Synthesis and antimycobacterial activity of new 2-hydroxy-N-(3-oxo-1-thia- 4-azaspiro[4.4]non-4-yl)/(3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2, 2-diphenylacetamide derivatives

Article abstract of DOI:10.1007/s00706-006-0475-3

2-Hydroxy-2,2-diphenylacetohydrazide (2), cyclic ketones, and mercaptoalkanoic acids were converted into 2-hydroxy-N-(3-oxo-1-thia-4- azaspiro[4.4]non/[4.5]dec-4-yl)-2,2-diphenylacetamide derivatives (3, 4) in a one pot procedure. Compounds 3 and 4 were tested for in vitro antimycobacterial activity against M. tuberculosis H37Rv. The compounds were found to provide 0-86% inhibition of mycobacterial growth in the primary screen conducted at 6.25 μg/cm³. Springer-Verlag 2006.

Full text of DOI:10.1007/s00706-006-0475-3

Monatshefte f u¨ r Chemie 137, 795–801 (2006)
DOI 10.1007/s00706-006-0475-3
Short Communication
Synthesis and Antimycobacterial Activity
of New 2-Hydroxy-N-(3-oxo-1-thia-4-
azaspiro[4.4]non-4-yl)=(3-oxo-1-thia-4-
azaspiro[4.5]dec-4-yl)-2,2-diphenylacetamide
Derivatives
¨
Ozlen G u¨ zel , Eser Ilhan, and Aydin Salman
ꢀ
˙
ꢁ
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University,
ꢁ
Beyazit, Istanbul, Turkey
Received February 20, 2006; accepted (revised) March 22, 2006
Published online May 15, 2006 # Springer-Verlag 2006
Summary. 2-Hydroxy-2,2-diphenylacetohydrazide (2), cyclic ketones, and mercaptoalkanoic acids
were converted into 2-hydroxy-N-(3-oxo-1-thia-4-azaspiro[4.4]non=[4.5]dec-4-yl)-2,2-diphenylaceta-
mide derivatives (3, 4) in a one pot procedure. Compounds 3 and 4 were tested for in vitro antimy-
cobacterial activity against M. tuberculosis H37Rv. The compounds were found to provide 0–86%
3
inhibition of mycobacterial growth in the primary screen conducted at 6.25ꢀg=cm .
Keywords. Spirothiazolidinones; Synthesis; Antimycobacterial activity.
Introduction
Tuberculosis (TB) is a contagious disease with high mortality worldwide. About
32% of the world’s population is currently infected with TB. Every year, approxi-
mately eight to nine million of these infected people develop clinical pulmonary
tuberculosis leading to nearly three million deaths annually [1]. In order to control
the rapid spread of tuberculosis and to overcome resistance, there is an urgent need
to develop new antimycobacterial agents with unique modes of action to replace
the current regimens.
4-Thiazolidinones and their spiroheterocyclic analogs have been shown to pos-
sess antibacterial [2, 3], antifungal [4, 5], and antituberculosis [6–8] activities.
ꢀ Corresponding author. E-mail: ozlen_guzel@yahoo.com

¨
O. G u¨ zel et al.
7
96
With the aim of obtaining new and more potent antituberculosis compounds
which can improve the current chemotherapeutic antituberculosis treatments, we have
synthesized and evaluated sixteen new 2-hydroxy-N-(3-oxo-1-thia-4-azaspiro[4.4]-
non-4-yl)=(3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-diphenylacetamide derivatives,
incorporating the thiazolidinone substructure, as potential antimycobacterials.
Results and Discussion
In an attempt to investigate the effects of modification of the ring substituents of
the spiroheterocyclic system on biological activity and to get an insight into the
substitution pattern required for the highest potencies, a series of 2-hydroxy-N-(3-
oxo-1-thia-4-azaspiro[4.4]non-4-yl)=(3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-
diphenylacetamides was prepared as described in the Scheme. Thus 2-hydroxy-2,2-
diphenylacetohydrazide (2), an appropriate cyclic ketone, and mercaptoacetic acid
or ꢁ-mercaptopropionic acid were refluxed in dry benzene using a Dean-Stark
water separator to afford 3 and 4 in an efficient one-pot nucleophilic addition and
cyclodehydration reaction.
