tolylacetamide (9j)
1
Isolated yield 76 %, (white solid), m.p. 194–196 °C, H
NMR (400 MHz, DMSO-d6) d (ppm): 2.26 (s, 3H), 3.73 (s,
2H), 7.13 (d, J = 7.84 Hz, 2H), 7.22 (d, J = 7.88 Hz, 2H),
7.37 (d, J = 7.96 Hz, 1H), 7.45 (t, J = 7.84 Hz, 1H), 7.76
(s, 1H), 7.85 (d, J = 7.72 Hz, 1H), 7.95 (s, 1H), 12.50 (s,
1H). 13C NMR (100 MHz, DMSO-d6) d (ppm):21.11
N-(4-(3-Chlorophenyl)thiazol-2-yl)-2-(3,4-
dimethylphenoxy)acetamide (9m)
Isolated yield 85 %, (pale yellow solid), m.p. 156–157 °C,
1H NMR (400 MHz, DMSO-d6) d (ppm): 2.13 (s, 3H), 2.18
(s, 3H), 4.82 (s, 2H), 6.68 (d, J = 5.96 Hz, 1H), 6.79 (s,
1H), 7.03 (d, J = 8.00 Hz, 1H), 7.38 (d, J = 7.32 Hz, 1H),
7.46 (t, J = 7.68 Hz, 1H), 7.81 (s, 1H), 7.87 (d,
J = 7.36 Hz, 1H), 7.96 (s, 1H), 12.49 (s, 1H). 13C NMR
(100 MHz, DMSO-d6) d (ppm):18.47(C-25), 19.68(CC-
24), 66.08(C-15), 109.89(C-5), 111.35(C-18), 116.06
(C-22), 124.25(C-14), 125.44(C-10), 127.61(C-12),
(C-23),
41.78(C-15),
110.04(C-5),
124.63(C-14),
125.84(C-10), 127.96(C-12), 129.44(C-18, C-20), 129.57
(C-17, C-21), 131.13(C-13), 132.27(C-16), 134.05(C-9),
136.38(C-11), 136.76(C-19), 147.66(C-4), 158.57(C-2),
170.19(C-7). IR(KBr, cm-1): 3,448 (N–H), 1,649 (C=O),
1,325 (C–N). MS calcd. For C18H15ClN2OS 342.84.
Found: 343.2. Anal. Calc. for C18H15ClN2OS C, 63.06; H,
123

Med Chem Res
128.82(C-20), 130.21(C-19), 130.74(C-13), 133.64(C-9),
136.24(C-11), 137.40(C-21), 147.33(C-4), 155.87(C-17),
157.55(C-2), 167.42(C-7). IR(KBr, cm-1): 3,155 (N–H),
1,627 (C=O), 1,381 (C–N). MS calcd. For C19H17ClN2O2S
372.87. Found: 373.2. Anal. Calc. for C19H17ClN2O2S C,
61.20; H, 4.60; Cl, 9.51; N, 7.51; O, 8.58; S, 8.60. Found:
C, 61.19; H, 4.58; S, 8.59.
129.90(C-18), 136.80(C-14), 144.02(C-4), 158.11(C-16),
159.71(C-2), 169.52(C-10), 170.95(C-7). MS calcd. For
C15H16N2O4S: 320.36. Found: 319.2 (M-), 321.0 (M?).
Anal. Calc. for C15H16N2O4S: C, 56.24; H, 5.03; N, 8.74;
O, 19.98; S, 10.01. Found: C, 56.22; H, 5.01; S, 10.01.
