Newer Thiazolopyrimidine-Based Sulfonamides Clubbed With Benzothiazole Moiety: Synthesis and Biological Evaluation

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:47894802

DOI 10.1007/s00044-014-1052-7
ORIGINAL RESEARCH
Newer thiazolopyrimidine-based sulfonamides clubbed

with benzothiazole moiety: synthesis and biological evaluation
Navin B. Patel Amit C. Purohit Dhanji Rajani
Received: 17 February 2014 / Accepted: 20 May 2014 / Published online: 4 June 2014
Springer Science+Business Media New York 2014
Abstract A new class of thiazolopyrimidine-based sulfonamides (5aj) was synthesized from a parent compound
2-methoxy benzoic acid by multistep reaction in order to
find new agents to fight against microbial infections.
Substituted thiazolopyrimidines (3ae) were prepared by
cyclocondensation of substituted thiazolidinediones (2a
e) with urea in the presence of acid catalyst P2O5. Finally,
desired compounds (5aj) were synthesized from intermediates (4ae) prepared from compounds (3ae) by
chlorosulfonation followed by condensation with corresponding benzothiazole moiety. The synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR
spectral data, and elemental analysis, and were evaluated
for in vitro antimicrobial activity against certain bacterial
and fungal strains using the broth microdilution method as
well as antitubercular activity against H37Rv using
LowensteinJensen agar method.
Keywords Thiazolopyrimidines Sulfonamides
Antimicrobial activity Antitubercular activity
Electronic supplementary material The online version of this

article (doi:10.1007/s00044-014-1052-7) contains supplementary
material, which is available to authorized users.
N. B. Patel (&) A. C. Purohit
Department of Chemistry, Veer Narmad South Gujarat
University, Surat 395007, Gujarat, India
e-mail: drnavin@satyam.net.in
A. C. Purohit
e-mail: amitrajpurohit11@gmail.com
D. Rajani
Microcare Laboratory, Surat 395003, Gujarat, India
Introduction
Pyrimidines represent an important class of heterocycles
with a wide range of biological applications (Cumming
et al., 2004; Jain et al., 2006; Chan et al., 2005), and their
structural framework is a key constituent of numerous
natural biologically active compounds. One possible reason
for their activity is the presence of a pyrimidine base in
thymine, cytosine, and uracil, which are essential building
blocks of nucleic acids i.e., DNA and RNA. Some heterocycles containing pyrimidine moiety are reported to
show a broad spectrum of pharmacological properties such
as antimicrobial (Kanth et al., 2006), antiviral and anticancer (Andreani et al., 2002) analgesic, anti-inflammatory
(Boyle et al., 2001), and anti-HIV (Rawal et al., 2007). In
addition, fused pyrimidine derivatives such as thiazolopyrimidines (Sherif et al., 1993), thienopyrimidines (Hafez
and El-Gazzar, 2008), and pyridopyrimidines (Wu et al.,
2008) are also valuable as pharmacological aspects. It has
been noticed that the introduction of different heterocyclic
moieties to the pyrimidine core tends to exert profound
influence in conferring novel biological activities in this
molecule.
One of the important classes of fused pyrimidine ring is
thiazolo-pyrimidine and its analogs. Thiazolo[4,5-d]pyrimidine-5,7-dione analogs, especially, have been described as
having antimicrobial, anti-inflammatory activity (Bekhit
et al., 2003), and anticancer activity (Fahmy et al., 2003).
2-Aminothiazolo[4,5-d]pyrimidines, that act as CXCR2
receptor antagonists, are also well known (Baxter et al.,
2006; Walters et al., 2007).
Literature survey revealed that the sulfonamide moiety
is a common pharmacophore found in diverse biologically
active molecules (Scozzafava et al., 2003). The sulfonamide nucleus is associated with diverse pharmacodynamic
123
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Med Chem Res (2014) 23:47894802
Fig. 1 Structre of pyrimidinebased sulfonamide drugs and

thiazolopyrimidine-based title
compounds 5aj
and chemotherapeutic activities including antibacterial

(Ghorab et al., 2004), anticancer activities (Abou El Ella
et al., 2008; Ismail et al., 2006), antiviral, antifungal
(Ezabadi et al., 2008), selective Cox II inhibitors (Penning
et al., 1997), HIV-1 protease inhibitors (Turner et al., 1998),
and antitumor agents against multidrug-resistant tumors
(Shan et al., 1999, Lin et al., 2009). In addition, benzothiazole derivatives have attracted a great deal of interest due to
their antibacterial, antifungal and antimicrobial activity
(Russo et al., 1994; Vicini et al., 2003; Kayhan Bolelli et al.,
2012), antitubercular activity (Patel et al., 2010, 2013), and
anticancer activity (Huang et al., 2006).
There are numbers of drugs containing pyrimidine and
sulfonamide moieties in a single compact system, which
are used as antibacterial viz. sulfamethiazine and sulfadiazine, antimalarial and antibacterial viz. sulfadoxin, etc. as
shown in Fig. 1. In addition, it has been also observed that
incorporation of benzothiazole and sulfonamide nucleus
with some pyrimidine analogs exhibits potential antimicrobial activity (Bondock et al., 2009, Lin et al., 2009).
Due to this wide range of biological activities, new
approaches toward the synthesis of substituted pyrimidine
sulfonamides are needed to expand the diversity of these
compounds.
In view of above-mentioned findings and in continuation
of our interest in the synthesis of newer pyrimidine-based
heterocycles (Patel and Patel, 2011, 2009), to identify new
candidates that may be value in designing new, potent,
selective, and less toxic antimicrobial agents, herein, we
synthesized some newer thiazolo pyrimidine analogs
incorporating sulfonamide and benzothiazole moieties in a
123
single compact system and evaluated for biological activity