The structures of the new compounds were confirmed by elemental analysis,
13
1
IR, H NMR, HSQC, C NMR(APT), and atmospheric pressure chemical ioniza-
tion [APCI(-)] mass spectrometry.
The IR spectra exhibited OH=N–H and C¼O bands in the 3435–3230 and
ꢂ1
1
685–1665 cm regions attributed to the common OH=NH and CONHN func-
tions of 3 and 4 [10]. The characteristic lactam C¼O absorptions of 3 and 4 were
ꢂ1
observed in the 1731–1704 cm region [4, 9].
Scheme 1. Reagents and conditions: i) hydrazine hydrate, EtOH, reflux, 6 h; ii) mercaptoacetic
acid=ꢁ-mercaptopropionic acid, dry benzene, reflux, 6 h

Synthesis and Antimycobacterial Activity of Spirothiazolidinones
1
797
The H NMR spectra of 3 and 4 displayed singlets and quartets attributed to the
methylene (SCH ) and methine (SCHCH ) ring protons at 2-position of the spir-
2
3
oheterocyclic system at about ꢂ ¼ 3.54–3.88 ppm [11]. The C–OH and CONH
protons were observed at about ꢂ ¼ 6.78–6.84 and 9.93–10.33 ppm, respectively
[
10].
Further structural confirmation was provided by the HSQC spectrum of 3f
which showed the expected C– H correlations. Existence of cross peaks connect-
1
3
1
ing 8-CH CH (ꢂ ¼ 12.02 ppm) and C (ꢂ ¼ 37.97 ppm) with the triplet at ꢂ ¼
2
3
8
0
.83 ppm; 8-CH CH (ꢂ ¼ 29.38 ppm) with the quintet at ꢂ ¼ 1.16 ppm and C
2
3
2
(
ꢂ ¼ 28.63 ppm) with the singlet at ꢂ ¼ 3.54 ppm was decisive evidence for unam-
bigous assignment. Cross peaks connecting spirodecane C (ꢂ ¼ 29.61 ppm) with
7,9
the multiplet at ꢂ ¼ 1.01–1.09 ppm assigned to the axial protons and with the
doublet at ꢂ ¼ 1.65 ppm assigned to the equatorial protons on C were also ob-
7
,9
served. Cross peaks existed also between C
at ꢂ ¼ 1.65 and 1.75 ppm assigned to the axial and equatorial protons on C
(ꢂ ¼ 37.28 ppm) and the doublets
6,10
6
,10
.
Carbon resonances at ꢂ ¼ 73.44, 81.60, 168.01, and 173.39 ppm showed no cross
peaks and were thus assigned to C , C–OH, CONH, and C (lactam C¼O) carbons,
5
3
respectively.
1
3
The C NMR(APT) spectra of 3b, 4e, and 4g also supported the anticipated
cyclization and showed the common spirodecane C , C (lactam C¼O), and C
2
3
5
resonances at about ꢂ ¼ 28.64–37.47, 173.27–173.40, and 71.74–73.30 ppm,
respectively [6, 12, 13]. The CONH and the (C H ) C–OH resonances were
6
5 2
observed at about ꢂ ¼ 167.98–170.67 and 81.57–81.61 ppm.
ꢂ
(M–H) ions with 100% relative abundance observed in the atmospheric pres-
sure chemical ionization [APCI(-)] mass spectra of 4e and 4h provided further
confirmation for the formation of the expected structures [14]. MS=MS clearly
ꢂ
showed the [(M–H)-SCH CO] fragments cited for the 4-thiazolidinone system
2
in the literature [9]. Further spectral details are presented in the experimental
section.
The in vitro antimycobacterial activity evalution of 3 and 4 against
M. tuberculosis H37Rv (ATCC 27294) was initially carried out using the micro-
3
plate alamar blue assay (MABA) at a concentration of 6.25 ꢀg=cm at the
Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF)
(
Table) [15].
As can be seen in the Table, the compounds were found to provide 0–86%
inhibition of mycobacterial growth of M. tuberculosis H37Rv in the primary screen
3
conducted at 6.25 ꢀg=cm .
Generally compounds bearing a methyl function at 2-position of the spirohe-
terocyclic system (4) showed higher inhibition when compared to the unsubstituted
entries (3). The highest inhibition (86%) was demonstrated by 4h, the 2-methyl and
8-phenyl substituted derivative.
