Design, synthesis of some new (2-aminothiazol-4-yl)methylester derivatives as possible antimicrobial and antitubercular agents

Article abstract of DOI:10.1016/j.ejmech.2012.01.008

A series of (2-aminothiazol-4-yl)methylester (5a-t) derivatives were synthesized in good yields and characterized by ¹H NMR, ¹³C NMR, mass spectral and elemental analyses. The crystal structure of 5a was evidenced by X-ray diffractio

Full text of DOI:10.1016/j.ejmech.2012.01.008

European Journal of Medicinal Chemistry 49 (2012) 172e182
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis of some new (2-aminothiazol-4-yl)methylester derivatives
as possible antimicrobial and antitubercular agents
,
b
b
a
Ranjith P. Karuvalam a, Karickal R. Haridas a , Susanta K. Nayak , Tayur N. Guru Row , P. Rajeesh ,
*
R. Rishikesan c, N. Suchetha Kumari d
a School of Chemical Sciences, Kannur University, Payyanur Campus, Edat P.O. 670327, Kannur, Kerala, India
b Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India
c Department of Chemistry, PG and Research Centre, Sri Paramakalyani College, Alwarkurichi, Tirunelveli 627412, Tamil Nadu, India
d Department of Biochemistry, Justice K.S. Hegde Medical Academy, Deralakatte, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of (2-aminothiazol-4-yl)methylester (5aet) derivatives were synthesized in good yields and
characterized by 1H NMR, 13C NMR, mass spectral and elemental analyses. The crystal structure of 5a was
evidenced by X-ray diffraction study. The compounds were evaluated for their preliminary in vitro
antibacterial, antifungal activity and were screened for antitubercular activity against Mycobacterium
tuberculosis H37Rv strain. The synthesized compounds displayed interesting antimicrobial activity.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Received 12 October 2011
Received in revised form
25 December 2011
Accepted 5 January 2012
Available online 12 January 2012
Keywords:
Thiazole
Antibacterial activity
Antifungal activity
Antimycobacterial
X-ray crystallography
1. Introduction
pharmaceuticals. Recently many natural products containing thia-
zole moiety were isolated and most of them exhibit considerable
Tuberculosis (TB) is an infectious disease. It affects lung and
other parts of body which leads to death of almost 3 million people
each year and it is positioned as the leading bacterial infectious
agent [1,2]. Among pharmacologically important heterocyclic
compounds, thiazole and its derivatives have been well known in
pharmaceutical chemistry because of their wide spectrum of bio-
logical activities [3,4] and their presence in naturally occurring
compounds e.g. antibiotic like penicillin, cephalosporin, micro-
coccin, vitamin B1. A major challenge of modern drug discovery is
the design of highly efficient chemical reaction sequences which
provide a maximum of the structural complexity and biological
diversity with just a minimum number of synthetic steps to
assemble compounds with interesting properties. Thiazole and its
derivatives are found to be associated with various biological
activities such as antibacterial, antifungal and anti-inflammatory
activities [5e7]. Different thiazole bearing compounds possess
anti-inflammatory activities [8] and some are known to be used as
cytotoxicities and anti tumor potentials [9e12] and also find
applications in the drug development for the treatment of allergies
[13], hypertension [14], inflammation [15], schizophrenia [16],
hypnotics [17], and for the treatment of pain [18], and HIV infec-
tions [19]. And more over being investigated for the other appli-
cations such as liquid crystals [20], and molecular diodes [21], the
interest in substituted thiazole with reactive functionalities resides
also in their synthetic potential as building blocks for natural
product synthesis [22e24]. Synthetic thiazoles offer the opportu-
nity to increase the structural diversity of natural thiazole
substrates. Thiazole core displayed a broad range of biological
activities and are found in many biologically relevant molecules
such as Sulfathiazole (antimicrobial drug), Ritonavir (antiretroviral
drug), Abafungin (antifungal drug). Thiazole derivatives were re-
ported to possess antidegenerative activity and coupling with other
aromatic ring system forms new biological active compounds [25].
The present study highlights the recently synthesized thiazoles
possessing important biological activities. In this communication,
we describe the synthesis of (2-aminothiazol-4-yl)methylester
(5aet) derivatives and evaluation of their in vitro antibacterial
activity against five strains, viz. Staphylococcus aureus, Bacillus
* Corresponding author. Tel./fax: þ91 497 2806402.
E-mail address: krharidas2001@yahoo.com (K.R. Haridas).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.01.008

R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
173
subtilis, Pseudomonas aeruginosa, Klebsiella pneumoniae and
Escherichia coli and in vitro antifungal activity against five strains,
viz. Aspergillus flavus, Aspergillus fumigatus, Penicillium marneffei,
Trichophyton mentagrophytes and Candida albicans. In addition, the
antituberculosis activity against Mycobacterium tuberculosis H37Rv
ATCC 27294, and non-tubercular mycobacterial (NTM) species like
Mycobacterium smegmatis (MC2) ATCC 19420, Mycobacterium for-
tuitum ATCC 19542 and MDR-TB strains were also carried out.
As a part of our research work on the development of useful
synthetic molecules [26], it has been planned to introduce active
was synthesized by coupling the intermediate 3 with different
substituted aryl/heteroaryl acids in presence of 1-(3-
dimethylaminopropyl)3-ethylcarbodiimide. HCl (EDC$HCl) and
dimethylaminopyridine (DMAP) in dichloromethane. The title
compounds 5aet synthesized by deprotecting the BOC anhydride
using ethanolic HCl in ethanol at ambient temperature.
The newly synthesized compounds were characterized by 1H
NMR, 13C NMR, LCMS and elemental analysis. The formation of
ethyl-2-aminothiazole-4-carboxylate (1) was confirmed by its 1H
NMR spectrum, where the appearance of a singlet peak at
aryl/heteroaryl methylester at the position
4
of potent 2-
d 7.46 ppm indicated the presence of aromatic hydrogen and the
aminosubstituted thiazole moiety using different aryl/heteroaryl
acids having active groups like fluoro, trifluoro, nitro, methoxy etc
at the ring. It has been hoped that the combination of these active
groups in the new molecular design would lead to better antimi-
crobial agents. In this communication, we report the synthesis of
newly designed (2-aminothiazol-4-yl)methylester derivatives
5(aet) (Scheme 1) starting from thiourea and evaluated these
compounds for the antimicrobial and antitubercular activities. In
addition, we report here the single crystal X-ray study of 5a to
understand its conformational feature and supramolecular
assembly. It helps in understanding the exact 3D structure of the
molecule which would help in further understanding the mecha-
nism of action of the drug and also in docking studies with various
receptors.
primary amine which disappeared on D2O exchange. The formation
of BOC protected derivative (2) was confirmed by its 1H NMR
spectrum. In its spectrum the disappearance of a broad peak at
d
7.23 ppm and the appearance of a singlet peak at higher
d value,
i.e.; at 11.80 ppm and was also evidenced by LCMS spectral data.
d
The formation of primary alcohol derivative was confirmed by its
1H NMR spectrum. In its spectrum appearance of a singlet at
d
6.84 ppm (eOH) and a doublet at d 4.4 ppm (eCH2). The formation
of (3) was also evidenced by LCMS spectral data. The spectral data is
discussed in the Experimental section. The characterization data of
5aet are tabulated in Table 1.
2.1. Structure activity relationship
In this present study we have mainly concentrated at the region
2 of the synthesized molecules (Fig. 3). It is believed that strong
lipophilic character of the molecule plays an essential role in
introducing biological effect [29]. These properties are seen as an
important parameter related to membrane permeation in biolog-
ical system. It has been well established that the fluorinated, in
particular CF3 substituted molecules have got a significant place in
modern medicinal chemistry [30]. Variety of substituted aryl
groups have been attached at region 2. For example, result showed
that compound 5b displayed good activity, one of the reasons could
be the presence of CF3 group attached to the aryl ring (region 2)
increases the lypophilicity of the compound there by making the
molecule more cell permeable. Similarly compounds with chloro,
fluoro, nitro substitution at the phenyl ring were found to be more
2. Results and discussion
The title compounds were synthesized by a series of reaction as
shown in the Scheme 1. The intermediate ethyl-2-aminothiazole-4-
carboxylate (1) was synthesized by cyclizing ethyl bromopyruvate
and thiourea in ethanol at 90 ꢀC [27,28]. The intermediate 1 was
then
converted
to
tert-butyl-4-(ethoxycarbonyl)thiazol-2-
carbamate (2) by treating with di-tert-butyldicarbonate (BOC
anhydride) and triethylamine in tetrahydrofuran at ambient
temperature. The required key intermediate tert-butyl-4-(hydrox-
ymethyl)thiazol-2-ylcarbamate (3) was obtained by reducing the
ester to a primary alcohol using diisobutylaluminiumhydride
(DIBAL-H) in dichloromethane at ꢁ78 ꢀC for 10 h. Compound 4aet
O
O
S
H3C
N
O
+
H3C
O
Br
H2N
NH2
A
NH2
O
S
1
O
N
H3C
N
S
HO
O
C
NHBOC
NHBOC
B
S
3
2
O
O
R
N
R
N
S
O
O
E
D
NHBOC
NH2
4(a-t)
S
(5a-t)
Scheme 1. (2-Aminothiazol-4-yl)methylester derivatives (A) Ethanol, 90 ꢀC,
4
h. (B) Tetrahydrofuran, triethylamine, di-tert-butyldicarbonate, 5 h, (C) Dichloromethane,
Diisobutylaluminiumhydride, ꢁ78 ꢀC, 10 h. (D) Dichloromethane, 1-(3-dimethylaminopropyl)3-ethylcarbodiimide. HCl, dimethylaminopyridine, RCOOH, room temperature, 8 h. (E)
Ethanol, ethanolic HCl, room temperature.

