Design, synthesis and antibacterial activity of novel 1,3-thiazolidine pyrimidine nucleoside analogues

Article abstract of DOI:10.1016/j.bmc.2006.07.014

The synthesis of a new class of 1,3-thiazolidine nucleoside analogues in which furanose oxygen atom was replaced with nitrogen atom and 2′-carbon atom with sulfur atom is described. N-tert-butoxycarbonyl-2-acyloxy-4-trityloxymethyl-1,3-thiazolidine was coupled with the pyrimidine bases like uracil, thymine, etc. in the presence of lewis acids stannic chloride or trimethyl silyl triflate following Vorbruggen procedure. The antibacterial activity of the novel 1,3-thiazolidine pyrimidine nucleoside analogues is highlighted. All compounds (7a-e) with free NH group in the pyrimidine moiety showed significant biological activity against all the standard strains used and in that compounds 7d and 7e showed significant activity against 14 human pathogens tested.

Full text of DOI:10.1016/j.bmc.2006.07.014

Bioorganic & Medicinal Chemistry 14 (2006) 7476–7481
Design, synthesis and antibacterial activity of novel 1,3-thiazolidine
pyrimidine nucleoside analogues
Shimoga Nagaraj Sriharsha,a Sridharamurthy Satish,b Sheena Shashikantha,*
and Koteshwara Anandarao Raveeshab
aDepartment of Studies in Chemistry, University of Mysore, Manasagangothri, Mysore 570 006, India
bDepartment of Studies in Microbiology, University of Mysore, Manasagangothri, Mysore 570 006, India
Received 13 May 2006; revised 3 July 2006; accepted 7 July 2006
Available online 4 August 2006
Abstract—The synthesis of a new class of 1,3-thiazolidine nucleoside analogues in which furanose oxygen atom was replaced with
nitrogen atom and 20-carbon atom with sulfur atom is described. N-tert-butoxycarbonyl-2-acyloxy-4-trityloxymethyl-1,3-thiazoli-
dine was coupled with the pyrimidine bases like uracil, thymine, etc. in the presence of lewis acids stannic chloride or trimethyl silyl
triflate following Vorbruggen procedure. The antibacterial activity of the novel 1,3-thiazolidine pyrimidine nucleoside analogues is
highlighted. All compounds (7a–e) with free NH group in the pyrimidine moiety showed significant biological activity against all the
standard strains used and in that compounds 7d and 7e showed significant activity against 14 human pathogens tested.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
formation of the 70 S ribosomal initiation complex.4
Thus, it inhibits the bacterial protein synthesis. The
1,3-thiazolidine structure is relatively simple and allows
for diverse synthetic modifications.
The chemical modification of nucleic acid fragments of-
fers a continuous challenge for the organic chemists in
search of compounds with antiviral and antibacterial
activity.1 Accordingly considerable efforts have been
made to develop new nucleoside analogues likely to
exhibit improved activity or decreased toxicity with
respect to the 30-azido 50-deoxythymidine (AZT). In this
context, design of novel ribose rings has resulted in the
discovery of effective biologically active agents; in par-
ticular promising results have been obtained from new
generation of nucleoside analogues where the ribose
moiety has been replaced by the alternative heterocyclic
rings.2
Based on the above observations, we have carried out
the synthesis of the new class of 1,3-thiazolidine nucleo-
side analogues using Vorbruggen procedure.5 In our
strategy, furanose oxygen atom has been replaced by
nitrogen atom and 20-carbon atom by sulfur atom.
Replacement of furanose oxygen atom by nitrogen atom
would provide the system with more conformational
flexibility.6 Moreover positive charge associated with
protonation to the nitrogen atom on 1,3-thiazolidine
ring would be expected to play an important role on
the inhibition of viral or cellular enzymes which are
essential for viral replication.7 The newly synthesized
1,3-thiazolidine nucleoside analogues 7a–e showed sig-
nificant antibacterial activity.