These preliminary results confirm the fact that the 3-oxo-1-thia-4-azaspiro
4.4]nonane=[4.5]decane derivatives which may be considered as spirothiazolidi-
[
nones have antimycobacterial potential. It is thus concluded that the new com-
pounds described in this work, especially 4h, deserve further investigation for
the development of more potent antitubercular agents for therapeutic use.

¨
O. G u¨ zel et al.
7
98
Table 1. Formulas, physical constants, elemental analysis, and primary in vitro antimycobacterial activity
evaluation of 3a–3h, 4a–4h against M. tuberculosis H37Rv
ꢃ
a
Compd.
Formula (MW)
Yield (%)
Mp ( C)
Analysis (%) (calcd.=found)
GI (%)
C
H
N
3
3
a
C H N O S
21 22 2 3
52
47
28
34
54
47
15
46
49
53
48
40
34
44
23
29
201–3
220–2
126–8
182–3
174–6
154–6
175–6
195–7
185–7
198–9
182–5
180–1
210–1
174–5
196–8
199–200
65.95
65.87
66.64
66.21
67.29
66.98
67.29
66.99
67.29
67.05
67.90
67.78
68.46
67.97
71.16
71.25
66.64
66.46
67.29
67.62
67.90
68.27
67.90
67.57
67.90
67.73
68.46
68.83
69.00
68.88
71.58
71.18
5.80
5.97
6.10
6.22
6.38
6.76
6.38
6.50
6.38
6.61
6.65
6.65
6.89
6.73
5.97
5.92
6.10
6.30
6.38
6.50
6.65
6.89
6.65
6.76
6.65
6.50
6.89
6.72
7.13
7.06
6.21
6.11
7.32
6.90
7.07
6.69
6.82
6.50
6.82
6.85
6.82
6.85
6.60
6.62
6.39
6.37
5.93
6.03
7.07
6.67
6.82
6.49
6.60
6.24
6.60
6.46
6.60
6.50
6.39
6.17
6.19
6.05
5.76
5.41
0
1
(
382.474)
b
C H N O S
22 24 2 3
(
396.494)
3
c
C H N O S
23 26 2 3
0
(
410.524)
3
d
C H N O S
23 26 2 3
4
(
410.524)
3
e
C H N O S
23 26 2 3
0
(
410.524)
3
f
C H N O S
24 28 2 3
26
38
31
0
(
424.544)
3g
3h
4a
4b
C H N O S
25 30 2 3
(
438.574)
C H N O S
28 28 2 3
(
472.584)
C H N O S
22 24 2 3
(
396.494)
C H N O S
23 26 2 3
0
(
410.524)
4
c
C H N O S
24 28 2 3
38
1
(
424.544)
4
d
C H N O S
24 28 2 3
(
424.544)
4
e
C H N O S
24 28 2 3
36
53
64
86
(
424.544)
4
f
C H N O S
25 30 2 3
(
438.574)
4
4
g
C H N O S
26 32 2 3
(
452.604)
h
C H N O S
29 30 2 3
(
486.614)
a
3
Growth Inhibition of virulent H37Rv strain of M. tuberculosis (MIC>6.25 ꢀg=cm ); MIC of rifampin:
3
.125 ꢀg=cm versus M. tuberculosis H37Rv (97% inhibition)
0
Experimental
All chemicals were purchased from E. Merck (Darmstadt, Germany). Melting points were mea-
sured in open capillary tubes with a B u¨ chi 530 melting point apparatus and are uncorrected. IR
1
KBr) spectra were recorded using a Perkin-Elmer 1600 FTIR spectrophotometer. H NMR,
(
1
HSQC, and C NMR(APT) spectra were recorded on a Varian
3
UNITY
INOVA 500 MHz spectro-
meter. Elemental analyses were performed on a Carlo Erba Model 1106 elemental analyzer. Mass
TM TM
spectra (LC=MS-APCI) were recorded on a Finnigan LCQ Mass Spectrometer in the nega-
tive ionization mode.