174
R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
Table 1 (continued)
Table 1
Characterization data of (2-aminothiazol-4-yl)methylester derivatives 5(aet)
Compound
R
Mol. Formula/
Mol wt
M.p.ꢀC
Yield *
(%)
O
Cl
N
R
O
C11H8ClFN2O2S
286.71
5j
110e112 81
H2N
F
S
F
F
C11H7F3N2O2S
288.25
Compound
R
Mol. Formula/
Mol wt
M.p.ꢀC
Yield *
(%)
5k
ND
68
F
C14H13ClN2O2S
308.78
5a
213e215 84
Cl
O
C9H8N2O3S
224.24
5l
183e185 78
157e159 68
C13H11F3N2O2S
316.3
5b
5c
ND
89
F3C
C15H12N2O2S
284.33
5m
OCF3
C13H11F3N2O3S
332.3
178e180 85
230e232 80
C11H9N2O2S
279.27
5n
5o
160e162 85
O2N
Cl
Cl
C12H8F4N2O2S
320.26
5d
F3C
C11H7Cl3N2O2S
337.61
ND
62
F
Cl
C14H13N3O2S
287.34
5e
5f
165e167 90
235e237 72
C11H10N2O2S
234.27
5p
5q
174e176 84
185e187 80
N
N
C11H10N2O2S
260.27
C12H9N3O2S
259.28
N
N
C11H9ClN2O2S
268.72
5r
171e173 76
S
Cl
Br
C9H8N2O2S2
240.3
5g
5h
192e194 63
150e152 68
C11H9BrN2O2S
313.17
5s
5t
163e165 72
166e168 82
C11H8ClN3O4S
313.72
O2N
Cl
C11H9N3O4S
279.27
N
5i
C11H8N4O2S 260.27 178e180 62
NO2
N
ND-Not detected, * Isolated yield after column purification.

R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
175
active (5d, 5h, 5j, 5n, 5r, 5t) than the compound with no substi-
tution at the phenyl ring (5p) at the region 2 of the molecule.
Further we have tried with different carboxylic acids with mono, di,
tri substituted electron withdrawing substituent at the phenyl ring.
The biological results indicated that the compound with electron
withdrawing group at the phenyl ring at the region 2 of the
molecule were more active. Furthermore some of the heterocyclic
substitutions (5i, 5l, 5g) at R of the region 2 were found to be active.
The weak activity of some of our compounds may be attributed to
the presence of certain functional groups in the molecule.
of in vitro antimycobacterial activity of the final compounds are
tabulated in Table 4.
2.3. X-ray crystallographic study of compound 5a
Single crystal X-ray diffraction study has carried out on the
intermediate 5a to understand the nature of its conformational
and molecular assembly. 5a forms colorless block shaped crystal
from ethanol solvents by slow evaporation method at room
temperature. Single crystal data of 5a were recollected on CrysAlis
CCD Xcalibur, Eos (Nova), Oxford Diffraction with X-ray generator
operating at 50 kV and 1 mA, using MoKa radiation (
l
¼ 0.7107 Å).
2.2. Biological activity
The structures were solved and refined by using SHELXL97 [31],
using the program suite WinGX. Thermal ellipsoid plot and
packing diagram were generated using ORTEP-3 [32] and Mercury
respectively. All the non hydrogen atoms were located in differ-
ence Fourier maps and were refined anisotropically, and hydrogen
atoms were fixed geometrically and refined isotropically. The
crystal structure of 5a is P 21/n space group in monoclinic space
group. Crystallographic information file (CIF) is provided as sup-
porting information file for the details crystallographic informa-
tion. Fig. 1 provides the thermal ellipsoid plot with atom
numbering which shows the keto group preferred the conforma-
tion anti to 4-chlorophenyl group and cis to cyclopropane ring. The
molecular assembly form dimer through NeH/N (2.09 Å, 174ꢀ)
hydrogen bonds and NeH/O (2.03 Å, 171ꢀ) hydrogen bond chain
links the dimer (Fig. 2).
All the title compounds were subjected to in vitro antibacterial,
antifungal and antitubercular properties following standard
methods.
2.2.1. Antibacterial activity
Antibacterial activity of the title compounds was investigated
against five different bacterial strains, S. aureus, B. subtilis, P. aeru-
ginosa, K. pneumoniae and E. coli using ciprofloxacin as reference, by
serial dilution method. Table 2 depicts the antibacterial screening
results (MIC mg/mL) of final compounds, 5aet.
2.2.2. Antifungal activity
Antifungal activity of the title compounds were investigated
against five different strains, A. flavus, A. fumigatus, P. marneffei
(recultured), T. mentagrophytes (recultured) and C. albicans using
Ciclopiroxolamine as reference, by serial dilution method. Table 3
2.4. Biological results
depicts the antifungal screening results (MIC
mg/mL) of final
compounds, 5aet.
The investigation of antibacterial screening (Table 2) revealed
that all the newly synthesizes compounds showed moderate to
2.2.3. Antitubercular study
good inhibition at 1.56e25 mg/mL in DMSO. Compounds 5b, 5e, 5f,
Based on the encouraging results from the antibacterial
screening, title compounds were further tested for their in vitro
antimycobacterial activity against M. tuberculosis H37Rv, M. smeg-
matis (ATCC 19420), M. fortuitum (ATCC 19542) and MDR-TB strains
using isoniazid and rifampicin as standards. The screening results
5g, 5i, 5k, 5l, 5m and 5r showed good activity against E. coli and P.
aeruginosa. Compounds 5b, 5e, 5i, 5j, 5l, 5m, 5o, 5p and 5r showed
good activity against S. aureus and B. subtilis. Compounds 5a, 5h, 5i,
5l, 5m, 5n, 5p, 5r, 5s and 5t showed good activity against K.
pneumoniae.
Table 2
Antibacterial activity data of (2-aminothiazol-4-yl)methylester derivatives 5(aet).
Compound
MIC in
m
g/mL and zone of inhibition in mm
E. coli
S. aureus
P. aeruginosa
B. subtilis
K. pneumoniae
ATCC 25922
ATCC 25923
ATCC 27853
(recultured)
(recultured)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
6.25(16e20)
6.25(16e20)
12.5(11e15)
25(<10)
6.25(16e20)
6.25(16e20)
6.25(16e20)
12.5(11e15)
6.25(16e20)
25(<10)
6.25(16e20)
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)
6.25(16e20)
6.25(16e20)
25(<10)
6.25(16e20)
6.25(16e20)
25(<10)
12.5(11e15)
6.25(16e20)
25(<10)
12.5(11e15)
6.25(16e20)
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)
12.5(11e15)
6.25(16e20)
12.5(11e15)
12.5(11e15)
6.25(16e20)
25(<10)
6.25(16e20)
12.5(11e15)
25(<10)
25(<10)
12.5(11e15)
12.5(11e15)
25(<10)
6.25(16e20)
6.25(16e20)
12.5(11e15)
25(<10)
6.25(16e20)
6.25(16e20)
6.25(16e20)
12.5(11e15)
6.25(16e20)
25(<10)
6.25(16e20)
6.25(16e20)
6.25(16e20)
6.25(23e27)
25(<10)
12.5(11e15)
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)
25(<10)
25(<10))
25(<10)
6.25(16e20)
25(<10)
25(<10)
5q
5r
5s
5t
12.5(11e15)
6.25(16e20)
25(<10)
12.5(11e15)
6.25(30e40)
6.25(16e20)
25(<10)
12.5(11e15)
6.25(22e30)
6.25(16e20)
25(<10))
12.5(11e15)
1.56(21)
Ciprofloxacin (Standard)
6.25(16e20)
Note: MIC values were evaluated at concentration ranging between 1.56 and 25
inhibition in mm inside the bracket. MIC (
m
g/mL. The figures in the table show the MIC values in
m
g/mL and corresponding zone of
m
g/mL) ¼ minimum inhibitory concentration, i.e., lowest concentration to completely inhibit bacterial growth.

176
R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
Table 3
Antifungal activity data of (2-aminothiazol-4-yl)methylester derivatives 5(aet).