1,3-Thiazolidines are the new class of antimicrobial
agents with activity against broad spectrum of Gram-
positive pathogens including Staphylococci, Streptococci
and Enterococci.3 These compounds inhibit the protein
synthesis in actively growing bacteria. Mechanism of ac-
tion supports 1,3-thiazolidinone moiety being binded to
the bacterial 50 S ribosomal sub units and inhibition of
2. Chemistry
Our synthetic strategy was based on the preparation of
N-tert-butoxycarbonyl-4-methoxycarbonyl-1,3-thiazoli-
dine-2-one 2 followed by the reduction and acylation to
give N-tert-butoxycarbonyl-2-acyloxy-4-trityloxymeth-
yl-1,3-thiazolidine 5.
Keywords: 1,3-Thiazolidine nucleosides; Vorbruggen coupling; NOE
experiment; Antibacterial activity.
*
Corresponding author. Tel.: +91 0821 2419668; e-mail:
skanth1@rediffmail.com
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.07.014

S. N. Sriharsha et al. / Bioorg. Med. Chem. 14 (2006) 7476–7481
7477
The compound 2 was prepared by condensing di-tert-
butyl-di-carbonate with L-cystiene methyl ester hydro-
chloride in the presence of dimethylaminopyridine
(DMAP) and triethylamine.8 The lactam and the ester
functional groups were reduced by using lithium trieth-
ylborohydride (Li(Et)3BH) at 0 ꢁC to get the N-tert-
butoxycarbonyl-4-hydroxymethyl-1,3-thiazolidine-2-ol 3
in quantitative yield.9 Protection of primary alcoholic
group using trityl chloride in the presence of pyridine
gave N-tert-butoxycarbonyl-4-trityloxymethyl-1,3-thiaz-
olidine-2-ol 4.10 Which upon treatment with acetic anhy-
dride, dimethylaminopyridine and triethylamine gave
compound 5 (Scheme 1). The compound 5 was coupled
with silylated pyrimidine bases in the presence of lewis
acids Stannic Chloride or trimethylsilyl triflate (TMS tri-
flate) (Scheme 2). This gave the desired nucleoside
analogues (7a–e) in moderate yield.11,12 The N-tert-bu-
toxycarbonyl (Boc) and trityl (T) groups were deprotec-
ted by stirring it with trifluoroacetic acid at room
temperature which gave the desired products (7a–e) in
excellent yeild.13
deoxyribonucleosides in contrast to the anomeric mix-
ture routinely obtained by using other methods.15–17
O
4
CH3
HN
5
3
6 H
2
O
1 N
OH
H
N
H5/
H4/
H1/
S
H3/
2/
Beta-L-Nucleoside
NOE Correlations from NOESY
Spectra of the compound 7b
The structure and configuration was obtained through
NOE experiment. According to NOE, 6H is giving cross
peak to 5-CH3, 50-H, 40-H and OH. 6H and 50-H cross
peak is more stronger compared to 6H to 40-H. So 50-
H is more nearer to 6H compared to 40-H. This is pos-
sible only in b configuration. The NOE between 6H to
50-H and 6H to OH suggests that it is L-configuration.
In this connection the structure is b-L-Nucleoside.
The proton NMR spectra of the 7b showed singlet due
to the 6H in the region at d 7.63. The signals due to
the NH protons of the pyrimidine moiety appeared
downfield in the region at d 11.27. The 10-H proton of
the 1,3-thiazolidine ring appeared as a singlet in the re-
gion at d 6.8 indicating the attachment of the 1,3-thiaz-
olidine moiety to the pyrimidine base.14 While triplet
due to the 50-OH protons appeared at d 4.98. The 5-
methyl group appeared in the region at d 1.71. The
30H and 40H appeared in the region between d 5.9 and
6.4. The NH proton of the 1.3-thiazolidine moiety
appeared in the region at d 4.75. The mass spectra of ob-
tained compounds showed molecular ion peaks, which
were consistent with their molecular formulae. The
structures of the synthesized compounds were character-
3. Antibacterial results
The target and intermediate test compounds were passed
through a general antibacterial screen. Fourteen human
pathogenic bacteria were chosen to evaluate the synthe-
sized nucleoside analogues for antibacterial activity. All
compounds were tested at a concentration of 15 mg. The
parent molecule 5, the synthesized nucleosides (7a–e)
and antibiotics Bacitracin and Ciprofloxacin were
screened against the bacteria shown in Table 1. The test
compounds exhibited quite diverse activities, 7d and 7e
showed significant activity against Gram +ve and Gram
ꢀve bacteria that was more than that of the parent mol-
ecule and the tested antibiotics. The control bacitracin
1
ized by the IR, H NMR, 13C NMR, mass spectra, ele-
mental analysis and NOE experiment.