5aj.
Results and discussion

Chemistry
The synthetic protocol for the synthesis of intermediates
and final compounds 5aj are depicted in Schemes 1 and 2.
According to Scheme 1, 5-arylidene-2,4-thiazolidinediones
(1ae) were synthesized by the method described in the
literature (Patil et al., 2010; Bruno et al., 2002; Maccari et
al., 2010) and the intermediates, 5-(arylidene)-3-(2methoxybenzoyl) thiazolidine-2,4-diones 2ae were synthesized from the parent compound 2-methoxy benzoyl
chloride resulted by refluxing 2-methoxy benzoic acid with
thionyl chloride using 1,4-dioxane as reaction medium
followed by refluxing intermediates 1ae with parent
compound of the series in dry DMF. The compounds 2a
e were used as precursors for the synthesis of final compounds 5aj.
According to Scheme 2, multi-component cyclocondensation reaction was performed by reacting corresponding
thiazolidine-2,4-diones 2ae with urea and phosphorus
pentoxide as a catalyst in ethanolic hydrochloric acid to
yield substituted thiazolo pyrimidines 3ae followed by
chlorosulfonation to yield corresponding substituted sulfonyl
chlorides 4ae. In the next step, the desired final substituted
sulfonamides 5aj were obtained through the reaction of
substituted sulfonyl chlorides 4ae with corresponding
Med Chem Res (2014) 23:47894802
4791
Scheme 1 Synthesis of
intermediates 1ae, 2ae
Scheme 2 Synthesis of final compounds 5aj
different benzothiazoles assigned at appropriate reaction

condition in water. The purity of the compounds was
checked by thin-layer chromatography (TLC).
The synthesized compounds were confirmed by the IR,

NMR, and mass spectra. In IR spectrum of compound 2d,
absorption bands at 1,789, 1,682, and 1,652 cm-1 due to
123
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Med Chem Res (2014) 23:47894802
Table 1 Results of antimicrobial screening of synthesized compounds

Compound
Gram-positive bacteria
Gram-negative bacteria
Fungal species
S. aureus
MTCC-96
S. pyogenes
MTCC-443
E. coli
MTCC-442
P. aeruginosa
MTCC-2488
C. albicans
MTCC-227
A. niger
MTCC-282
2a
200
250
500
500
500
1,000
1,000
2b
250
500
500
62.5
200
500
500
2c
2d
500
125
1,000
100
500
250
500
125
100
500
500
500
1,000
[1,000
2e
500
500
500
500
1,000
1,000
1,000
3a
500
500
500
250
250
500
500
3b
250
500
1,000
500
100
500
1,000
3c
100
1,000
500
250
200
500
500
3d
200
250
100
125
100
500
500
3e
500
500
500
250
250
250
1,000
5a
250
500
100
62.5
200
500
500
5b
250
100
100
100
500
1,000
1,000
5c
250
250
125
125
500
500
500
5d
250
250
500
500
200
500
1,000
5e
125
100
500
500
250
1,000
1,000
5f
250
250
100
250
1,000
500
500
5g
100
100
500
250
250
500
1,000
5h
5i
200
200
250
200
500
250
500
100
250
1,000
1,000
1,000
500
500
5j
100
100
250
250
1,000
500
250
Ampicillin
100
100
250
100
Griseofulvin
500
100
100
C=O were observed, whereas in 1H-NMR spectrum of 2b,

two singlet observed at d 7.23 and 3.73 ppm for CH of
benzylidine and OCH3, respectively, which confirmed the
formation of compound 2b. Two absorption bands of NH
were observed at 3,427 and 3,179 cm-1 in IR spectrum of
3d, whereas the presence of two singlets at d 9.93 and
9.58 ppm for two NH of pyrimidine ring confirmed the
formation of thiazolo pyrimidine by cyclocondensation.
According the results from literature survey, singlet for CH
of pyrimidine was supposed to appear in the range of d
6.06.5 ppm but, in 1H-NMR spectrum of 3b, which
appeared in the range of d 7.267.65 ppm which is highly
downfielded region. One of the reason behind that downfield shift might be the attachment of nitrogen atom of
thiazolo nucleus with two carbonyl groups that decrease
the influence of electron density and shielding effect on
proton of pyrimidine ring. From IR spectrum of 5d, the
presence of absorption bands at 3,384, 3,231, and
3,156 cm-1 due to NH and also new band at 2,156 cm-1
due to SCN (thiocyanato) group confirmed the coupling of
thiocyanato benzothiazole to 4d.
In 1H-NMR spectrum of 5d, three singlet signals at d
10.09, 9.98, and 9.55 ppm were attributed to NH protons,
and also a signal was observed at d 2.55 ppm for CH3.
123
A. clavatus
MTCC-323
Moreover, the presence of signals at d 169.22, 166.67, and

165.96 (C=O) ppm due to carbon of CO, at d 83.90 and
53.43 ppm due to carbon of pyrimidine and at d 59.38,
19.09 ppm due to carbon of OCH3 and CH3, respectively,
in 13C-NMR spectrum of 5g and a molecular ion peak at m/
z: 701[M?] in mass spectrum of 5g gave the confirmation
of final compound 5g.
Antimicrobial activity
The MICs of synthesized compounds were carried out by
antibacterial and antifungal activity data of compounds 2a
e, 3ae, and 5aj are described in Tables 1 and 2,
respectively. The MICs of compounds were determined
against Mycobacterium tuberculosis H37Rv strain using
LowensteinJensen medium (conventional method) as
shown in Table 1. All MTCC cultures were collected from
the Institute of Microbial Technology, Chandigarh, India.
Antibacterial activity
Antibacterial activity was screened against two grampositive (Staphylococcus aureus MTCC 96 and Streptococcus pyogenes MTCC 442) and two gram-negative
Med Chem Res (2014) 23:47894802

Table 2 Results
compounds
of
antitubercular
4793
screening
of
synthesized
compared with ampicillin. Compound 5a containing

N(CH3)2 showed excellent activity of 62.5 lg/ml, whereas
compounds 3a and 5i showed good bacterial inhibition
(100 mg/ml), and rest of all compounds were poorly active
against S. pyogenous.
Compound
MIC values (lg/ml) of