Compound
MIC in ug/mL and zone of inhibition in mm
A. flavus
A. fumigatus
P. marneffei
T. mentagrophytes
C. albicans
(NCIM No. 524)
(NCIM No. 902)
(recultured)
(recultured)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
25(<10)
12.5(11e15)
6.25(16e20)
6.25(16e20)
6.25(16e20)
12.5(11e15)
25(<10)
25(<10)
25(<10)
25(<10)
6.25(16e20)
6.25(16e20)
12.5(11e15)
6.25(16e20)
6.25(16e20)
25(<10)
25(<10)
12.5(11e15)
6.25(16e20)
6.25(16e20)
25(<10)
12.5(11e15)
6.25(16e20)
25(<10)
6.25(16e20)
25(<10)
6.25(16e20)
25(<10)
25(<10)
25(<10)
6.25(16e20)
6.25(16e20)
6.25(16e20)
25(<10)
25(<10)
12.5(11e15)
25(<10)
25(<10)
12.5(11e15)
6.25(16e20)
6.25(16e20)
25(<10)
25(<10)
6.25(16e20)
25(<10)
6.25(16e20)
25(<10)
6.25(16e20)
25(<10)
12.5(11e15)
6.25(16e20)
6.25(16e20)
25(<10)
25(<10)
25(<10)
6.25(16e20)
6.25(16e20)
12.5(11e15)
6.25(16e20)
12.5(11e15)
25(<10)
25(<10)
25(<10)
12.5(11e15)
6.25(16e20)
6.25(16e20)
6.25(16e20)
6.25(16e20)
6.25(16e20)
25(<10)
6.25(16e20)
6.25(16e20)
12.5(11e15)
6.25(16e20)
6.25(16e20)
25(<10)
12.5(11e15)
6.25(16e20)
6.25(16e20)
25(<10)
5q
5r
5s
5t
6.25(16e20)
25(<10)
25(<10)
25(<10)
6.25(25e30)
12.5(11e15)
6.25(16e20)
25(<10)
25(<10)
6.25(25e30)
6.25(16e20)
25(<10)
25(<10)
12.5(11e15)
6.25(20e27)
12.5(11e15)
6.25(16e20)
12.5(11e15)
25(<10)
25(<10)
25(<10)
6.25(16e20)
25(<10)
6.25(20)
Ciclopiroxolamine
(Standard)
6.25(27e33)
Note: MIC values were evaluated at concentration ranging between 6.25 and 100
inhibition in mm inside the bracket. MIC (
m
g/mL. The figures in the table show the MIC values in
m
g/mL and corresponding zone of
m
g/mL) ¼ minimum inhibitory concentration, i.e., lowest concentration to completely inhibit bacterial growth.
The investigation of antifungal screening (Table 3) revealed
that all the newly synthesizes compounds showed moderate
antimycobacterial screening of the title compounds were carried
out at 1, 10 and 100 g/mL concentrations against three different
m
to good inhibition at 1.56e25
m
g/mL in DMSO. Compounds
TB strains and also against MDR-TB strain. From the result, it was
5cee, 5k, 5l, 5n, 5o and 5q showed good activity against A.
flavus and P. marneffei. Compounds 5c, 5d, 5g, 5i, 5k, 5n, 5o and
5r showed good activity against T. mentagrophytes and A. fumiga-
tus. Compounds 5c, 5d, 5f, 5k, 5l, 5m, 5n, 5o and 5s showed
good activity against C. albicans. Further, the preliminary
noticed that the compounds 5aee, 5g, 5h, 5j, 5k, 5meo, 5q, 5s and
5t were active between 1 and 10 mg/mL concentrations against M.
tuberculosis H37Rv strain. The active compounds from the
preliminary investigation were further subjected to second level
of testing. The compounds which were active at 100
mg/mL
Table 4
Antitubercular activity data of (2-aminothiazol-4-yl)methylester derivatives 5(aet).
Preliminary in vitro screening results, MIC(
m
g/mL)
Second level screening results, MIC(
m
g/mL)
MF
d
Compound
MTBa
MSb
MFc
10
10
>100
10
10
>100
10
10
>100
10
>100
>100
10
%
MTB
MS
MDR-TB
5a
5b
1
1
1
90
95
<90
90
1.25
0.625
5
1.25
10
e
1.25
10
e
>50
6.25
>50
>50
6.25
>50
>50
6.25
e
10
>100
>100
1
5c
5d
5e
10
1
1
1.25
0.625
5
e
10
10
e
95
1.25
e
5f
5g
10
10
>100
10
<90
<90
90
10
0.625
e
10
1.25
e
10
10
e
5h
1
1
5i
5j
>100
1
>100
10
0
95
<90
0
<90
90
<90
0
<90
0
<90
95
95
95
0.625
5
10
10
e
10
e
6.25
25
5k
10
10
5l
5m
>100
10
>100
10
e
e
e
2.5
1.25
10
10
10
e
10
10
e
>50
1.25
>50
e
5n
1
10
10
5o
5p
5q
5r
10
>100
10
>100
10
>100
>100
>100
>100
10
>100
>100
>100
>100
>100
10
e
e
e
10
e
e
>50
e
e
e
e
5s
2.5
0.625
0.7
0.5
2.5
10
50
1.5
e
2.5
5t
1
10
50
1.5
10
12.5
1.5
12.5
12.5
25
Isoniazid
Rifampicin
0.7
0.5
12.5
1.5
a
Mycobacterium tuberculosis H37Rv.
Mycobacterium smegmatis (ATCC 19420).
Mycobacterium fortuitum (ATCC 19542).
b
c
d
Percentage of inhibition against M. tuberculosis H37Rv; ‘e’ Not detected.

R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
177
O
R
O
N
Region 2
H2N
S
Region 1
Fig. 3. Selected regions of interest for structure activity relationship.
6.25
and 5j showed promising activity against the MDR-TB strain at
6.25 g/mL. These are just initial screening results to check the
mg/mL concentrations. Similarly the compounds 5b, 5e, 5h
m
antimicrobial potential, since this is established and further work
would be done to understand their mechanism of action.
3. Conclusion
Fig. 1. ORTEP diagram of 5a with 30% thermal ellipsoid plot for non hydrogen atoms
with the atom labeling and hydrogen atoms as open circle.
We herein report the successful synthesis of twenty newly
designed derivatives of (2-aminothiazol-4-yl)methylester. They
have been characterized by spectral studies. The structure of 5a has
been confirmed by X-ray crystallographic study. All the title
compounds have been investigated for their antimicrobial and
antimycobacterial activities, the investigation of antibacterial and
antifungal screening revealed that all the newly synthesizes
concentration were not taken for further studies. The second level
testing was carried out at concentrations 0.3125, 0.625, 1.25, 2.5,
and 5
are active at 0.625
H37Rv strain and compounds 5a, 5d and 5n are active at 1.25
mL concentrations. Similarly the target molecules 5a, 5e and 5h
displayed significant activity at 1.25 g/mL against M. smegmatis
(ATCC 19420) whereas compound 5s is active at 2.5 g/mL. It is
m
g/mL. Amongst the tested compounds, 5b, 5e, 5h, 5j and 5t
g/mL concentrations against M. tuberculosis
g/
m
compounds showed moderate to good inhibition at 1.56e25 mg/mL
m
in DMSO. Compounds 5b, 5e, 5i, 5l, 5m and 5r exhibited compar-
atively good activity against the tested bacterial strains.
Compounds 5c, 5d, 5k, 5n and 5o exhibited comparatively good
activity against the five fungal strains. Further, the compounds 5b,
5e, 5h, 5j and 5t displayed significant activity against M. tubercu-
losis H37Rv strain. Furthermore, the target molecules 5a, 5e and 5h
m
m
interesting to note that most of the compounds showed either
enhanced activity or activity in line with the reference compound
isoniazid against M. fortuitum (ATCC 19542). Further, the
compounds 5b, 5h displayed substantial activity against the MDR-
displayed significant activity at 1.25
(ATCC 19420) whereas compound 5s was shown to be active at
2.5 g/mL. Similarly the compounds 5b, 5e, 5h and 5j showed
substantial activity against the MDR-TB strain at 6.25 g/mL. The
mg/mL against M. smegmatis
TB strain at 12.5 mg/mL whereas 5e exhibited promising activity at
m
m
halogen substituted aromatic compounds will improve the lipo-
philic nature of the compound at the same time methoxy
substituted compound would act as an electron donors. In addition
the presence of an amine group at the 2nd position of thiazole
would be the essential element for hydrogen bonding with
receptor. The above mentioned properties of these pharmaco-
phores would be responsible for the promising activities of the title
compounds. The scaffold synthesized in the research work can be
taken for further derivatization in order to find the lead in these
series.
4. Experimental
4.1. General
All reagents were purchased from Aldrich. Solvents used were
extra dried. TLC experiments were performed on alumina backed
silica gel 40 F254 plates (Merck, Darmstadt, Germany). The plates
were illuminated under UV (254 nm) and molybdic acid. All 1H and
13C NMR spectra were recorded on a Bruker AM-300 (300.12 MHz)
and AM-400 (400.13 MHz), Bruker Biospin Corp., Germany.
Molecular weights of unknown compounds were checked by LCMS
6200 series Agilent Technology. Chemical shifts are reported in
Fig. 2. Molecular assembly through hydrogen bonds of NeH/N dimer and NeH/O
chains along a-axis.