Synthesis and Antimycobacterial Activity of Spirothiazolidinones
-Hydroxy-2,2-diphenylacetohydrazide (2)
799
2
3
Methyl 2-hydroxy-2,2-diphenylacetate (0.05 mol) and 12cm hydrazine hydrate (98%) were heated
under reflux for 12 h. The reaction mixture was transferred to a crystallizing dish and left aside until
crystallization. The crude product thus obtained was recrystallized from ethanol.
2-Hydroxy-N-(3-oxo-1-thia-4-azaspiro[4.4]non-4-yl)=(3-oxo-1-thia-4-
azaspiro[4.5]dec-4-yl)-2,2-diphenylacetamides 3 and 4 (General Procedure)
A mixture of 2 (0.005 mol), an appropriate cyclic ketone (0.005mol), and mercaptoacetic acid or ꢁ-
3
mercaptopropionic acid (0.02 mol) was refluxed in 20cm dry benzene for 5–6 h using a Dean-Stark
water separator. Excess benzene was evaporated in vacuo. The resulting residue was triturated with
saturated NaHCO solution until CO evolution ceased and was allowed to stand overnight or in some
2
3
cases refrigerated until solidification. The solid thus obtained was washed with water, dried, and
recrystallized from ethanol.
2
-Hydroxy-N-(3-oxo-1-thia-4-azaspiro[4.4]non-4-yl)-2,2-diphenylacetamide (3a)
1
ꢂ1
IR(KBr): ꢃꢀ ¼ 3353 (O–H=N–H), 1682, 1729 (C¼O) cm ; H NMR (DMSO-d , 500 MHz): ꢂ ¼
6
b
.41–1.49 (m, 4H, spn ), 1.69–1.73 (m, 2H, spn), 2.03 (s, 2H, spn), 3.61 (s, 2H, C –H ), 6.82 (s,
1
1
1
2
2
H, COH), 7.28–7.35 (m, 6H, Ar–H), 7.43–7.44 (m, 2H, Ar–H), 7.45–7.46 (m, 2H, Ar–H), 10.31 (s,
H, CONH) ppm.
2
-Hydroxy-N-(3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-diphenylacetamide (3b)
1
ꢂ1
IR(KBr): ꢃꢀ ¼ 3354 (O–H=N–H), 1685, 1726 (C¼O) cm ; H NMR (DMSO-d , 500 MHz): ꢂ ¼ 0.80–
6
c
.07 (m, 1H, spd ), 1.34–1.38 (m, 2H, spd), 1.49–1.63 (m, 5H, spd), 1.73, 1.76 (2s, 2H, spd), 3.54 (s,
1
2
H, C –H ), 6.81 (s, 1H, COH), 7.28–7.35 (m, 6H, Ar–H), 7.46 (s, 2H, Ar–H), 7.47–7.48 (m, 2H,
2
2
1
3
Ar–H), 10.21 (s, 1H, CONH) ppm; C NMR(APT) (DMSO-d , 125MHz): ꢂ ¼ 23.56 (C spd), 24.83
6
7,9
(
(
C spd), 28.64 (C spd), 37.61 (C
8
spd), 73.30 (C spd), 81.61 (C–OH), 128.05, 128.25, 128.30
6,10 5
2
ar CH), 144.40 (ar C), 167.98 (amide C¼O), 173.40 (lactam C¼O) ppm.
2
-Hydroxy-N-(8-methyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-diphenylacetamide (3e)
1
ꢂ1
IR(KBr): ꢃꢀ ¼ 3435, 3230 (O–H=N–H), 1682, 1704 (C¼O) cm ; H NMR (DMSO-d , 500MHz):
6
ꢂ ¼ 0.83 (d, 3H, J ¼ 4.88Hz, 8-CH spd), 1.06 (t, 4H, J ¼ 7.07Hz, spd), 1.58–1.63 (m, 4H, spd), 1.71–
3
1
.74 (m, 1H, spd), 3.54 (s, 2H, C –H ), 6.80 (s, 1H, COH), 7.28–7.36 (m, 6H, Ar–H), 7.44–7.45 (m,
2 2
2
H, Ar–H), 7.46–7.47 (m, 2H, Ar–H), 10.20 (s, 1H, CONH) ppm.