This modification was envisaged by the formation of
nucleosides in enhanced yield and if the sugar moiety
carries a 2-a-acyloxy function, the reaction reaches
absolute stereospecificity, resulting in the b-ribo or
Boc
Boc
NH2
O
N
ii
COOCH3
N
CH2OH
i
HO
SH
H3COOC
S
S
1
3
2
iii
Boc
N
Boc
CH2OTr
HO
N
CH2OTr
H3COCO
iv
S
S
4
5
Scheme 1. Reagents and conditions: (i) (Boc)2O, DMAP, (Et)3N, rt; (ii) Li(Et)3BH, THF, 0 ꢁC; (iii) trityl chloride, pyridine, reflux; (iv) (CH3CO)2O,
DMAP, (Et)3N, rt.

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S. N. Sriharsha et al. / Bioorg. Med. Chem. 14 (2006) 7476–7481
O
O
R
R
HN
HN
O
N
O
N
ii
i
5
OH
OTr
H
Boc
N
N
S
S
7a-e
6a-e
Scheme 2. Reagents and conditions: (i) Silylated pyrimidine base, TMSOTf or SnCl4, CH3CN, 0 ꢁC; (ii) triflouroacetic acid, rt. Base (a) R=H, uracil;
(b) R=CH3, thymine; (c) R=SH, 5-thiouracil; (d) R=Br, 5-bromouracil; (e) R=Cl, 5-chlorouracil.
Table 1. Antibacterial activity of five newly synthesized nucleoside analogues and antibiotics against human pathogenic bacteria
S. No Pathogens
5
7a
7b
7c
7d
7e
Bacitracin
Ciprofloxacin
1
2
3
4
5
Citrobacter sp.
Escherichia coli
Klebsiella sp.
12.33 0.17 13.66 0.22 28.50 0.27 12.50 0.39 37.16 0.15 28.66 0.15 0.00 0.00 19.62 0.18
14.50 0.28 17.00 0.00 29.50 0.25 15.16 0.22 36.66 0.15 27.83 0.20 0.00 0.00 0.00 0.00
09.83 0.20 10.33 0.16 21.50 0.17 09.50 0.28 32.50 0.13 25.50 0.27 0.00 0.00 20.25 0.16
07.50 0.13 08.50 0.27 22.66 0.15 18.00 0.00 28.66 0.25 23.33 0.17 0.00 0.00 18.25 0.16
12.50 0.27 11.50 0.23 34.50 0.13 10.00 0.00 30.66 0.12 27.83 0.27 0.00 0.00 34.25 0.16
Proteus mirabilis
Pseudomonas
aeruginosa
6
7
S. parathyphi A
S. parathyphi B
Salmonella typhi
S. typhimurium
Shigella boydii
Shigella flexneri
Shigella sonnei
08.50 0.27 13.50 0.21 29.50 0.25 11.50 0.18 34.66 0.12 24.50 0.12 0.00 0.00 27.75 0.16
06.50 0.28 17.33 0.18 30.66 0.66 16.50 0.19 32.50 0.13 27.83 0.20 0.00 0.00 27.63 0.18
15.66 0.15 16.50 0.19 27.83 0.20 18.83 0.14 29.50 0.25 19.66 0.11 0.00 0.00 20.25 0.16
10.50 0.12 15.50 0.20 25.50 0.27 12.33 0.15 34.66 0.12 23.33 0.17 0.00 0.00 18.75 0.31
12.66 0.15 17.33 0.18 27.83 0.20 15.50 0.20 37.50 0.07 28.66 0.25 0.00 0.00 17.75 0.16
07.33 0.17 08.5 0.27 19.66 0.11 10.33 0.16 35.66 0.08 25.50 0.27 0.00 0.00 27.63 0.18
08.66 0.25 07.66 0.14 21.50 0.17 08.50 0.27 32.50 0.13 37.50 0.07 0.00 0.00 21.75 0.16
8
9
10
11
12
13
14
Staphylococcus aureus 7.00 0.00 0.00 0.00 17.33 0.18 0.00 0.00 37.50 0.07 32.50 0.13 26.75 0.84 18.13 0.48
Streptococcus faecalis 0.00 0.00 6.50 0.30 19.66 0.11 05.50 0.33 38.50 0.12 35.66 0.08 0.00 0.00 0.00 0.00
Zone of inhibition (mean of six replicate standard error).