178
R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
ppm (
d
) with reference to internal standard TMS. The signals are
1H, ArH); 13C
d
ppm (DMSO) ¼ 28.36, 60.32, 81.40, 107.57, 153.06,
designated as follows: s, singlet; d, doublet; t, triplet; m, multiplet.
153.24, 159.88; LC/MS(ESI-MS)m/z ¼ 231.29 (M þ 1); Anal. Calcd
for C9H14N2O3S; C, 46.94; H, 6.13; N, 12.16; Found C, 47.01; H,
6.27; N, 12.12.
4.2. Procedure for the preparation of ethyl-2-aminothiazole-4-
carboxylate (1)
Thiourea (12.93 g, 0.170 mol) was taken in a round bottom flask
and charged ethanol (45 mL), stirred for 10 min, slowly added ethyl
bromopyruvate (19.36 mL, 0.155 mol). The reaction mass was
heated to 90 ꢀC for 4 h. Reaction completion was monitored by TLC.
Reaction was complete. The reaction mass was filtered and the
ethanol layer was concentrated under reduced pressure to give
a pale yellow solid. The crude product was recrystallized in ethyl-
acetate/hexane to afford (1) (23.58 g, 90%) an off white solid.
4.5. General procedure for the preparation of (4aet)
The intermediate (3) (0.5 g, 0.00217 mol), EDCl (0.622 g,
0.00325 mol), DMAP (0.345 g, 0.0028 mol) were stirred in dichloro-
methane (6 mL) at 0 ꢀC, and the substituted acid (0.00217 mol) were
dissolved in (4 mL) of dichloromethane and charged to the reaction
mixture and stirred at room temperature for 8 h. The reaction
completion was monitored by TLC. Reaction was completed. The
reaction mixture was diluted with (10 mL) of dichloromethane, and
was washed with 10% NaHCO3 (10 mL). Separated the organic layer
and was washed with saturated brine solution (10 mL). The organic
layer was dried over sodium sulfate and concentrated the organic
layer under reduced pressure to afford compounds 4aet. The spectral
data of compounds 4(aet) are given below.
M.p. ¼ 177e178 ꢀC; 1H NMR (DMSO)
ppm ¼ 1.26 (t, 3H, CH3), 4.21
d
(m, 2H, CH2), 7.23 (s, 2H, NH2), 7.46 (s, 1H, ArH); 1H NMR
(DMSOeD2O)
d
ppm ¼ 1.26 (t, 3H, CH3), 4.21 (m, 2H, CH2), 7.46 (s,
1H, ArH); LC/MS(ESI-MS)m/z ¼ 173.1 (M þ 1); Anal. Calcd for
C6H8N2O2S; C, 41.85; H, 4.68; N, 16.27; Found C, 41.94; H, 4.69; N,
16.50.
4.3. Procedure for the preparation of tert-butyl-4-(ethoxycarbonyl)
4.5.1. tert-Butyl 4-((1-(4-chlorophenyl)
thiazol-2-carbamate (2)
cyclopropanecarboxyloyloxy)methyl)thiazol-2-ylcarbamate (4a)
1H NMR (DMSO)
d
ppm ¼ 1.24 (t, 2H, cyclopropylCH2), 1.48 (s,
The intermediate ethyl-2-aminothiazole-4-carboxylate (20 g,
0.116 mol) in tetrahydrofuran (300 mL) was stirred for 5 min, cooled
the reaction mass to 0 ꢀC and charged triethylamine (48.54 mL,
0.348 mol), the added BOC anhydride (28.26mL, 0.123 mol) slowlyto
the reaction mixture, during the addition temperature was main-
tained at 0e10 ꢀC, after complete addition reaction temperature was
raised to ambient temperature and stirred for 5 h. Reaction
completion was monitored by TLC. Reaction was complete. The
reaction mass was filtered and the THF was concentrated under
reduced pressure. The crude obtained was dissolved in
ethylacetate (250 mL) and the organic layer was washed with
water (3ꢂ100 mL). The organic layer was dried over sodium
sulfate and concentrated under reduced pressure to afford (2)
(29 g, 91.6%) as an off white solid. M.p. ¼ 151e152 ꢀC; 1H NMR
9H, Boc), 1.53 (t, 2H, cyclopropylCH2), 4.98 (s, 2H, CH2), 6.93 (s, 1H,
ArH), 7.39 (s, 4H, ArH), 11.46 (s, 1H, NH); LC/MS(ESI-MS)m/
z ¼ 409.62 (M þ 1).
4.5.2. tert-Butyl 4-((2-(3-(trifluoromethyl)phenyl)acetoyloxy)
methyl)thiazol-2-ylcarbamate (4b)
1H NMR (DMSO)
d
ppm ¼ 1.49 (s, 9H, Boc), 3.80 (s, 2H, CH2), 5.04
(s, 2H, CH2), 7.12 (s, 1H, ArH), 7.51 (s, 1H, ArH), 7.65 (m, 3H, ArH),
11.48 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 317.51 (M þ 1).
4.5.3. tert-Butyl 4-((2-(2-(trifluoromethoxy)phenyl)acetoyloxy)
methyl)thiazol-2-ylcarbamate (4c)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 3.82 (s, 2H, CH2), 5.12
(s, 2H, CH2), 7.16 (s, 1H, ArH), 7.65 (t, 1H, ArH), 7.95 (t, 1H, ArH), 7.98
(d, 1H, ArH), 8.07 (d, 1H, ArH), 11.48 (s, 1H, NH); LC/MS(ESI-MS)m/
z ¼ 433.31 (M þ 1).
(DMSO)
d
ppm ¼ 1.26 (t, 3H, CH3),1.48 (s, 9H, BOC), 4.26 (m, 2H, CH2),
8.0 (s,1H, ArH),11.80 (s,1H, NH); LC/MS(ESI-MS)m/z ¼ 273.1 (M þ 1);
Anal. Calcd for C11H16N2O4S; C, 48.52; H, 5.92; N, 10.29; Found C,
48.64; H, 5.97 N, 10.38.
4.5.4. tert-Butyl 4-((3-fluoro-5-(trifluoromethyl)benzoyloxy)
methyl)thiazol-2-ylcarbamate (4d)
4.4. Procedure for the preparation of tert-butyl-4-(hydroxymethyl)
thiazol-2-ylcarbamate (3)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.32 (s, 2H, CH2), 7.29
(s, 1H, ArH), 8.08 (s, 1H, ArH), 8.10 (s, 1H, ArH), 11.51 (s, 1H, ArH),
13.81 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 421.19 (M þ 1).
The
intermediate
tert-butyl-4-(ethoxycarbonyl)thiazol-2-
ylcarbamate (2), (28 g, 0.102 mol) in dichloromethane (280 mL),
and the reaction mixture was cooled to ꢁ78 ꢀC, then slowly
charged DIBAL-H (82.51 mL, 0.463 mol) to the reaction mixture.
After the complete addition of DIBAL-H reaction temperature was
raised to ambient temperature and was stirred for 10 h. Reaction
completion was monitored by TLC. Reaction was complete. Then
cooled the reaction mass to 0 ꢀC, Charged MTBE (400 mL) very
slowly to the reaction mass followed by 0.5 N HCl (280 mL). The
reaction mass temperature was raised to ambient temperature
and stirred for an hour. The reaction mixture was filtered and the
organic layer was concentrated under reduced pressure. The
crude obtained was dissolved in ethylacetate (300 mL) and
washed the organic layer with water (3ꢂ100 mL). The organic
layer was concentrated and the crude product was purified by
flash chromatography on silica gel (230e400 mesh) using ethyl-
acetate (20e40%) in petroleum ether as eluent to afford (3) (18 g,
76%) as a white solid. M.p. 101e102 ꢀC; 1H NMR (DMSO)
4.5.5. tert-Butyl 4-((4-(2-cyanoethyl)benzoyloxy)methyl)thiazol-2-
ylcarbamate (4e)
1H NMR (DMSO)
d
ppm ¼ 1.49 (s, 9H, Boc), 2.78 (t, 2H, CH2), 2.96
(t, 2H, CH2), 5.28 (s, 2H, CH2), 7.23 (s, 1H, ArH), 7.53 (t, 1H, ArH), 7.74
(t, 1H, ArH), 7.94 (d, 1H, ArH), 8.01 (d, 1H, ArH), 11.51 (s, 1H, NH); LC/
MS(ESI-MS)m/z ¼ 388.62 (M þ 1).
4.5.6. tert-Butyl 4-((3-cyanobenzoyloxy)methyl)thiazol-2-
ylcarbamate (4f)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.14 (s, 2H, CH2), 7.28
(s,1H, ArH), 7.56 (d,1H, ArH), 7.75 (t,1H, ArH), 8.22 (t,1H, ArH), 8.25
(d, 1H, ArH), 11.52 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 360.27 (M þ 1).
4.5.7. tert-Butyl 4-((thiophene-2-carboxyloyloxy)methyl)thiazol-2-
ylcarbamate (4g)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.24 (s, 2H, CH2), 7.20
(s, 1H, ArH), 7.24 (d, 1H, ArH), 7.84 (t, 1H, ArH), 7.98 (d, 1H, ArH),
d
ppm ¼ 1.47 (s, 9H, BOC), 4.4 (d, 2H, CH2), 5.17 (t, 1H, OH), 6.80 (s,
11.52 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 341.31 (M þ 1).