M. tuberculosis H37Rv
% Inhibition
2a
250
96
2b
250
98
2c
2d
500
500
80
85
2e
250
98
3a
100
99
3b
250
89
3c
100
99
3d
250
91
3e
250
96
5a
25
99
5b
100
97
5c
250
97
5d
100
98
5e
100
99
5f
25
99
5g
500
81
Antifungal activity was screened against three fungal species Candida albicans MTCC 227, Aspergillus niger
MTCC 282, and Aspergillus clavatus MTCC 1323, and
griseofulvin was used as a standard antifungal agent.
Minimum Inhibition concentrations (MICs for fungus) of
the synthesized compounds are shown in Table 1. Results
reveal that most of the compounds 2a, 2d, 2e, 3b, 5a, 5b,
and 5c possessed good antifungal activity (500 lg/ml)
which is equipotent to griseofulvin, some compounds 5d,
5e, 5g, and 5h displayed higher antifungal activity
(200250 lg/ml) against C. albicans, whereas all the
synthesized intermediates and final compounds showed
poor activity against both A. niger and A. clavatus in
comparison to griseofulvin.
5h
5i
100
250
98
97
Antitubercular activity
5j
100
99
Clotrimazole
20.4
96
Econazole
12.5
99
Isoniazid
0.2
99
Rifampicin
40
99
(Escherichia coli MTCC 443 and Pseudomonas aeruginosa MTCC 2488) bacteria using ampicillin as a standard
antibacterial agent as shown in Table 1 using broth microdilution method as described in literature (Rattan, 2000).
Results revealed that most of the compounds possessed
comparable activity (MIC, 100250 lg/ml) against
S. aureus; some of them displayed excellent compared to
ampicillin. The antibacterial screening results revealed that
most of the compounds 2d, 3b, 3d, 5i, and 5j showed good
bacterial inhibition (250 mg/ml) while compounds 2a, 2d,
3c, and 5c possessed pronounced activity (125200 mg/ml)
against S. aureus. Compounds 5b and 5f bearing F and
N(CH3)2 moieties, respectively, exhibited the highest
activity (100 mg/ml) against S. aureus, whereas compounds 5a and 5b having N(CH3)2 and F-substituted
thiocyanato benzathiazole compounds also displayed
excellent activity (62.5 lg/ml) against E. coli. Compounds
5g and 5j showed good activity (100 lg/ml), whereas
others displayed moderate activity against E. coli. Results
reveal that most of the compounds showed moderate
activity against P. areuginosa except compounds 5e, 5g,
and 5j that showed good activity (100 lg/ml) when
Antifungal activity
The investigation of antitubercular activity screening data

is summarized in Table 1. The interesting results from the
antibacterial studies encouraged us to go for preliminary
screening of synthesized compounds against M. tuberculosis H37Rv. The data show compounds 5a, 5f bearing
N(CH3)2, and benzothiazole moiety, as the most active
among the tested compounds, and it was also found to
exhibit higher antitubercular activity (25 mg/ml), whereas
other compounds showed poor activity (50500 mg/ml) in
comparison to rifampicin (40 mg/ml) against M. tuberculosis H37Rv.
Structureactivity relationship
The results of the antimicrobial screening of compounds
(5aj) demonstrated that the substitution pattern of the
hybrid thiazolopyrimidines and sulfonamide-based benzothaizoles were carefully selected to impart different electronic environment to the molecules. Result revealed that
antibacterial activity was considerably affected by substitution pattern on the phenyl ring and benzothiazole moiety.
The incorporation of benzothiazole ring, specific electron
withdrawing and donating groups at the fourth position on
phenyl ring was responsible for enhancing the activity
against specific microorganisms. The role of benzothiazole
moiety in improving antimicrobial activity is very significant and well supported by screening result. From antimicrobial activity data, some analogs of this series were
123
4794
found to have even more potency than the reference drugs,

while some of them have comparable potency. Compounds
5b, 5g, and 5j with electron withdrawing substituents (F,
Br) on aromatic ring were very significant against both
gram-negative and positive-bacterial strains viz. E. coli and
S. aureus, respectively, while compounds 5a, 5f with
electron-donating substituent, N(CH3)2), on aromatic ring
showed better potency against only gram-negative bacterial
strains viz. E. coli and P. aeruginosa, respectively. In
addition, antibacterial activity showed substituents at para
position which displayed higher activity than without
substitution. On the other hand, the results of the antitubercular screening of compounds (5aj) demonstrated that
the presence of benzothiazole nucleus and electron-donating group N(CH3)2 on phenyl ring at the fourth position
was essential for enhancing antitubercular activity and
showed better antitubercular activity compared to
rifampicin.
Experimental
All the reagents and solvents were purchased from commercial suppliers Ficher Scientific Ltd. and Rankem India
Ltd. All the solvents were dried and distilled before use.
Melting points were determined in open capillaries on
PMPDM scientific melting point apparatus and are
uncorrected. The progress of each reaction and the purity
of the compounds were monitored by ascending TLC on
silica gel G (Merk), visualized by iodine vapor or UV light.
The IR spectra (in potassium bromide pellets) were
recorded on a Thermo Scientific Nicolet iS10 FT-IR
spectrometer, and the wave numbers were given in cm-1.
The 1H-NMR and 13C-NMR spectra were recorded
(CDCl3/DMSO-d6 mixture) on a Bruker Avance II 400
NMR spectrometer. Chemical shifts (d) are reported in
parts per million (ppm) using TMS as an internal standard.
The splitting pattern abbreviations are designed as s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m,
multiplet; and br, broad. The mass spectra were recorded
on micromass QT of micro (TOF MS ES?). Microanalysis
of the compounds was done on a Heraeus Carlo Erba 1180
CHN analyzer, and the values were recorded within
0.5 % of the theoretical values. All spectral data were
consistent with the proposed structure.
Procedure for the synthesis of 5-arylidene-2,4thiazolidinediones (1ae)

5-Arylidene-2,4-thiazolidinediones (1ae) were synthesized by the method described in the literature (Patil et al.,
2010; Bruno et al., 2002; Maccari et al., 2010).
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Med Chem Res (2014) 23:47894802
General method for the synthesis of 5-(arylidene)-3-(2methoxybenzoyl)thiazolidine-2,4-diones (2ae)