2
-Hydroxy-N-(8-ethyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-diphenylacetamide (3f)
1
ꢂ1
IR(KBr): ꢃꢀ ¼ 3337 (O–H=N–H), 1665, 1723 (C¼O) cm ; H NMR (DMSO-d , 500 MHz): ꢂ ¼ 0.83
6
(
t, 4H, J ¼ 7.56 Hz, 8-CH CH and C -H spd), 1.01–1.09 (m, 2H, C -H spd), 1.16 (quint, 2H,
2
3
8
7,9 ax
J ¼ 7.32Hz, 8-CH CH ), 1.65 (d, 4H, J ¼ 12.20 Hz, C -H and C7,10-Heq spd), 1.75 (d, 2H, J ¼
2
3
6,10 ax
1
3.67 Hz, C -H spd), 3.54 (s, 2H, C –H ), 6.81 (s, 1H, COH), 7.28–7.36 (m, 6H, Ar–H), 7.46–
6,10 eq 2 2
1
3
7
.48 (m, 4H, Ar–H), 10.21 (s, 1H, CONH) ppm; C NMR(HSQC) (DMSO-d , 125MHz): ꢂ ¼ 12.02
6
(8-CH CH spd), 28.63 (C spd), 29.38 (8-CH CH spd), 29.61 (C spd), 37.28 (C
7,9
spd), 37.97 (C
6,10 8
2
3
2
2
3
spd), 73.344 (C spd), 81.60 (C–OH), 128.03, 128.24, 128.28, 128.36 (ar CH), 144.45 (ar C), 168.01
5
(amide C¼O), 173.39 (lactam C¼O) ppm.
2
-Hydroxy-N-(2,6-dimethyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-diphenylacet-amide (4c)
1
ꢂ1
IR(KBr): ꢃꢀ ¼ 3335 (O–H=N–H), 1679, 1731 (C¼O) cm ; H NMR (DMSO-d , 500 MHz): ꢂ ¼ 0.93
6
(t, 3H, J ¼ 6.83 Hz, 6-CH ), 0.95–1.10 (m, 1H, spd), 1.11–1.14 (m, 1H, spd), 1.19–1.27 (m, 1H, spd),
3
b
c
spn ¼ spirononane
spd ¼ spirodecane

¨
O. G u¨ zel et al.
8
00
1
1
7
.41 (t, 3H, J ¼ 7.32 Hz, 2-CH ), 1.45–1.67 (m, 5H, spd), 1.83–1.87 (m, 1H, spd), 3.77, 3.85 (2q,
3
H, J ¼ 6.83 Hz, C –H), 6.78 (s, 1H, COH), 7.26–7.31 (m, 2H, Ar–H), 7.33–7.35 (m, 4H, Ar–H),
2
.45–7.49 (m, 4H, Ar–H), 9.93, 10.05 (2s, 1H, CONH) ppm.
2
-Hydroxy-N-(2,8-dimethyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-diphenylacetamide (4e)
1
ꢂ1
IR(KBr): ꢃꢀ ¼ 3365 (O–H=N–H), 1682, 1722 (C¼O) cm ; H NMR (DMSO-d , 500 MHz): ꢂ ¼ 0.83
6
(
d, 3H, J ¼ 5.86 Hz, 8-CH ), 1.05–1.12 (m, 3H, spd), 1.42 (d, 3H, J ¼ 5.85 Hz, 2-CH ), 1.60 (d, 3H,
3
3
J ¼ 11.23 Hz, spd), 1.70 (d, 3H, J ¼ 8.79 Hz, spd), 3.83 (q, 1H, J ¼ 6.99Hz, C –H), 6.80 (s, 1H, COH),
2
1
.28–7.36 (m, 6H, Ar–H), 7.46–7.49 (m, 4H, Ar–H), 10.25 (s, 1H, CONH) ppm; C NMR(APT)
3
7
(
DMSO-d , 125 MHz): ꢂ ¼ 20.39 (2-CH spd), 22.49 (8-CH spd), 31.39 (C spd), 31.89 (C spd),
6
3
3
8
7
3
1
2.39 (C spd), 37.44 (C spd), 37.47 (C spd), 38.23 (C spd), 71.74 (C spd), 81.60 (C–OH), 128.04,
9 6 2 10 5
28.07, 128.23, 128.26, 128.29, 128.32 (ar CH), 144.43, 144.47 (ar C), 170.67 (amide C¼O), 173.30
ꢂ
(
lactam C¼O) ppm; LC=MS: m=z ¼ 423 (M–H) .