p < 0.05.
exhibited no activity towards any of the Gram ꢀve bac-
teria and showed activity only against Staphylococcus
aureus (Gram +ve). Antibacterial activity was maximum
against Streptococcus faecalis (35.66 mm) and was min-
imum against Salmonella typhi (29.50 mm) in 7e synthe-
sized nucleoside. In case of 7d synthesized nucleoside the
antibacterial activity was more against S. faecalis
(38.50 mm) and less against Proteus mirabilis (28.66).
The antibacterial activity was observed in the parent
molecule and all the synthesized nucleosides (7a–e).
4. Conclusion
In conclusion, we have presented short and efficient
preparations of the 1,3-thiazolidine nucleoside ana-
logues, which as a consequence of their low toxicity
should prove to be important antibacterial agents. The
antibacterial activity of these compounds was studied.
All compounds (7a–e) with free NH group in the pyrim-
idine moiety showed significant biological activity and in
that compounds 7d and 7e showed significant activity
against 14 human pathogens tested. The results of exper-
iments suggest that these nucleosides are good candidate
for further investigation on their therapeutic value for
management of diseases caused by the test bacteria. Fur-
ther studies should also explore the relevance of substi-
tutions on the halogen at human cell toxicity and the
scope of antibacterial activity.
All compounds (7a–e) with free NH group in pyrimidine
moiety showed significant biological activity against all
the test bacteria. Further compounds replaced with alkyl
group at the 5th position of the pyrimidine moiety might
have increased the activity 7b. There is an important role
of the mercapto and halogens attached at the 5th posi-
tion of the pyrimidine moiety in enhancing the activi-
ty.18 Which reveals that the compounds replaced with
different nucleophiles show significant activity. In that
compounds replaced with highly electronegative halo-
gens, for example, bromine 7d and chlorine 7e show in-
creased activity against all test bacteria. It is interesting
to note that both 7d and 7e synthesized nucleosides are
active against Bacitracin-resistant bacteria. The degree
of activity of the parent molecule 5 is generally less than
that of all the synthesized nucleosides, but the activity
was nearer to the compound 7c.
5. Experimental
5.1. Instrumentation and general materials
All reagents used were of AR grade. THF was distilled
from sodium/benzophenone prior to use. Melting points
were determined using a Thomas Hoover melting point
apparatus and are uncorrected. The 1H (300 MHz)
and 13C NMR (300 MHz) spectra were recorded on a

S. N. Sriharsha et al. / Bioorg. Med. Chem. 14 (2006) 7476–7481
7479
Bruker 300 NMR spectrometer in CDCl3 and DMSO-d6
(with TMS for 1H and DMSO-d6 for 13C as internal ref-
erences) unless otherwise stated. MS were recorded on
Agluent 1100 ES-MS, Karlsruhe, Germany. Infrared
spectra (tmax) were recorded on Perkin Elmer FT-IR
spectrophotometer as thin films on KBr plates (for oils)
or KBr discs (for solids). Column chromatography was
performed on silica gel (230–400 mesh). Microanalyses
were obtained with an Elemental Analysensysteme
GmbH VarioEL V3.00 element analyzer. The reactions
were monitored by thin-layer chromatography (TLC)
using aluminium sheets with silica gel 60 F254 (Merck).
All the reactions were carried out under nitrogen
atmosphere.
5.1.3. N-tert-Butoxycarbonyl-4-hydroxymethyl-2-acyl-
oxy-1,3-thiazolidine (5). A solution of trityl derivative
(4) in CH2Cl2 was treated with acetic anhydride (2.6 g,
26.3 mmol), triethylamine (2.6 g, 26.3 mmol) and a cat-
alytic amount of 4-DMAP (dimethyl amino pyridine)
at room temperature for 3 h. The resultant mixture
was washed with 5% HCl, extracted with CH2Cl2, evap-
orated to dryness and purified by silica gel column chro-
matography with 5% chloroform/ethyl acetate 7:2 to get
white solid.