Antibacterial activity
Methyl 2-(2-(2-p-tolylacetamido)thiazol-4-yl)acetate (9n)
The newly synthesized thiazoles were screened for their
antibacterial activity against bacterial strains by disc dif-
fusion method. The discs measuring 6.25 mm in diameter
were punched from Whatman No. 1 filter paper. Batches of
100 discs were dispensed to each screw-capped bottle sand
sterilized by dry heat at 140 °C for an hour. The test
compounds were prepared with different concentrations
using dimethylformamide. 1 ml containing 100 times the
amount of chemical required in each disc was added to
each bottle which contains 100 discs. The discs of each
concentration were placed in triplicate in nutrient agar
medium seeded with fresh bacteria separately. The incu-
bation was carried out at 37.8 °C for 24 h. Ampicillin was
used as a standard drug. Solvent and growth controls were
kept. The zone of inhibition and MICs were noted. The
MIC values of tested compounds are given in Table 1.
Isolated yield 73 %, (pale yellow solid), m.p. 128–130 °C,
1H NMR (400 MHz, DMSO-d6) d (ppm): 2.27 (s, 3H), 3.61
(s, 3H), 3.68 (s, 2H), 3.70 (s, 2H), 6.97 (s, 1H), 7.13 (d,
J = 7.88 Hz, 2H), 7.20 (d, J = 8.00 Hz, 2H), 12.38 (bs,
1H). 13C NMR (100 MHz, DMSO-d6) d (ppm):20.68(C-
21), 36.52(C-9), 41.36(C-13), 51.76(C-12), 110.49(C-5),
129.00(C-15, C-19) 131.92(C-16, C-18), 135.92(C-14),
143.57(C-4), 157.73(C-2), 169.40(C-10), 170.52(C-7). MS
calcd. For C15H16N2O3S:304.36. Found: 303.2 (M-), 305.2
(M?). Anal. Calc. for C15H16N2O3S: C, 59.19; H, 5.30; N,
9.20; O, 15.77; S, 10.54. Found: C, 59.16; H, 5.28; S,
10.52.
Methyl 2-(2-(2-m-tolylacetamido)thiazol-4-yl)acetate (9o)
Isolated yield 71 %, (pale yellow solid), m.p. 116–118 °C,
1H NMR (400 MHz, DMSO-d6) d (ppm): 2.28 (s, 3H), 3.61
(s, 3H), 3.69 (s, 2H), 3.71 (s, 2H), 6.97 (s, 1H), 7.06 (d,
J = 7.48 Hz, 1H), 7.12 (d, J = 7.72 Hz, 1H), 7.14 (s, 1H),
7.21 (t, J = 7.48 Hz, 1H), 12.40 (bs, 1H). 13C NMR
(100 MHz, DMSO-d6) d (ppm):21.41(C-21), 36.39(C-9),
42.14(C-13), 52.17(C-12), 110.93(C-5), 126.72(C-19),
127.90(C-17), 128.77(C-18), 130.26(C-15), 135.29(C-14),
137.96(C-16), 144.01(C-4), 158.14(C-2), 169.71(C-10),
170.95(C-7). MS calcd. For C15H16N2O3S:304.36. Found:
303.2 (M-), 305.2 (M?). Anal. Calc. for C15H16N2O3S: C,
59.19; H, 5.30; N, 9.20; O, 15.77; S, 10.54. Found: C,
59.17; H, 5.29; S, 10.51.
Antifungal activity
Antifungal activity for newly prepared compounds was
screened by serial plate dilution method. Sabouraud agar
media was prepared by dissolving peptone (1 g), D-glucose
(4 g) and agar (2 g) in distilled water (100 ml) and
adjusting the pH to 5.7. Normal saline was used to make a
suspension of spores of fungal strain for lawning. A loopful
of particular fungal strain was transferred to 3 ml saline to
get a suspension of corresponding species. A 20 ml of agar
media was poured into each of the petri dishes. Excess of
suspension was decanted and the plates were dried by
placing in an incubator at 37 °C for 1 h. Using an agar
punch, wells were made on these seeded agar plates and
10 lg/ml of the test compounds in DMSO was added into
each well labelled. A control was also prepared for the
plates in the same way using solvent DMSO. The petri dish
was prepared in triplicate and maintained at 37 °C for
3–4 days. Antifungal activity was determined by measur-
ing the diameter of the inhibition zone. Activity of each
compound was compared with itraconazole as standard.