A mixture of 2-methoxy benzoic acid (0.012 mol), thionyl
chloride (0.21 mol), and anhydrous dioxane (35 ml) protected from humidity with CaCl2 tube was refluxed for
10 h. The solvent was distilled off, and the residue was
cooled to room temperature. To this, residue was added
100 ml of dry chloroform, and the mixture was stirred for
10 min and evaporated to dryness. The semisolid compound obtained was directly used in forward step.
2-Methoxy benzoyl chloride (semisolid) was dissolved in
dry DMF (10 ml), and the solution was cooled in an ice
bath.
A mixture of 5-arylidene-thiazolidine-2,4-dione 1a
e (0.012 mol), anhydrous potassium carbonate (0.024 mol)
in dry DMF (30 ml) was taken, cooled to 05 C in an ice
bath, and stirred for 10 min. To the stirred solution was
successively added in small portion the cold solution of
2-methoxy benzoyl chloride in DMF and stirred overnight
at room temperature; completion of reaction was monitored
by TLC (Toluene: ethylacetate, 7:3). Then, the reaction
mixture was quenched with ice water and stirred for 1 h.
The solid product 2ae was filtered, dried and as such taken
for the next step.
5-(4-(Dimethylamino)benzylidene)-3-(2methoxybenzoyl)thiazolidine-2,4-dione (2a)
Brownish crystals; yield 73 %; mp 138140 C; IR (KBr,
cm-1): 3058, 2998, 2965, 2831, 1769, 1692, 1671, 1269,
1151; 1H-NMR (CDCl3, 400 MHz): 7.95 (d, 1H,
J = 12.1 Hz, H-6 aromatic), 7.897.75 (m, 2H, H-4,5
aromatic), 7.51 (d, 1H, J = 6.9 Hz, H-3 aromatic), 7.50 (d,
2H, J = 8.2 Hz, H-20 ,60 aromatic), 7.24 (s, 1H, CH), 6.98
(d, 2H, J = 8.7 Hz, H-30 ,50 aromatic), 3.72 (s, 3H, OCH3),
3.24 (s, 6H, N(CH3)2); 13C-NMR (DMSO, 100 MHz):
168.28 (C=O), 166.33 (C=O, C-2 thiazolidinedione),
165.66 (C=O, C-4 thiazolidinedione), 157.77 (C-2 aromatic), 152.67 (C-40 aromatic), 145.22 (CH aliphatic ethylene), 135.31 (C-4 aromatic), 131.79 (C-20 ,60 aromatic),
130.98 (C-6 aromatic), 127.96 (C-10 aromatic), 122.27 (C-5
aromatic), 119.45 (C-1 aromatic), 116.32 (C-5 thiazolidinedione), 114.67 (C-30 ,50 aromatic), 110.61 (C-3 aromatic), 57.67 (OCH3), 44.32 (N(CH3)2); MS: m/z:
382[M?]; Anal. calcd for C20H18N2O4S: C 62.81, H 4.74,
N 7.33 %; Found C 62.77, H 4.63, N 7.22 %.
5-(4-Fluorobenzylidene)-3-(2methoxybenzoyl)thiazolidine-2,4-dione (2b)
Buff-colored powder; yield 71 %; mp 178180 C; IR
(KBr, cm-1): 3064, 2973, 2837, 1764, 1689, 1667, 1262,
Med Chem Res (2014) 23:47894802
1154, 989; 1H-NMR (CDCl3, 400 MHz): 7.89 (d, 1H,

(d, 2H, J = 8.9 Hz, H-30 ,50 aromatic), 3.80 (s, 3H, OCH3);
13
C-NMR (DMSO, 100 MHz): 168.18 (C=O), 166.27
(C=O, C-2 thiazolidinedione), 165.77 (C=O, C-4 thiazolidinedione), 163.36 (C-40 aromatic), 157.70 (C-2 aromatic), 145.12 (CH aliphatic ethylene), 135.17 (C-4
aromatic), 131.97 (C-20 ,60 aromatic), 130.91 (C-6 aromatic), 127.80 (C-10 aromatic), 122.20 (C-5 aromatic),
119.14 (C-1 aromatic), 116.17 (C-5 thiazolidinedione),
114.94 (C-30 ,50 aromatic), 110.47 (C-3 aromatic), 57.53
(OCH3); MS: m/z: 357[M?]; Anal. calcd for
C18H12FNO4S: C 60.50, H 3.38, N 3.92 %; Found C 60.37,
H 3.43, N 3.81 %.
3-(2-Methoxybenzoyl)-5-(4propylbenzylidene)thiazolidine-2,4-dione (2c)
Off-white colored powder; yield; 79 %; mp 145147 C; IR
(KBr, cm-1): 3052, 2993, 2947, 2847, 1769, 1694, 1674,
1257, 1162; 1H-NMR (CDCl3, 400 MHz): 7.82 (d, 1H,
J = 12.3 Hz, H-6 aromatic), 7.787.65 (m, 2H, H-4,5 aromatic), 7.42 (d, 1H, J = 6.3 Hz, H-3 aromatic), 7.41 (d, 2H,
J = 8.2 Hz, H-20 , 60 aromatic), 7.15 (s, 1H, CH), 6.77 (d, 2H,
J = 8.6 Hz, H-30 , 50 aromatic), 3.84 (s, 3H, OCH3), 2.51 (t,
2H, CH2), 1.82 (m, 2H, CH2), 1.12 (t, 3H, CH3); 13C-NMR
(DMSO, 100 MHz): 168.32 (C=O), 166.18 (C=O, C-2
thiazolidinedione), 165.64 (C=O, C-4 thiazolidinedione),
157.87 (C-2 aromatic), 145.34 (CH aliphatic ethylene),
142.30 (C-40 aromatic), 135.27 (C-4 aromatic), 131.87 (C20 ,60 aromatic), 130.66 (C-6 aromatic), 127.71 (C-10 aromatic), 122.30 (C-5 aromatic), 119.24 (C-1 aromatic),
116.26 (C-5 thiazolidinedione), 114.88 (C-30 ,50 aromatic),
110.62 (C-3 aromatic), 57.44 (OCH3), 40.11 (CH2CH2CH3),
25.78 (CH2CH2CH3), 14.88 (CH2CH2CH3); MS: m/z:
381[M?]; Anal. calcd for C21H19NO4S: C 66.12, H 5.02, N
3.67 %; Found C 66.04, H 5.13, N 3.55 %.
5-Benzylidene-3-(2-methoxybenzoyl)thiazolidine-2,4-dione
(2d)
(KBr, cm-1): 3089, 2962, 2822, 1789, 1682, 1652, 1266,
1162; 1H-NMR (CDCl3, 400 MHz): 8.1 (d, 1H,
(s, 3H, OCH3); 13C-NMR (DMSO, 100 MHz): 167.98
(C=O), 166.35 (C=O, C-2 thiazolidinedione), 165.71
(C=O, C-4 thiazolidinedione), 157.66 (C-2 aromatic),
145.23 (CH aliphatic ethylene), 135.29 (C-4 aromatic),
4795