R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
179
4.5.8. tert-Butyl 4-((2-chloro-3-nitrobenzoyloxy)methyl)thiazol-2-
4.5.19. tert-Butyl 4-((4-bromobenzoyloxy)methyl)thiazol-2-
ylcarbamate (4h)
ylcarbamate (4s)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.22 (s, 2H, CH2), 7.18
1H NMR (DMSO)
d
ppm ¼ 1.46 (s, 9H, Boc), 5.30 (s, 2H, CH2), 7.26
(s, 1H, ArH), 7.54 (t, 1H, ArH), 8.31 (d, 1H, ArH), 8.38 (d, 1H, ArH),
11.48 (s, 1H, NH).
(s, 1H, ArH), 8.22 (m, 2H, ArH), 8.31 (m, 2H, ArH), 11.49 (s, 1H, NH);
LC/MS(ESI-MS)m/z ¼ 414.3 (M þ 1).
4.5.9. tert-Butyl 4-((6-cyanopyridine-3-carboxyloyloxy)methyl)
4.5.20. tert-Butyl 4-((4-nitrobenzoyloxy)methyl)thiazol-2-
thiazol-2-ylcarbamate (4i)
ylcarbamate (4t)
1H NMR (DMSO)
d
ppm ¼ 1.46 (s, 9H, Boc), 5.18 (s, 2H, CH2), 7.20
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.32 (s, 2H, CH2),
(s, 1H, ArH), 8.52 (d, 1H, ArH), 8.82 (d, 1H, ArH), 9.64 (s, 1H, ArH),
7.28 (s, 1H, ArH), 7.59 (t, 1H, ArH), 7.67 (t, 1H, ArH), 8.28 (d, 1H,
ArH), 8.43 (d, 1H, ArH), 11.50 (s, 1H, NH); LC/MS(ESI-MS)m/
z ¼ 380.2 (M þ 1).
11.52 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 414.62 (M þ 1).
4.5.10. tert-Butyl 4-((2-chloro-6-fluorobenzoyloxy)methyl)thiazol-
2-ylcarbamate (4j)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.23 (s, 2H, CH2), 6.92
4.6. General procedure for the preparation (2-aminothiazol-4-yl)
methylester derivatives (5aet)
(t, 1H, ArH), 7.20 (s, 1H, ArH), 7.31 (d, 1H, ArH), 7.62 (d, 1H, ArH),
11.48 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 387.89 (M þ 1).
The intermediate (4) (1.5 mmol) was taken in ethanol (5 mL),
cooled to 0 ꢀC, slowly added ethanolic HCl (5 mL), to the reaction
mixture and stirred the reaction mixture at ambient temperature
for 4 h. The reaction completion was monitored by TLC. Reaction
was completed. The ethanol layer was concentrated under reduced
pressure. Charged 10% NaHCO3 (10 mL) and extracted with ethyl-
acetate (2ꢂ25 mL) and the organic layer was concentrated under
pressure. The crude obtained was recrystalized in ethylacetate/
hexane, and the solid formed was filtered to afford the title
compounds 5aet. The spectral data of compounds 5(aet) are given
below.
4.5.11. tert-Butyl 4-((2,4,5-trifluorobenzoyloxy)methyl)thiazol-2-
ylcarbamate (4k)
1H NMR (DMSO)
d
ppm ¼ 1.47 (s, 9H, Boc), 5.23 (s, 2H, CH2), 6.72
(s, 1H, ArH), 7.22 (s, 1H, ArH), 7.68 (s, 1H, ArH), 11.46 (s, 1H, NH); LC/
MS(ESI-MS)m/z ¼ 389.2 (M þ 1).
4.5.12. tert-Butyl 4-((furan-2-carboxyloyloxy)methyl)thiazol-2-
ylcarbamate (4l)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.24 (s, 2H, CH2), 7.20
(s, 1H, ArH), 7.28 (t, 1H, ArH), 7.45 (d, 1H, ArH), 7.98 (d, 1H, ArH),
11.52 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 325.3 (M þ 1).
4.6.1. (2-Aminothiazol-4-yl)methyl 1-(4-chlorophenyl)
cyclopropanecarboxylate (5a)
4.5.13. tert-Butyl 4-((2-naphthoyloxy)methyl)thiazol-2-
ylcarbamate (4m)
Appearance: white solid; m.p. 213e215 ꢀC; 1H NMR (DMSO)
1H NMR (DMSO)
d
ppm ¼ 1.46 (s, 9H, Boc), 5.22 (s, 2H, CH2), 7.22
d
ppm
propylCH2), 4.82 (s, 2H, CH2), 6.31 (s, 1H, ArH), 6.98 (s, 2H, NH2),
7.38 (s, 4H, ArH); 13C
ppm (DMSO) ¼ 16.77, 28.61, 62.78,
104.43, 128.47, 132.14, 132.62, 138.65, 146.90, 169.21, 173.26; LC/
MS(ESI-MS)m/z 309.62 (M 1); Anal. Calcd for
¼
1.22 (t, 2H, cyclopropylCH2), 1.23 (t, 2H, cyclo-
(s, 1H, ArH), 7.38 (m, 2H, ArH), 7.76 (m, 2H, ArH), 7.82 (d, 1H, ArH),
7.94 (t, 1H, ArH), 8.51 (d, 1H, ArH), 11.48 (s, 1H, NH); LC/MS(ESI-MS)
m/z ¼ 385.6 (M þ 1).
d
¼
þ
4.5.14. tert-Butyl 4-((4-nitrobenzoyloxy)methyl)thiazol-2-
C14H13ClN2O2S; C, 54.46; H, 4.24; N, 9.07; Found C, 54.52; H,
4.32; N, 10.10.
ylcarbamate (4n)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.32 (s, 2H, CH2), 7.28
(s, 1H, ArH), 8.21 (m, 2H, ArH), 8.32 (m, 2H, ArH), 11.50 (s, 1H, NH);
4.6.2. (2-Aminothiazol-4-yl)methyl 2-(3-(trifluoromethyl)phenyl)
acetate (5b)
LC/MS(ESI-MS)m/z ¼ 380.4 (M þ 1).
Appearance: yellow oil; 1H NMR (DMSO)
d
ppm ¼ 3.57 (s, 2H,
CH2), 5.03 (s, 2H, CH2), 6.11 (s, 1H, ArH), 7.02 (s, 2H, NH2), 7.06 (t,1H,
ArH), 7.07 (d, 1H, ArH), 7.25 (s, 1H, ArH), 7.29 (d, 1H, ArH); 13C
ppm
4.5.15. tert-Butyl 4-((2,4,6-trichlorobenzoyloxy)methyl)thiazol-2-
ylcarbamate (4o)
d
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.21 (s, 2H, CH2), 6.70
(DMSO) ¼ 46.46, 62.91, 103.28, 123.68, 124.01, 126.38, 128.74,
130.69, 132.64, 134.92, 152.91, 168.61, 171.14; LC/MS(ESI-MS)m/
z ¼ 317.42 (M þ 1); C13H11F3N2O2S; C, 49.36; H, 3.51; N, 8.86; Found
C, 49.41; H, 3.48; N, 8.79.
(s, 1H, ArH), 7.21 (s, 1H, ArH), 7.67 (s, 1H, ArH), 11.48 (s, 1H, NH); LC/
MS(ESI-MS)m/z ¼ 438.6 (M þ 1).
4.5.16. tert-Butyl 4-((benzoyloxy)methyl)thiazol-2-ylcarbamate (4p)
1H NMR (DMSO)
d
ppm ¼ 1.46 (s, 9H, Boc), 5.18 (s, 2H, CH2), 7.26
4.6.3. (2-Aminothiazol-4-yl)methyl 2-(2-(trifluoromethoxy)phenyl)
acetate (5c)
(s, 1H, ArH), 7.34 (m, 2H, ArH), 7.48 (t, 1H, ArH), 8.01 (m, 2H, ArH),
11.47 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 335.2 (M þ 1).
Appearance: off white solid; m.p. 178e180 ꢀC; 1H NMR (DMSO)
d
ppm ¼ 3.86 (s, 2H, CH2), 4.98 (s, 2H, CH2), 6.84 (s,1H, ArH), 7.40 (d,
4.5.17. tert-Butyl 4-((6-cyanopyridine-2-carboxyloyloxy)methyl)
2H, ArH), 7.49 (m, 2H, ArH), 7.51 (s, 2H, NH2); 13C
d
ppm
thiazol-2-ylcarbamate (4q)
(DMSO) ¼ 32.19, 58.95, 107.86, 119.28, 121.83, 127.18, 127.89, 129.78,
133.07, 135.73, 147.54, 170.13, 170.40; LC/MS(ESI-MS)m/z ¼ 333.2
(M þ 1); C13H11F3N2O3S; C, 46.99; H, 3.34; N, 8.43; Found C, 47.03;
H, 3.39; N, 8.39.