White solid (from EtOAc/hexanes), (0.7493 g, 65%);
mp 164–167 ꢁC; IR (nujol): 1710–1720 (C@O of
Boc-ester group), 1690 (C@O), 1500 cmꢀ1 (Ar H).
1H NMR (CDCl3): d, 4.24 (dd, J = 8.5, 2.25 Hz, 1H)
3.64 (dd, J = 11.75, 8.5 Hz, 1H), 3.34 (dd, J = 11.75,
2.25 Hz, 1H), 3.38 (t, 2H), 1.51 (s, 9H, Boc ester),
6.68 (s, 1H, CH), 3.0 (s, 3H, CH3), 7.19 (m, 15H,
ArH). 13C NMR (CDCl3): d 64.6, 29.0, 89.4, 154.1,
79.8, 28.5, 28.5, 28.5, 85.9, 128.3, 129.3, 126.3,
129.3, 128.3, 129.3, 126.3, 128.3, 143.3, 143.9, 128.3,
129.3, 126.3, 129.3, 129.3, 170.3,20.7; LC–MS (m/z)
471.6 (M+1, 70%). Anal. Calcd For C30H33NO5S: C,
69.34; H, 6.40; N, 2.70; S, 6.17. Found: C, 68.35; H,
5.42; N, 2.12; S, 6.05.
5.1.1. N-tert-Butoxycarbonyl-4-(hydroxyl methyl)-1,3-
thiazolidin-2-ol (3). Compound 2 was dissolved in THF
(20 ml), cooled to 0 ꢁC and was added 3 equiv of 1 M
solution of Li(Et)3BH. The reaction requires 10–
60 min to go to completion. Excess of reagent was de-
stroyed by the addition of saturated solution of NH2Cl
aq solution at 0 ꢁC and the reaction mixture was extract-
ed with 15 ml dichloromethane, dried over anhydrous
MgSO4 and evaporated to dryness followed by the puri-
fication by flash chromatography (hexane/ethyl acetate
7:2) to get the compound 3 as light yellow oil.
5.1.4. General procedure for the synthesis of 1,3-thiazoli-
dine nucleoside analogues (7a–e).
Light yellow oil (from EtOAc/hexanes) (0.119 g, 67%);
IR (nujol): 1710–1720 (C@O of Boc-ester group),
A
mixture of
pyrimidine base (2.35 mmol) in HMDS (hexamethyldi-
silazane) (10 ml) and CH3CN was heated under reflux
for 5 h. After removal of solvent by vacuum pump, a
solution of acetate (5) (0.786 mmol) in 15 ml CH3CN
was added to the reaction flask containing the silylat-
ed pyrimidine bases and then SnCl4 (1.4 mmol) was
added dropwise at room temperature. After 16 h, the
reaction was quenched with 1 ml of saturated solution
of NaHCO3 and the resultant mixture was concentrat-
ed. The crude mixture was diluted with 100 ml
CH2Cl2, washed with 5% NaHCO3, dried over
MgSO4, filtered and concentrated. The crude product
was purified by silica gel column chromatography with
30% ethyl acetate in hexane to give nucleoside ana-
logues. Finally Boc and trityl groups were deprotected
by stirring it with trifluoroacetic acid at room temper-
ature to get the desired products (7a–e) in moderate
yield.
1
3200–3220 cmꢀ1 (OH). H NMR (CDCl3): d, 4.24 (dd,
J = 8.5, 2.25 Hz, 1H), 3.64 (dd, J = 11.75, 8.5 Hz, 1H),
3.32 (dd, J = 11.75, 2.25 Hz, 1H), 1.51 (s, 9H, Boc ester),
3.88 (t, 2H), 5.2 (2H, s, OH), 6.68 (1H, s, CH): 13C
NMR (CDCl3): d 66.0, 32.3, 86.0, 154.1, 79.8, 28.5,
28.5, 68.5. LC–MS (m/z) 219.2 (M+1, 55%). Anal. Calcd
for C9H17NO4S: C, 45.95; H, 7.23; N, 5.95; S, 13.6.
Found: C, 44.89; H, 7.05; N, 5.86; S, 12.9.