2
-Hydroxy-N-(8-propyl-2-methyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-
diphenylacetamide (4g)
1
IR(KBr): ꢃꢀ ¼ 3388, 3276 (O–H=N–H), 1682, 1722 (C¼O); H NMR (DMSO-d , 500 MHz): ꢂ ¼ 0.83 (t,
6
3
1
1
H, J ¼ 6.59 Hz, 8-CH CH CH ), 0.96–1.01 (m, 3H, spd), 1.10 (q, 2H, J ¼ 7.16 Hz, 8-CH CH CH ),
2
2
3
2
2
3
.22–1.28 (m, 2H, 8-CH CH CH ), 1.41 (d, 3H, J ¼ 9.02 Hz, 2-CH ), 1.64 (d, 3H, J ¼ 12.20 Hz, spd),
2
2
3
3
.69–1.71 (m, 3H, spd), 3.82 (q, 1H, J ¼ 6.99Hz, C –H), 6.79 (s, 1H, COH), 7.28–7.35 (m, 6H, Ar–
2
1
3
H), 7.45–7.47 (m, 4H, Ar–H), 10.24 (s, 1H, CONH) ppm; C NMR(APT) (DMSO-d , 125 MHz)
6
ꢂ ¼ 14.82 (8-CH CH CH spd), 20.15 (8-CH CH CH spd), 20.39 (2-CH spd), 29.81 (C spd), 30.29
2
2
3
2
2
3
3
7
(C spd), 35.89 (C spd), 37.39 (8-CH CH CH spd), 37.46 (C spd), 38.18 (C spd), 39.01 (C spd),
9 8 2 2 3 2 6 10
7
2.03 (C spd), 81.57 (C–OH), 128.02, 128.23, 128.25, 128.28, 128.30 (ar CH), 144.43, 144.47 (ar C),
5
1
70.65 (amide C¼O), 173.27 (lactam C¼O) ppm.
2
-Hydroxy-N-(2-methyl-8-phenyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)-2,2-
diphenylacetamide (4h)
IR(KBr): ꢃꢀ ¼ 3395 (O–H=N–H), 1683, 1721 (C¼O) cm ; H NMR (DMSO-d , 500 MHz): ꢂ ¼ 1.44
ꢂ1
1
6
(
d, 3H, J ¼ 6.84Hz, 2-CH ), 1.49–1.71 (m, 3H, spd), 1.77–1.84 (m, 6H, spd), 3.88 (q, 1H, J ¼ 6.99 Hz,
3
C –H), 6.84 (s, 1H, COH), 7.16–7.19 (m, 3H, Ar–H), 7.26–7.32 (m, 4H, Ar–H), 7.34–7.37 (m, 4H,
2
Ar–H), 7.49–7.51 (m, 4H, Ar–H), 10.33 (s, 1H, CONH) ppm; LC=MS: m=z ¼ 485 (M–H)ꢂ.
In Vitro Evaluation of Antituberculosis Activity
3
Primary screen was conducted at 6.25ꢀg=cm against Mycobacterium tuberculosis H37Rv in BACTEC
1
2B medium using a broth microdilution assay: Microplate Alamar Blue Assay (MABA). Compounds
3
effecting <90% inhibition in the primary screen (MIC>6.25 ꢀg=cm ) were not evaluated further [15].
Acknowledgements
Antimycobacterial data were provided by the Tuberculosis Antimicrobial Acquisition and Coordinat-
ing Facility (TAACF) through a research and development contract with the U.S. National Institute of
Allergy and Infectious Diseases. Thanks are addressed to Dr. Joseph A. Maddry (TAACF) and his team
for their collaboration. This work was supported by The Research Fund of Istanbul University (Project
Number 290=05012005).
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1] Corbett EL, Watt CJ, Walker N (2003) Arch Intern Med 163: 1009
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¨
[
2] Ates O, Kocabalkanli A, Sanis Ot u¨ k G, Ekinci AC, Vidin A (1997) Arzneim-Forsch=Drug Res
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4

Synthesis and Antimycobacterial Activity of Spirothiazolidinones
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