1H NMR (DMSO)
d
ppm ¼ 1.46 (s, 9H, Boc), 5.18 (d, 2H, CH2), 7.20
(s, 1H, ArH), 8.41 (d, 1H, ArH), 8.67 (t, 1H, ArH), 9.29 (d, 1H, ArH),
11.50 (s, 1H, NH); LC/MS(ESI-MS)m/z ¼ 361.29 (M þ 1).
4.5.18. tert-Butyl 4-((4-chlorobenzoyloxy)methyl)thiazol-2-
4.6.4. (2-Aminothiazol-4-yl)methyl 3-fluoro-5-(trifluoromethyl)
benzoate (5d)
ylcarbamate (4r)
1H NMR (DMSO)
d
ppm ¼ 1.48 (s, 9H, Boc), 5.31 (s, 2H, CH2), 7.28
Appearance: off white solid; m.p. 230e232 ꢀC; 1H NMR (DMSO)
(s, 1H, ArH), 8.20 (m, 2H, ArH), 8.36 (m, 2H, ArH), 11.48 (s, 1H, NH);
d
ppm ¼ 5.28 (s, 2H, CH2), 7.06 (s, 1H, ArH), 8.09 (s, 1H, ArH), 8.11 (s,
LC/MS(ESI-MS)m/z ¼ 369.91 (M þ 1).
1H, ArH), 8.13 (s, 1H, ArH), 9.23 (s, 2H, NH2); 13C
d
ppm

180
R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
(DMSO) ¼ 60.18, 108.20, 118.68, 120.92, 121.15, 122.43, 132.17,
133.35, 135.47, 161.25, 163.74, 170.54; LC/MS(ESI-MS)m/z ¼ 321.31
(M þ 1); C12H8F4N2O2S; C, 45.00; H, 2.52; N, 8.75; Found C, 4.13; H,
2.61; N, 8.68.
1H, ArH); 13
C
d
ppm (DMSO) ¼ 64.18, 105.76, 132.24, 132.68, 132.94,
133.14, 134.68, 140.07, 154.17, 167.38, 170.13; LC/MS(ESI-MS)m/
z ¼ 289.32 (M þ 1); C11H7F3N2O2S; C, 45.84; H, 2.45; N, 9.72; Found
C, 45.75; H, 2.53; N, 9.68.
4.6.5. (2-Aminothiazol-4-yl)methyl 3-(2-cyanoethyl)benzoate (5e)
Appearance: white solid; m.p. 165e167 ꢀC; 1H NMR (DMSO)
4.6.12. (2-Aminothiazole-4-yl)methyl furan-2-carboxylate (5l)
Appearance: white solid; m.p. 183e185 ꢀC; 1H NMR (DMSO)
d
ppm ¼ 2.74 (t, 2H, CH2), 2.98 (t, 2H, CH2), 5.28 (s, 2H, CH2),
7.17 (s, 1H, ArH), 7.23 (d, 1H, ArH), 7.28 (t, 1H, ArH), 8.17 (s, 2H,
NH2), 8.23 (d, 1H, ArH), 8.42 (s, 1H, ArH); 13C
ppm
d
ppm ¼ 5.07 (s, 2H, CH2), 6.69 (s, 1H, ArH), 6.71 (d, 1H, ArH),
7.01 (s, 2H, NH2), 7.34 (d, 1H, ArH), 7.97 (s, 1H, ArH); 13C
d
d
ppm (DMSO) ¼ 62.27, 106.01, 112.81, 119.07, 144.16, 146.48,
(DMSO) ¼ 17.02, 32.84, 62.82, 104.42, 116.91, 127.41, 127.62,
127.98, 130.02, 152.74, 167.39, 169.32; LC/MS(ESI-MS)m/z ¼ 288.31
(M þ 1); C14H13N3O2S; C, 58.52; H, 4.56; N, 14.62; Found C, 58.63;
H, 4.48; N, 14.71.
148.17, 158.06, 169.33; LC/MS(ESI-MS)m/z ¼ 225.32 (M þ 1);
C9H8N2O3S; C, 48.21; H, 3.60; N, 12.49; Found C, 48.38; H, 3.69;
N, 12.53.
4.6.13. (2-Aminothiazole-4-yl)methyl 2-naphthoate (5m)
4.6.6. (2-Aminothiazole-4-yl)methyl 2-cyanobenzoate (5f)
Appearance: off white solid; m.p. 157e159 ꢀC; 1H NMR (DMSO)
Appearance: brown solid; m.p. 235e237 ꢀC; 1H NMR (DMSO)
d
ppm ¼ 5.23 (s, 2H, CH2), 6.69 (s, 1H, ArH), 7.06 (s, 2H, NH2), 7.67
(m, 4H, ArH), 8.05 (s, 1H, ArH), 8.21 (d, 1H, ArH), 8.78 (d, 1H, ArH);
13C
d
ppm ¼ 5.17 (s, 2H, CH2), 6.68 (s, 1H, ArH), 7.02 (s, 2H, NH2), 7.88 (d,
2H, ArH), 8.12 (t, 1H, ArH), 8.14 (t, 1H, ArH); 13C
d
ppm
d
ppm (DMSO) ¼ 62.84, 104.84, 126.09, 126.82, 128.32, 128.87,
(DMSO) ¼ 63.55, 105.98, 112.19, 117.80, 131.39, 131.99, 133.86,
134.06, 135.75, 146.17, 163.74, 169.36; LC/MS(ESI-MS)m/z ¼ 260.31
(M þ 1); C12H9N3O2S; C, 55.59; H, 3.50; N, 16.20; Found C, 55.63; H,
3.61; N, 16.09.
129.82, 130.17, 131.98, 135.61, 154.70, 166.19, 170.09; LC/MS(ESI-MS)
m/z ¼ 285.3 (M þ 1); C15H12N2O2S; C, 63.36; H, 4.25; N, 9.85; Found
C, 63.42; H, 4.38; N, 9.76.
4.6.14. (2-Aminothiazole-4-yl)methyl 4-nitrobenzoate (5n)
4.6.7. (2-Aminothiazole-4-yl)methyl thiophene-2-carboxylate (5g)
Appearance: brown solid; m.p. 192e194 ꢀC; 1H NMR (DMSO)
Appearance: pale yellow solid; m.p. 160e162 ꢀC; 1H NMR
(DMSO)
d
ppm ¼ 5.17 (s, 2H, NH2), 5.24 (s, 2H, CH2), 6.60 (s, 1H,
d
ppm ¼ 5.08 (s, 2H, CH2), 6.61 (s, 1H, ArH), 7.02 (s, 2H, NH2),
ArH), 8.25 (m, 4H, ArH); 13C
d
ppm (DMSO) ¼ 62.96, 108.34, 123.51,
7.23 (d, 1H, ArH), 7.84 (d, 1H, ArH), 7.97 (d, 1H, ArH); 13C
130.93, 135.41, 146.25, 150.62, 164.45, 168.17; LC/MS(ESI-MS)m/
z ¼ 280.3 (M þ 1); C11H9N2O2S; C, 47.31; H, 3.25; N, 15.05; Found C,
47.28; H, 3.31; N, 15.12.
d
ppm (DMSO) ¼ 62.69, 105.86, 128.87, 133.24, 134.36, 134.54,
146.62, 161.61, 169.35; LC/MS(ESI-MS)m/z ¼ 241.21 (M þ 1);
C9H8N2O2S2; C, 44.98; H, 3.36; N, 11.66; Found C, 45.13; H, 3.41;
N, 11.59.
4.6.15. (2-Aminothiazole-4-yl)methyl 2,4,6-trichlorobenzoate (5o)
Appearance: semi solid; 1H NMR (DMSO)
d
ppm ¼ 5.12 (s, 2H,
CH2), 6.63 (s,1H, ArH), 7.01 (s, 2H, NH2), 7.89 (s,1H, ArH), 7.96 (s,1H,
ArH); 13C
4.6.8. (2-Aminothiazole-4-yl)methyl 2-chloro-3-nitrobenzoate (5h)
Appearance: yellow solid; m.p. 150e152 ꢀC; 1H NMR (DMSO)
d
ppm (DMSO) ¼ 63.21, 104.32, 131.20, 131.62, 131.79,
d
ppm ¼ 5.17 (s, 2H, CH2), 6.72 (s, 1H, ArH), 7.16 (s, 2H, NH2), 7.64 (t,
132.90, 134.19, 139.65, 154.09, 166.00, 168.59; LC/MS(ESI-MS)m/
z ¼ 338.6 (M þ 1); C11H7Cl3N2O2S; C, 39.13; H, 2.09; N, 8.30; Found
C, 39.24; H, 2.12; N, 8.23.
1H, ArH), 8.28 (d, 1H, ArH), 8.92 (d, 1H, ArH); 13C
d
ppm
(DMSO) ¼ 62.62, 103.78, 125.48, 126.97, 131.09, 131.82, 136.81,
148.31, 154.26, 166.41, 170.14; LC/MS(ESI-MS)m/z ¼ 314.81 (M þ 1);
C11H8ClN3O4S; C, 42.11; H, 2.57; N, 13.39; Found C, 42.20; H, 2.43; N,
13.58.