5.1.2. N-tert-Butoxycarbonyl-4-(trityloxy methyl)-1,3-
thiazolidine-2-ol (4). Compound 3 (4 mmol) and trityl
chloride (triphenylmethylchloride) (5 mmol) were dis-
solved in 20 ml of pyridine. The mixture was heated at
100 ꢁC (steam bath) with swirling for 30 min. The reac-
tion mixture was cooled at room temperature and then
poured into 100 ml of ice water. The slurry was stirred
vigorously during quenching. The solid was filtered
and it was washed thoroughly with water until it is free
from pyridine. The solid was dried separately. The white
product O-trityl derivative was purified by recrystalliza-
tion from acetone–toluene.
5.1.4.1. Procedure for the deprotection of Boc and
trityl groups in compounds 6a–e. To a solution of 6a–e
(2.34 mmol) in CH2Cl2 (2.5 ml) was added TFA (2 ml)
under nitrogen atmosphere at RT. After stirring at the
same temperature for 24 h, the solvent was evaporated
under reduced pressure. Purification of the residue by
washing with ether afforded the targeted nucleoside ana-
logues 7a–e in excellent yield.
White solid (from EtOAc/hexanes), (1.05 g, 60%); mp
154–156 ꢁC; IR (nujol): 1710–1720 (C@O of Boc-ester
1
group), 3200–3220 (OH), 1500 cmꢀ1 (ArH). H NMR
(CDCl3): d, 4.24 (dd, J = 8.5, 2.25 Hz, 1H), 3.64 (dd,
J = 11.75, 8.5 Hz, 1H), 3.30 (dd, J = 11.75, 2.25 Hz,
1H), 3.88 (t, 2H), 1.51 (s, 9H, Boc ester), 6.68 (1H, s,
CH), 2 (2H, s, OH), 7.19 (m, 15H, ArH). 13C NMR
(CDCl3): d 66.0, 32.3, 86.0, 154.1, 79.8, 28.5, 85.9, 143.9,
128.3, 129.3, 126.3, 128.3, 143.3, 143.9, 128.3, 129.3,
126.3, 129.3, 129.3, 70.1. LC–MS (m/z) 429 (M+1, 65%).
Anal. Calcd for C27H30NO4S: C, 70.41; H, 6.54; N,
2.93;S, 6.71: Found: C, 69.42; H, 5.53; N, 2.04; S, 6.22.
5.1.4.2.
1-(4-Hydroxymethyl-1,3-thiazolidine-2-yl)-
25
D
uracil (7a). ½aꢁ ꢀ146 (c 2.5, CH3OH); white needles
(from EtOAc/hexanes), (0.6344 g, 52%); mp 143–
146 ꢁC; IR (nujol): 1890 (C@O), 1690 (C@O), 2950
(NH), 3557 cmꢀ1 (OH). 1H NMR (DMSO-d6): d,
3.10–3.50 (m, 2H, 20-H), 3.95–4.10 (m, 2H, 50-H), 5.01
(t, 1H, 50-OH), 5.20 (t, 1H, 40-H), 5.50 (d, J = 7.9 Hz,

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S. N. Sriharsha et al. / Bioorg. Med. Chem. 14 (2006) 7476–7481
1H, 5H), 5.88 (s, 1H, NH), 6.33 (m, 1H, 10-H), 7.95 (d,
7.9 Hz, 1H, 6-H), 11.20 (br s, 1H, NH). 13C NMR
(DMSO-d6): d 80.5, 34.5, 64.0, 141.3, 102.4, 163.6,
150.9, 65.0. LC–MS (m/z) 229 (M+, 87), 175 (15), 153
(7), 95 (38), 83 (8). Anal. Calcd for C8H11N3O3S: C,
41.91; H, 4.84; N, 18.33; S, 13.99. Found: C, 41.84; H,
4.75; N, 18.20; S, 13.88.
in the suspension was adjusted to a minimum of
1 · 105 cfu/ml in nutrient broth solution. Agar cup
of 5 mm diameter was made in the plates. Each test
sample (5 and 7a–e) was dissolved in dimethyl form-
amide (DMF), 50 ll of test solution containing
15 mg of the test compound was placed in each cup.
The plates were left to stay for an hour in order to
facilitate the diffusion of the drug solution. Negative
controls were prepared using the same solvent
(DMF) employed to dissolve the test compounds.19
Then the plates were incubated at 37 ꢁC for 24 h.
The zone of inhibition if any against the test bacteria
was measured in mm. Bacitracin and Ciprofloxacin
were used as positive reference to determine the sensi-
tivity of each bacterial species tested.