(C-40 aromatic), 127.88 (C-10 aromatic), 122.32 (C-5 aromatic), 119.32 (C-1 aromatic), 116.27 (C-5 thiazolidinedione), 114.78 (C-30 ,50 aromatic), 110.37 (C-3 aromatic),
57.66 (OCH3); MS: m/z: 339[M?]; Anal. calcd for
C18H13NO4S: C 63.71, H 3.86, N 4.13 %; Found C 63.67,
H 3.73, N 4.02 %.
5-(4-Bromobenzylidene)-3-(2methoxybenzoyl)thiazolidine-2,4-dione (2e)
Brown powder; yield 65 %; mp 212214 C; IR (KBr,
cm-1): 3054, 2964, 2833, 1768, 1696, 1659, 1259, 1152,
879; 1H-NMR (CDCl3, 400 MHz): 7.89 (d, 1H,
aromatic), 7.62 (d, 2H, J = 8.1 Hz, H-30 ,50 aromatic), 7.52
(d, 1H, J = 6.1 Hz, H-3 aromatic), 7.51 (d, 2H,
J = 7.9 Hz, H-20 ,60 aromatic), 7.22 (s, 1H, CH), 3.65 (s,
3H, OCH3); 13C-NMR (DMSO, 100 MHz): 168.28 (C=O),
166.34 (C=O, C-2 thiazolidinedione), 165.83 (C=O, C-4
thiazolidinedione), 157.79 (C-2 aromatic), 145.32 (CH
aliphatic ethylene), 135.24 (C-4 aromatic), 131.87 (C-20 ,60
aromatic), 130.81 (C-6 aromatic), 127.89 (C-10 aromatic),
aromatic), 116.27 (C-5 thiazolidinedione), 114.79 (C-30 ,50
aromatic), 110.32 (C-3 aromatic), 57.43 (OCH3); MS: m/z:
416[M?]; Anal. calcd for C18H12BrNO4S: C 51.69, H 2.89,
N 3.35 %; Found C 51.48, H 2.75, N 3.42 %.
General method for the synthesis of 7-(substituted)-3(2-methoxybenzoyl)-6,7-dihydrothiazolo[4,5d]pyrimidine-2,5(3H,4H)-diones (3ae)
A mixture of 5-arylidene-3-(2-methoxy-benzoyl)-thiazolidine-2,4-dione 2ae (0.0058 mol), urea (0.006 mol), P2O5
(0.2 g), and ethanolic HCl (50 ml) was refluxed with stirring for 810 h. The reaction mixture was cooled to room
temperature and allowed to stand overnight; the separated
solid was isolated, washed with ethanol, and recrystallized
from ethanol to form 3ae.
7-(4-(Dimethylamino)phenyl)-3-(2-methoxybenzoyl)-6,7dihydrothiazolo[4,5-d]pyrimidine-2,5(3H,4H)-dione (3a)
Reddish powder; yield 70 %; mp 170172 C; IR (KBr,
cm-1): 3398, 3193, 3071, 2857, 1742, 1685, 1659, 1343,
1251, 1157; 1H-NMR (CDCl3, 400 MHz): 9.84 (s, 1H,
NH), 9.45 (s, 1H, NH), 7.89 (d, 1H, H-6 aromatic), 7.67 (s,
1H, H-5 aromatic), 7.66 (d, 2H, J = 8.7 Hz, H-30 , 50 aromatic), 7.52 (s, 1H, CH pyrimidine), 7. 23 (d, 1H,
J = 8.5 Hz, H-3 aromatic), 7.11 (d, 2H, J = 8.5 Hz, H-20 ,
60 aromatic), 6.92 (s, 1H, H-4 aromatic), 3.75 (s, 3H,
OCH3), 3.23 (s, 6H, N(CH3)2); 13C-NMR (DMSO,
123
4796
100 MHz): 164.77 (C=O), 162.34, (C=O, C-2 thiazolidinedione), 157.33 (C-2 aromatic), 151.32 (C-40 aromatic),
150.2 (C=O, pyrimidine), 137.17 (C-4 aromatic), 134.79
(C-20 , 60 aromatic), 129.94 (C-6 aromatic), 128.85 (C-10
aromatic), 124.46 (C=O, C-4 thiazolidinedione), 121.38
(C-5 aromatic), 119.24 (C-1 aromatic), 116.24 (C-30 ,50
aromatic), 111.28 (C-3 aromatic), 76.73 (C-5 thiazolidinedione), 58.59 (OCH3), 55.37 (CH aliphatic ethylene),
45.64 (N(CH3)2); MS: m/z: 424[M?]; Anal. calcd for
C21H20N4O4S: C 59.42, H 4.75, N 13.20 %; Found C
59.32, H 4.67, N 13.06 %.
7-(4-Fluorophenyl)-3-(2-methoxybenzoyl)-6,7dihydrothiazolo[4,5-d]pyrimidine-2,5(3H,4H)-dione (3b)
Brownish powder; 65 %; mp 172174 C; IR (KBr, cm-1):
3383, 3238, 3066, 2846, 1756, 1685, 1659, 1333, 1238,
1147; 1H-NMR (CDCl3, 400 MHz): 9.93 (s, 1H, NH), 9.58
(s, 1H, NH), 7.92 (d, 1H, H-6 aromatic), 7.72 (d, 2H,
J = 8.5 Hz, H-20 ,60 aromatic), 7.69 (s, 1H, H-5 aromatic),
7.59 (s, 1H, CH pyrimidine), 7. 18 (d, 1H, J = 8.3 Hz, H-3
aromatic), 6.96 (s, 1H, H-4 aromatic), 6.66 (d, 2H,
J = 8.3 Hz, H-30 ,50 aromatic), 3.80 (s, 3H, OCH3); 13CNMR (DMSO, 100 MHz): 164.98 (C=O), 162.45 (C-40
aromatic), 160.10, (C=O, C-2 thiazolidinedione), 157.40
(C-2 aromatic), 151.12 (C=O, pyrimidine), 137.27 (C-4
aromatic), 134.77 (C-20 ,60 aromatic), 129.92 (C-6 aromatic), 128.80 (C-10 aromatic), 124.40 (C=O, C-4 thiazolidinedione), 121.44 (C-5 aromatic), 119.14 (C-1
aromatic), 116.27 (C-30 ,50 aromatic), 111.41 (C-3 aromatic), 76.92 (C-5 thiazolidinedione), 58.63 (OCH3), 55.16
(CH aliphatic ethylene); MS: m/z: 399[M?]; Anal. calcd
for C19H14FN3O4S: C 57.14, H 3.53, N 10.52 %; Found C
57.02, H 3.47, N 10.43 %.
3-(2-Methoxybenzoyl)-7-(4-propylphenyl)-6,7dihydrothiazolo[4,5-d]pyrimidine-2,5(3H,4H)-dione (3c)
Buff-colored powder; yield 77 %; mp 132134 C; IR (KBr,
cm-1): 3365, 3234, 3062, 2848, 1739, 1683, 1662, 1341,
1237, 1152; 1H-NMR (CDCl3, 400 MHz): 9.62 (s, 1H, NH),
9.44 (s, 1H, NH), 7.79 (d, 1H, H-6 aromatic), 7.69 (d, 2H,
aromatic), 6.91 (s, 1H, H-4 aromatic), 6.76 (d, 2H,
J = 8.4 Hz, H-30 ,50 aromatic), 3.76 (s, 3H, OCH3), 2.73 (t,
2H, CH2), 1.68 (m, 2H, CH2), 1.08 (t, 3H, CH3); 13C-NMR
(DMSO, 100 MHz): 164.39 (C=O), 162.22 (C-40 aromatic),
157.26, (C=O, C-2 thiazolidinedione), 151.52 (C-2 aromatic),
150.19 (C=O, pyrimidine), 142.34 (C-40 aromatic), 137.16 (C4 aromatic), 134.71 (C-20 ,60 aromatic), 129.28 (C-6 aromatic),
128.84 (C-10 aromatic), 124.46 (C=O, C-4 thiazolidinedione),
121.58 (C-5 aromatic), 119.19 (C-1 aromatic), 116.21 (C-30 ,50
123
Med Chem Res (2014) 23:47894802
aromatic), 111.46 (C-3 aromatic), 76.94 (C-5 thiazolidinedione), 58.73 (OCH3), 55.34 (CH aliphatic ethylene), 40.42
(CH2CH2CH3), 26.39 (CH2CH2CH3), 15.11 (CH2CH2CH3);
MS: m/z: 423[M?]; Anal. calcd for C22H21N3O4S: C 62.40, H
5.00, N 9.92 %; Found C 62.33, H 4.97, N 9.79 %.
3-(2-Methoxybenzoyl)-7-phenyl-6,7-dihydrothiazolo[4,5d]pyrimidine-2,5(3H,4H)-dione (3d)
Brownish powder; 74 %; mp 144146 C; IR (KBr, cm-1):
3427, 3179, 3080, 2837, 1748, 1693, 1654, 1338, 1241,
1146, 744; 1H-NMR (CDCl3, 400 MHz): 9.67 (s, 1H, NH),
9.27 (s, 1H, NH), 7.95 (d, 1H, H-6 aromatic), 7.75 (d, 2H,
aromatic), 7.19 (s, 1H, H-4 aromatic), 7.15 (m, 1H, H-40
(s, 3H, OCH3); 13C-NMR (DMSO, 100 MHz): 165.05
(C=O), 162.52 (C-40 aromatic), 157.34, (C=O, C-2 thiazolidinedione), 151.25 (C-2 aromatic), 150.44 (C=O,
pyrimidine), 137.21 (C-4 aromatic), 134.72 (C-20 ,60 aromatic), 129.96 (C-6 aromatic), 128.75 (C-10 aromatic),
128.32 (C-40 aromatic), 125.56 (C=O, C-4 thiazolidinedione), 124.48 (C-5 aromatic), 121.36 (C-1 aromatic), 119.28
(C-30 ,50 aromatic), 116.15 (C-3 aromatic), 76.84 (C-5
thiazolidinedione), 58.51 (OCH3), 55.29 (CH aliphatic
ethylene); MS: m/z: 381[M?]; Anal. calcd for
C19H15N3O4S: C 59.83, H 3.96, N 11.02 %; Found C
59.02, H 3.77, N 10.93 %.
7-(4-Bromophenyl)-3-(2-methoxybenzoyl)-6,7dihydrothiazolo[4,5-d]pyrimidine-2,5(3H,4H)-dione (3e)
cm-1): 3375, 3254, 3067, 1742, 1683, 1663, 1343, 1234,
1142, 982; 1H-NMR (CDCl3, 400 MHz): 10.13 (s, 1H,
NH), 9.72 (s, 1H, NH), 7.82 (d, 1H, H-6 aromatic), 7.75 (d,
2H, J = 8.3 Hz, H-30 ,50 aromatic), 7.72 (s, 1H, H-5 aromatic), 7.65 (s, 1H, CH pyrimidine), 7. 24 (d, 1H,
J = 8.1 Hz, H-3 aromatic), 7.12 (s, 1H, H-4 aromatic),
6.80 (d, 2H, J = 8.1 Hz, H-20 ,60 aromatic), 3.86 (s, 3H,
OCH3); 13C-NMR (DMSO, 100 MHz): 164.25 (C=O),
162.55 (C-40 aromatic), 157.42, (C=O, C-2 thiazolidinedione), 151.22 (C-2 aromatic), 150.23 (C=O, pyrimidine),
137.29 (C-4 aromatic), 134.81 (C-20 ,60 aromatic), 129.98
(C-6 aromatic), 128.88 (C-10 aromatic), 124.49 (C=O, C-4
thiazolidinedione), 121.46 (C-5 aromatic), 120.56 (C-1
aromatic), 119.24 (C-30 ,50 aromatic), 116.34 (C-3 aromatic), 76.83 (C-5 thiazolidinedione), 58.57 (OCH3), 55.23
(CH aliphatic ethylene); MS: m/z: 460[M?]; Anal. calcd
for C19H14BrN3O4S: C 49.58, H 3.07, N 9.13 %; Found C
49.42, H 3.15, N 9.06 %.
Med Chem Res (2014) 23:47894802
General method for the synthesis of 3-(2,5-dioxo-7(substituted)-2,3,4,5,6,7-hexahydrothiazolo[4,5d]pyrimidine-3-carbonyl)-4-methoxybenzene-1sulfonyl chlorides (4ae)