4.6.16. (2-Aminothiazole-4-yl)methyl benzoate (5p)
Appearance: white solid; m.p. 174e176 ꢀC; 1H NMR (DMSO)
d
ppm ¼ 5.12 (s, 2H, CH2), 6.62 (s, 1H, ArH), 7.11 (s, 2H, NH2), 7.55
4.6.9. (2-Aminothiazole-4-yl)methyl 6-cyanopyridine-3-
carboxylate (5i)
(d, 2H, ArH), 7.69 (t, 1H, ArH), 8.00 (d, 2H, ArH); 13C
d
ppm (DMSO) ¼ 62.72, 105.59, 129.25, 129.68, 130.08, 133.86,
Appearance: white solid; m.p. 178e180 ꢀC; 1H NMR (DMSO)
146.81, 165.88, 169.34; LC/MS(ESI-MS)m/z ¼ 235.3 (M þ 1);
C11H10N2O2S; C, 56.39; H, 4.30; N, 11.96; Found C, 56.47; H, 4.21;
N, 11.85.
d
ppm ¼ 5.19 (s, 2H, CH2), 6.72 (s, 1H, ArH), 7.02 (s, 2H, NH2), 8.21 (d,
1H, ArH), 8.53 (d, 1H, ArH), 9.09 (s, 1H, ArH); 13C
d
ppm
(DMSO) ¼ 63.28, 116.87, 103.81, 126.32, 130.13, 134.84, 136.91,
150.98, 154.15, 166.43, 170.48; LC/MS(ESI-MS)m/z ¼ 261.3 (M þ 1);
C11H8N4O2S; C, 50.76; H, 3.10; N, 21.53; Found C, 50.61; H, 3.21; N,
21.58.
4.6.17. (2-Aminothiazole-4-yl)methyl 6-cyanopyridine-2-
carboxylate (5q)
Appearance: white solid; m.p. 185e187 ꢀC; 1H NMR (DMSO)
d
ppm ¼ 5.20 (s, 2H, CH2), 6.83 (s,1H, ArH), 7.14 (s, 2H, NH2), 8.30 (d,
1H, ArH), 8.87 (t, 1H, ArH), 9.31 (d, 1H, ArH); 13C
ppm
(DMSO) ¼ 63.7, 117.96, 105.64, 128.39, 130.04, 136.78, 138.31, 152.10,
154.16, 167.12, 169.64; LC/MS(ESI-MS)m/z 261.3 (M 1);
4.6.10. (2-Aminothiazole-4-yl)methyl 2-chloro-6-fluorobenzoate
(5j)
d
Appearance: off white solid; m.p. 110e112 ꢀC; 1H NMR (DMSO)
¼
þ
d
ppm ¼ 5.15 (s, 2H, CH2), 6.66 (s, 1H, ArH), 7.06 (s, 2H, NH2), 7.41 (d,
C11H8N4O2S; C, 50.76; H, 3.10; N, 21.53; Found C, 50.87; H, 3.21; N,
21.65.
1H, ArH), 7.57 (d, 1H, ArH), 7.62 (s, 1H, ArH); 13C
d
ppm
(DMSO) ¼ 64.05, 106.78, 115.47, 122.21, 126.41, 131.30, 133.55,
145.67, 157.98, 160.47, 169.33; LC/MS(ESI-MS)m/z ¼ 287.82 (M þ 1);
C11H8ClFN2O2S; C, 46.08; H, 2.81; N, 9.77; Found C, 46.21; H, 2.30;
N, 9.62.
4.6.18. (2-Aminothiazole-4-yl)methyl 4-chlorobenzoate (5r)
Appearance: off white solid; m.p. 171e173 ꢀC; 1H NMR (DMSO)
d
ppm ¼ 5.02 (s, 2H, NH2), 5.18 (s, 2H, CH2), 6.48 (s, 1H, ArH), 8.19
(m, 4H, ArH); 13C
d
ppm (DMSO) ¼ 61.89, 107.67, 122.49, 128.67,
4.6.11. (2-Aminothiazole-4-yl)methyl 2,4,6-trifluorobenzoate (5k)
133.59, 146.01, 149.69, 162.34, 167.96; LC/MS(ESI-MS)m/z ¼ 269.81
(M þ 1); C11H9ClN2O2S; C, 49.17; H, 3.38; N, 10.42; Found C, 49.23;
H, 3.461; N, 10.39.
Appearance: yellow oil; 1H NMR (DMSO)
CH2), 6.68 (s, 1H, ArH), 7.04 (s, 2H, NH2), 7.98 (s, 1H, ArH), 8.08 (s,
d
ppm ¼ 5.14 (s, 2H,

R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
181
4.6.19. (2-Aminothiazole-4-yl)methyl 4-bromobenzoate (5s)
Appearance: brown solid; m.p. 163e165 ꢀC; 1H NMR (DMSO)
each compound was compared with Ciclopiroxolamine as standard.
MIC ( g/mL) and Zone of inhibition (mm) were determined for all
m
d
ppm ¼ 4.98 (s, 2H, NH2), 5.12 (s, 2H, CH2), 6.41 (s, 1H, ArH), 8.10
the synthesized compounds and their corresponding results are
summarized in Table 3.
(m, 4H, ArH); 13C
d
ppm (DMSO) ¼ 60.96, 107.43, 121.90, 128.04,
132.91, 145.79, 148.84, 161.62, 167.21; LC/MS(ESI-MS)m/z ¼ 314.21
(M þ 1); C11H9BrN2O2S; C, 42.19; H, 2.90; N, 8.95; Found C, 42.26; H,
2.92; N, 8.92.
4.9. Antituberculosis study
The compounds were screened for their in vitro anti-
mycobacterial activity against M. tuberculosis H37Rv ATCC 27294
and non-tubercular mycobacterial (NTM) species like M. smegmatis
(MC2) ATCC 19420, and M. fortuitum ATCC 19542 by Resazurin
Assay method [39] and their MIC values were determined. The
standard drugs, viz. isoniazid and rifampicin were used for
comparison. M. tuberculosis strains were grown in Middlebrook
7H9 broth (Difco BBL, Sparks, MD, USA) supplemented with 10%
OADC (Becton Dickinson, Sparks, MD, USA). The culture was diluted
4.6.20. (2-Aminothiazole-4-yl)methyl 2-nitrobenzoate (5t)
Appearance: pale yellow solid; m.p. 166e168 ꢀC; 1H NMR
(DMSO)
ArH), 8.19 (t, 1H, ArH) 8.34 (t, 1H, ArH) 8.79 (d, 1H, ArH) 8.98 (d, 1H,
ArH); 13C
d
ppm ¼ 5.19 (s, 2H, NH2), 5.28 (s, 2H, CH2), 6.64 (s, 1H,
d
ppm (DMSO) ¼ 60.71, 107.39, 121.86, 128.19, 133.42,
148.61, 154.67, 159.18, 160.43, 163.87, 169.42; LC/MS(ESI-MS)m/
z ¼ 280.34 (M þ 1); C11H9N3O4S; C, 47.31; H, 3.25; N,15.05; Found C,
47.39; H, 3.31; N, 15.16.
to McFarland 2 standard with the same medium. From this, 50
mL of
4.7. Antibacterial studies
this culture was added to 150 L of fresh medium in 96 well
m
microtitre plates. Stock solutions (2 mg/mL) of the test compounds
were prepared in dimethyl formamide (DMF). The compounds
The synthesized compounds were screened for their antibac-
terial activity against E. coli (ATTC-25922), S. aureus (ATTC-25923),
P. aeruginosa (ATCC-27853) and K. pneumoniae (recultured) and S.
pyogenes bacterial strains by serial plate dilution method [33,34].
Serial dilutions of the drug in MuellereHinton broth were taken in
tubes and their pH was adjusted to 5.0 using phosphate buffer. A
standardized suspension of the test bacterium was inoculated and
incubated for 16e18 h at 37 ꢀC. The minimum inhibitory concen-
tration (MIC) was noted by seeing the lowest concentration of the
drug at which there was no visible growth. A number of antimi-
crobial discs are placed on the agar for the sole purpose of
producing zone of inhibition in the bacterial lawn. Twenty millili-
ters of agar media was poured into each Petri dish. Excess of
suspension was decanted and plates were dried by placing in an
incubator at 37 ꢀC for an hour. Using an agar punch, wells were
made on these seeded agar plates and minimum inhibitory
concentration of the test compounds in dimethylsulfoxide (DMSO)
were added into each labeled well. A control was also prepared for
the plates in the same way using solvent DMSO. The Petri dishes
were prepared in triplicate and maintained at 37 ꢀC for 3e4 days.
Antibacterial activity was determined by measuring the diameter of
the inhibition zone. Activity of each compound was compared with
were tested at 1, 10 and 100
second level testing was carried out at concentrations 0.3125,
0.625,1.25, 2.5, and 5 g/mL. Control tubes had the same volumes of
DMF without any substrate. Rifampicin and isoniazid were used as
the reference compounds. After incubation at 37 ꢀC for 7 days, 20
mg/mL concentrations. Further the
m
mL
of 0.01% Resazurin (Sigma, St. Louis. MO, USA) in water was added
to each tube. Resazurin, a redox dye, is blue in the oxidized state
and turns pink when reduced by the growth of viable cells. The
control tubes showed a color change from blue to pink after 1 h at
37 ꢀC. Compounds which prevented the change of color of the dye
were considered to be inhibitory to M. tuberculosis.