5.1.4.3.
1-(4-Hydroxymethyl-1,3-thiazolidine-2-yl)-
25
thymine (7b). ½aꢁ ꢀ121 (c 2.5, CH3OH); white solid
D
(from EtOAc/hexanes), (0.622 g, 58%); mp 148–150 ꢁC;
IR (nujol): 1890 (C@O), 1690 (C@O), 2950 (NH),
3557 cmꢀ1 (OH). H NMR (DMSO-d6): d, 1.71 (s, 3H,
1
5-CH3), 3.59 (m, 2H, 50-H), 4.98 (t, 1H, 50-OH), 4.79
(s, 1H, 61 NH), 6.8 (s, 1H, 10-H), 6.38 (t, 1H, 40-H),
5.9 (dd, J = 6.3 and 8.8 Hz, 2H, 30-H), 7.63 (s, 1H, 6-
H), 11.27 (br s, 1H, NH). 13C NMR (DMSO-d6): d
80.8, 34.5, 64.0, 137.5, 110.9, 163.8, 150.9, 65.0. LC–
MS (m/z) 243 (M+, 92), 175 (15), 167.5 (5), 109 (35),
82 (7). Anal. Calcd for C8 H11N3O3S: C, 44.43; H,
5.39; N, 17.27; S, 13.18. Found: C, 44.35; H, 5.25; N,
17.20; S, 13.10.
Acknowledgments
S.N.S. thanks CSIR, Government of India, New Delhi,
for Senior Research Fellowship and acknowledges Dr.
K. R. Prabhu, senior scientific officer, Department of
organic chemistry, IISC, Bangalore, for recording IR,
NMR and mass spectra.
5.1.4.4. 1-(4-Hydroxymethyl-1,3-thiazolidine-2-yl)-5-
25
D
thiouracil (7c). ½aꢁ ꢀ98 (c 2.5, CH3OH); yellow foam
(from EtOAc/hexanes), (0.517 g, 55%); IR (nujol):
1890 (C@O), 1690 (C@O), 3557 (OH, NH),
2600 cmꢀ1 (SH). 1H NMR (DMSO-d6): d 1.5 (s,
1H, SH), 3.10–3.50 (m, 2H, 20-H), 3.95–4.05 (m,
2H, 50-H), 5.00 (t, 1H, 50-OH), 5.20 (t, 1H, 40-H),
5.85 (s, 1H, NH), 5.95 (m, 1H, 10-H), 7.95 (s, 1H,
6-H), 11.20 (br s, 1H, NH). 13C NMR d: 80.1,
34.5, 64.0, 142, 100, 162.4, 150.9, 65.0. LC–MS (m/
z) 261 (M+, 89), 175 (15), 148.8 (15), 126.9 (35), 98
(6). Anal. Calcd for C8H11N3O3S2: C, 36.77; H,
4.24; N, 16.08; S, 24.54. Found: C, 36.65; H, 4.12;
N, 15.98; S, 24.43.
Supplementary data
1H NMR and 2D NOESY NMR spectral data of the
compound 7b are provided.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmc.2006.
07.014.
References and notes
5.1.4.5. 1-(4-Hydroxymethyl-1,3-thiazolidine-2-yl)-5-
bromouracil (7d). ½aꢁ ꢀ152 (c 2.5, CH3 OH); yellow
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25
D
oil (from EtOAc/hexanes), (0.3917 g, 52%); IR (nujol):
1890 (C@O), 1690 (C@O), 2950 (NH), 3557 cmꢀ1
1
(OH). H NMR (DMSO-d6): d 3.10–3.50 (m, 2H, 20-
H), 3.95-4.05 (m, 2H, 50-H), 5.00 (t, 1H, 50-OH), 5.20
(t, 1H, 40-H), 5.85 (s, 1H, NH), 5.95 (m, 1H, 10-H),
8.10 (s, 1H, 6-H), 11.20 (br s, 1H, NH). 13C NMR
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H, 3.56; N, 20.31; S, 11.55.
5.1.4.6. 1-(4-Hydroxymethyl-1,3-thiazolidine-2-yl)-5-
25
D
chlorouracil (7e). ½aꢁ ꢀ102 (c 2.5, CH3OH).
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