Compound 3ae (0.0052 mol) was added to a mixture of
thionyl chloride (0.0052 mol) and chlorosulfonic acid
(0.0314 mol), while keeping the temperature below 10 C;
the temperature was maintained very carefully in order to
avoid further chlorosulfonation of pyrimidine nucleus, and
the resulting mixture was stirred overnight at room temperature. The resulting mixture was quenched into a mixture of ice (50g) and water (10 ml). The precipitates of 4a
e were formed, which were stirred for 60 min and filtrated,
washed with water, and as such taken for the next step.
General method for the synthesis of 3-(7-(substituted)2,5-dioxo-2,3,4,5,6,7-hexahydrothiazolo [4,5d]pyrimidine-3-carbonyl)-4-methoxy-N-(substituted)
benzene sulfonamides (5ae)
Compound 4ae (0.004 mol) was added to water (25 ml),
and the resulting suspension cooled to 10 C. Then, the
corresponding benzothiazole (0.004 mol) was added to the
resulting suspension, keeping the temperature below 20 C.
The resulting solution was cooled to 10 C. After 30 min,
the title compound started to crystallize. The solid was
collected after 2 h and washed with ice water, and the
resulting solid 5aj was dried and recrystallised from
ethanol.
3-(7-(4-(Dimethylamino)phenyl)-2,5-dioxo-2,3,4,5,6,7hexahydrothiazolo[4,5-d] pyrimidine-3-carbonyl)-4methoxy-N-(6-thiocyanatobenzo[d]thiazol-2-yl)benzene
sulfonamide (5a)
cm-1): 3418, 3310, 3214, 3036, 2158, 1755, 1679, 1663,
1337, 1243, 1151; 1H-NMR (CDCl3, 400 MHz): 9.21 (s,
1H, SO2NH), 8.88 (s, 1H, NH), 8.43 (s, 1H, NH),
8.027.17 (m, 8H, CH pyrimidine, benzothiazole H-4,5,7,
H-2,6,30 ,50 aromatic), 7.59 (d, 2H, J = 6.6 Hz, H-20 ,60
aromatic), 7.03 (d, 1H, J = 8.3 Hz, H-3 aromatic), 3.47 (s,
3H, OCH3), 3.17 (s, 6H, N(CH3)2); 13C-NMR (DMSO,
100 MHz): 172.39 (C-1 benzothiazole), 165.19 (C=O),
162.56 (C=O, C-2 thiazolidinedione), 161.89 (C-2 aromatic), 158.32 (C-3, benzothiazole), 151.56 (C=O, pyrimidine), 150.26 (C-40 aromatic), 133.79 (C-4 aromatic),
132.19 (C-20 , 60 aromatic), 130.19 (C-6 aromatic), 128.69
(C-10 aromatic), 128.39 (C-5 benzothiazole), 127.75 (C-8
benzothiazole), 127.19 (C=O, C-4 thiazolidinedione),
126.77 (C-4 benzothiazole), 124.49 (C-7 benzothiazole),
123.93 (C-5 aromatic), 123.43 (C-6 benzothiazole), 118.89
4797
(C-1 aromatic), 113.57 (C-30 ,50 aromatic), 111.69 (C-3