Acknowledgment
We thank to DST-India, for providing X-ray facility at SSCU,
Indian Institute of Science, Bangalore, and Head of the Department
of Biochemistry, Justice K. S. Hegde Medical Academy, to carry out
biological studies. We are grateful to the Head, Chemistry Depart-
ment and School of Chemical Sciences for the kind support and
providing necessary laboratory facilities.
ciprofloxacin as standard [35,36]. MIC (mg/mL) and Zone of inhibi-
tion (mm) was determined for all the synthesized compounds and
the corresponding results are summarized in Table 2.
Appendix. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ejmech.2012.01.008.
4.8. Antifungal studies
References
Newly prepared compounds were screened for their antifungal
activity against A. flavus (NCIM No. 524), Aspergillus fumigarus (NCIM
No. 902), P. marneffei(recultured) and T. mentagrophytes (recultured)
and C. albicans in DMSO by serial plate dilution method [37,38].
[1] J.P. Cegielski, D.P. Chin, M.A. Espinal, T.R. Frieden, R. Rodriquez Cruz,
E.A. .Talbot, D.E. Weil, R. Zaleskis, M.C. Raviglione, Infect. Dis. Clin. North Am.
161 (2002) 1e58.
[2] M.K. Spigelman, J. Infect. Dis. 196 (2007) S28eS34.
[3] M.R. Shiradkar, K.K. Murahari, H.R. Gangadasu, T. Suresh, C.A. Kalyan,
D. Panchal, R. Kaur, P. Burange, J. Ghogare, V. Mokale, M. Raut, Bioorg. Med.
Chem. Lett. 15 (2007) 3997e4008.
[4] S.K. Bharti, G. Nath, R. Tilak, S.K. Singh, Eur. J. Med. Chem. 45 (2010) 651e660.
[5] N. Hans, Swiss Patent 592103, (1977), Chem. Abstract 88 (1978) 22886.
[6] K.J. Wilson, C.R. Utig, N. Subhasinghe, J.B. Hoffman, N.J. Rudolph, R. Soll,
C.J. Molloy, R. Bone, D. Green, J. Randall, Bioorg. Med. Chem. Lett. 11 (2001)
915e918.
[7] K.D. Berlin, M.D. Herd, Proc. Okla. Acad. Sci. 71 (1991) 29e33.
[8] P.K. Sharma, S.N. Swonhney, A. Gupta, G.B. Sing, S. Bani, Indian J. Chem. 37B
(1998) 371e375.
Sabourands 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 spore
of fungal stain for lawning. A loopful of particular fungal strain was
transferred to 3 mL saline to get a suspension of corresponding
species. Twenty milliliters of agar medias was poured into each Petri
dish. Excess of suspension was decanted and plates were dried by
placing in incubator at 37 ꢀC for 1 h. Using a punch, wells were made
on these seeded agar plates minimum inhibitory concentrations of
the test compounds in DMSO were added into each labeled well. A
control was also prepared for the plates in the same way using
solvent DMSO. The Petri dishes were prepared in triplicate and
maintained at 37 ꢀC for 3e4 days. Antifungal activity was deter-
mined by measuring the diameter of the inhibition zone. Activity of
[9] K. Taori, V.J. Paul, H. Luesch, J. Am. Chem. Soc. 130 (2008) 1806e1807.
[10] F. Sasse, H. Steinmetz, G. Hofle, H. Reichenbach, J. Antibiot. 56 (2003)
520e525.
[11] S. Kehraus, G.M. Konig, A.D. Wright, J. Org. Chem. 67 (2002) 4989e4992.
[12] K. Gerth, N. Bedorf, G. Hofle, H. Irschik, H. Reichenbach, J. Antibiot. 49 (1996)
560e563.
[13] K.D. Hargrave, F.K. Hess, J.T. Oliver, J. Med. Chem. 26 (1983) 1158e1163.

182
R.P. Karuvalam et al. / European Journal of Medicinal Chemistry 49 (2012) 172e182
[14] W.C. Patt, H.W. Hamilton, M.D. Taylor, M.J. Ryan, D.G. Taylor, C.J.C. Connolly,
A.M. Doharty, S.R. Klutchko, I. Sircar, B.A. Steinbaugh, B.L. Bately,
C.A. Painchand, S.T. Rapundalo, B.M. Michniewicz, S.C.J. Olzon, J. Med. Chem.
35 (1992) 2562e2572.
[26] P.K. Ranjith, M. Siji, N. Divia, K.R. Haridas, J. Korean Chem. Soc. 54 (2010)
589e593.
[27] M. Kaspady, V.K. Narayanaswamy, M. Raju, G.K. Rao, Lett. Drug Des. Discovery
6 (2009) 21e28.
[15] P.K. Sharma, S.N. Sawnhney, A. Gupta, G.B. Sing, S. Bani, Indian J. Chem. 37B
(1998) 376e381.
[16] J.C. Jaen, L.D. Wise, B.W. Caprathe, H. Tecle, S. Bergmeier, C.C. Humblet,
T.G. Heffner, L.T. Meltzner, T.A. Pugsley, J. Med. Chem. 33 (1990) 311e317.
[17] N. Ergenc, G. Capan, N.S. Gunay, S. Oskirimli, M. Gungor, S. Ozbey, E. Kendi,
Arch. Pharm. Pharm. Med. Chem. 332 (1999) 343e347.
[18] J.S. Carter, S. Kramer, J.J. Talley, T. Penning, P. Collins, M.J. Graneto, K. Seibert,
C. Koboldt, J. Masferrer, B. Zweifel, Bioorg. Med. Chem. Lett. 9 (1999) 1171e1174.
[19] F.W. Bell, A.S. Cantrell, M. Hoberg, D.R. Jaskunas, N.G. Johansson, C.L. Jordon,
M.D. Kinnick, P. Lind, J.M. Morin Jr., R. Noreen, B. Oberg, J.A. Palkowitz,
C.A. Parrish, J. Pranc, H. Zhang, X.X. Zhou, J. Med. Chem. 38 (1995) 4929e4936.
[20] A. Mori, A. Sekiguchi, K. Masui, T. Shimada, M. horie, K. Osakada,
M. Kawamoto, T. Ikeda, J. Am. Chem. Soc. 125 (2003) 1700e1701.
[21] M. Ng, L. Yu, Angew. Chem. Int. Ed. 41 (2002) 3598e3601.
[22] K.C. Nicolaou, F. Sarabia, S. Ninkovic, M.R. Finlay, C.N.C. Boddy, Angew. Chem.
Int. Ed. 37 (1998) 81e84.
[28] W.K. George, R.M. Arjun, Tetrahedron. Lett. 47 (2006) 5171e5172.
[29] M.A. Parker, D.M. Kurrasch, D.E. Nichols, Bioorg. Med. Chem. 16 (2008)
4661e4669.
[30] H. Nakayama, K. Ishihara, S. Akiba, J. Uenishi, Chem. Pharm. Bull. 59 (2011)
1069e1072.
[31] G.M. Sheldrick, Acta Crystallogr. A64 (2008) 112e122.
[32] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565e566.
[33] A.L. Barry, Procedure for testing antimicrobial agents in agar media, in:
V.L. Corian (Ed.), Antibiotics in Laboratory Medicine, Williams and Wilkins,
Baltimore, MD, 1980, pp. 1e23.
[34] D. James Mac. Lowry, J.M. Jaqua, T.S. Sally, Appl. Microbiol. 20 (1970) 46e53.
[35] C.H. Fenlon, M.H. Cynamon, Antimicrob. Agents Chemother. 29 (1986)
386e388.
[36] R. Davis, A. Markham, J.A. Balfour, Ciprofloxacin, an update review of its
pharmacology, therapeutic efficiency and tolerability, Drugs 51 (1996)
1019e1074.
[23] T.R. Kelly, F. Lang, J. Org. Chem. 61 (1996) 4623e4633.
[37] B.A. Arthington-Skaggs, M. Molestely, D.W. Warnock, C.J. Morrison, J. Clin.
Microbiol. (2000) 2254e2260.
[38] R.S. Verma, Z.K. Khan, A.P. Sing (Eds.), Antifungal Agents: Past, Present and
Future Prospects, National Academy of Chemistry and Biology, Lucknow,
India, 1998, pp. 55e128.
[24] K.C. Nicolaou, N.P. King, M.R.V. Finlay, Y. He, F. Roschangar, D. Vourloumis,
H. Vallberg, S. Sarabia, S. Ninkovic, D. Hepworth, Bioorg. Med. Chem. 7 (1999)
665e697.
[25] A.M. Panico, A. Geronikaki, R. Mgonzo, V. Cardile, B. Gentile, I. Doytchinova,
Bioorg. Med. Chem. 11 (2003) 2983e2989.
[39] K.T. Neetu, S.T. Jaya, J. Antimicrob. Chemother. 60 (2007) 288e293.