The MIC for the itraconazole in DMSO was more than
1 lg/ml against the tested species. The MIC values of
tested compounds are given in Table 2.
Methyl 2-(2-(2-(3-methoxyphenyl)acetamido)thiazol-4-
yl)acetate (9p)
Isolated yield 68 %, (pale yellow solid), m.p. 128–129 °C,
1H NMR (400 MHz, DMSO-d6) d (ppm): 3.61 (s, 3H), 3.69
(s, 2H), 3.70 (s, 2H), 3.74 (s, 3H), 6.82–6.84 (m, 1H), 6.88
(s, 1H), 6.89–6.90 (m, 1H), 24,200.49 (t, J = 7.84 Hz, 1H),
12.40 (s, 1H). 13C NMR (100 MHz, DMSO-d6) d (ppm):
36.94(C-9), 42.23(C-13), 52.18(C-12), 55.45(C-22),
110.96(C-5), 112.66(C-17), 115.49(C-15), 121.84(C-19),
123

Med Chem Res
Table 1 Antibacterial activity of the compounds 9a–9p (MIC in lg/ml)
Compound
R2
R3
Staphylococcus
aureus
(ATTC-25923)
Escherichia
coli
(ATTC-25922)
Pseudomonas
aeruginosa
(ATTC-27853)
Klebsiella
pneumonia
(recultured)
9a
9b
9c
9d
9e
9f
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
12.5
6.25
6.25
12.5
6.25
R
6.25
12.5
R
12.5
6.25
12.5
R
R
12.5
R
O
R
R
O
12.5
12.5
R
6.25
R
12.5
6.25
R
O2N
F
F
9g
9h
9i
12.5
R
100
100
R
100
6.25
R
100
12.5
R
F
O
R
Cl
Cl
Cl
Cl
9j
12.5
6.25
R
6.25
R
9k
9l
R
R
12.5
12.5
100 lg/ml
12.5
R
12.5
12.5
100 lg/ml
12.5
O
O
9m
9n
9o
6.25
R
6.25
100 lg/ml
6.25
O
O
O
O
O
12.5
9p
12.5
R
R
12.5
O
O
Ampicillin
\6.25
\6.25
\6.25
\6.25
123

Med Chem Res
Table 2 Antifungal activity of the compounds 9a–9p (MIC in lg/ml)
Compound
R2
R3
Penicillium
marneffei
(Recultured)
Trichophyton
mentagrophytes
(Recultured)
Aspergillus
flavus
(NCIM No. 524)
Aspergillus
fumigatus
(NCIM No. 902)
9a
9b
9c
9d
9e
9f
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
12.5
12.5
6.25
12.5
12.5
12.5
6.25
R
12.5
12.5
R
12.5
12.5
12.5
6.25
R
12.5
12.5
R
O
6.25
R
R
O
12.5
R
12.5
R
R
O2N
F
F
9g
9h
9i
12.5
6.25
100
6.25
R
12.5
R
R
F
O
100
6.25
R
Cl
9j
12.5
12.5
Cl
Cl
Cl
9k
9l
12.5
12.5
6.25
12.5
12.5
12.5
R
6.25
6.25
12.5
6.25
12.5
6.25
R
O
O
9m
9n
9o
R
R
O
12.5
R
12.5
R
O
O
O
O
O
9p
6.25
12.5
12.5
6.25
O
Itraconazole
\6.25
\6.25
\6.25
\6.25
123

Med Chem Res
Acknowledgments ASP thanks UOM for research facilities.
2-hydroxybenzamide and their 2-alkoxy derivatives as possible
antifungal agents. Eur J Med Chem 39:867–872
Ning X, Yunxin B, Elizabeth MD, Christopher F, Narender RG,
Nianhe H, Randall WH, Lana K, Qingyian L, Rami T, Shimin X,
James JST, Mark HN (2005) Synthesis and evaluation of
thiazole carboxamides as vanilloid receptor 1 (TRPV1). Bioorg
Med Chem Lett 15:5211–5217
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