aromatic), 110.65 (SCN), 82.49 (C-5 thiazolidinedione),
53.67 (OCH3), 52.55 (CH aliphatic ethylene), 40.67
(N(CH3)2); MS: m/z: 693[M?]; Anal. calcd for
C29H23N7O6S4: C 50.20, H 3.34, N 14.13 %; Found C
50.07, H 3.23, N 14.02 %.
3-(7-(4-Fluorophenyl)-2,5-dioxo-2,3,4,5,6,7hexahydrothiazolo[4,5-d]pyrimidine-3-carbonyl)-4methoxy-N-(6-thiocyanatobenzo[d]thiazol-2yl)benzenesulfonamide (5b)
Brownish powder; yield 65 %; mp 201203 C; IR (KBr,
cm-1): 3398, 3281, 3178, 3028, 2151, 1732, 1681, 1651,
1333, 1247, 1142, 885; 1H-NMR (CDCl3, 400 MHz): 9.83
(s, 1H, SO2NH), 8.73 (s, 1H, NH), 8.29 (s, 1H, NH),
3H, OCH3); 13C-NMR (DMSO, 100 MHz): 171.89 (C-1
benzothiazole), 165.35 (C=O), 162.35 (C-40 aromatic),
161.25 (C=O, C-2 thiazolidinedione), 159.69 (C-2 aromatic), 158.79 (C-3, benzothiazole), 151.59 (C=O, pyrimidine), 133.39 (C-4 aromatic), 132.56 (C-20 ,60 aromatic),
benzothiazole), 127.35 (C-8 benzothiazole), 127.1 (C=O,
C-4 thiazolidinedione), 126.59 (C-4 benzothiazole), 124.23
(C-7 benzothiazole), 123.54 (C-5 aromatic), 123.19 (C-6
benzothiazole), 118.57 (C-1 aromatic), 113.13 (C-30 ,50
aromatic), 111.46 (C-3 aromatic), 110.56 (SCN), 82.23 (C5 thiazolidinedione), 53.78 (OCH3), 52.35 (CH aliphatic
ethylene); MS: m/z: 668[M?]; Anal. calcd for
C27H17FN6O6S4: C 48.49, H 2.56, N 12.57 %; Found C
48.27, H 2.43, N 12.48 %.
3-(2,5-Dioxo-7-(4-propylphenyl)-2,3,4,5,6,7hexahydrothiazolo[4,5-d]pyrimidine-3-carbonyl)-4methoxy-N-(6-thiocyanatobenzo[d]thiazol-2yl)benzenesulfonamide (5c)
(KBr, cm-1): 3375, 3248, 3135, 3045, 2967, 2865, 2153,
1754, 1692, 1667, 1346, 1242, 1149; 1H-NMR (CDCl3,
400 MHz): 9.18 (s, 1H, SO2NH), 8.82 (s, 1H, NH), 8.38 (s,
1H, NH), 7.097.13 (m, 8H, CH pyrimidine, benzothiazole
H-4,5,7, H-2,6, 20 ,60 aromatic), 7.67 (d, 2H, J = 6.4 Hz,
H-30 ,5 aromatic), 6.94 (d, 1H, J = 8.6 Hz, H-3 aromatic),
3.46 (s, 3H, OCH3), 2.76 (t, 2H, CH2), 1.76 (s, 3H, CH3),
1.12 (m, 2H, CH2); 13C-NMR (DMSO, 100 MHz): 170.39
(C-1 benzothiazole), 166.23 (C=O), 162.39 (C=O, C-2
thiazolidinedione), 160.45 (C-2 aromatic), 158.11 (C-3,
benzothiazole), 150.89 (C=O, pyrimidine), 143.25 (C-40
aromatic), 133.45 (C-4 aromatic), 132.12 (C-20 ,60
123
4798
aromatic), 130.67 (C-6 aromatic), 128.71 (C-10 aromatic),

127.15 (C=O, C-4 thiazolidinedione), 126.72 (C-4 benzothiazole), 124.59 (C-7 benzothiazole), 123.14 (C-5 aromatic), 122.89 (C-6 benzothiazole), 118.65 (C-1 aromatic),
(SCN), 82.23 (C-5 thiazolidinedione), 54.72 (OCH3), 52.73
(CH aliphatic ethylene), 40.29 (CH2CH2CH3), 28.98
(CH2CH2CH3), 17.51 (CH2CH2CH3); MS: m/z: 692[M?];
Anal. calcd for C30H24N6O6S4: C 52.01, H 3.49, N
12.13 %; Found C 51.95, H 3.43, N 12.04 %.
3-(2,5-Dioxo-7-phenyl-4,5,6,7-tetrahydro-thiazolo[4,5d]pyrimidine-3-carbonyl)-4-methoxy-N-(6-thiocyanatobenzothiazol-2-yl)-benzenesulfonamide (5d)
cm-1): 3384, 3231, 3156, 3031, 2156, 1748, 1683, 1656,
1337, 1237, 1132; 1H-NMR (CDCl3, 400 MHz): 9.32 (s,
1H, SO2NH), 8.73 (s, 1H, NH), 8.28 (s, 1H, NH),
H-2,6,40 ,30 ,50 aromatic), 7.58 (d, 2H, J = 6.4 Hz, H-20 ,60
3H, OCH3); 13C-NMR (DMSO, 100 MHz): 172.12 (C-1
benzothiazole), 166.69 (C=O), 161.79 (C=O, C-2 thiazolidinedione), 159.31 (C-2 aromatic), 158.29 (C-3, benzothiazole), 151.19 (C=O, pyrimidine), 133.59 (C-4
aromatic), 132.68 (C-20 ,60 aromatic), 130.69 (C-6 aromatic), 128.75 (C-10 aromatic), 128.19 (C-5 benzothiazole), 127.82 (C-8 benzothiazole), 127.22 (C=O, C-4
thiazolidinedione), 126.85 (C-40 aromatic), 126.39 (C-4
benzothiazole), 124.79 (C-7 benzothiazole), 123.34 (C-5
aromatic), 122.58 (C-6 benzothiazole),, 118.40 (C-1 aromatic), 112.93 (C-30 ,50 aromatic), 111.95 (C-3 aromatic),
110.49 (SCN), 82.49 (C-5 thiazolidinedione), 54.38
(OCH3), 52.63 (CH aliphatic ethylene); MS: m/z: 650[M?];
Anal. calcd for C27H18N6O6S4: C 49.83, H 2.79, N
12.91 %; Found C 49.67, H 2.84, N 12.80 %.
3-(7-(4-Bromophenyl)-2,5-dioxo-2,3,4,5,6,7hexahydrothiazolo[4,5-d]pyrimidine-3-carbonyl)-4methoxy-N-(6-thiocyanatobenzo[d]thiazol-2yl)benzenesulfonamide (5e)
cm-1): 3365, 3267, 3183, 3043, 2148, 1745, 1689, 1662,
1344, 1247, 1139, 948; 1H-NMR (CDCl3, 400 MHz): 9.63 (s,
1H, SO2NH), 8.82 (s, 1H, NH), 8.46 (s, 1H, NH), 8.117.22
(m, 8H, CH pyrimidine, benzothiazole H-4,5,7, H-2,6,20 ,60
aromatic), 7.71 (d, 2H, J = 6.3 Hz, H-30 ,5 aromatic), 7.05 (d,
1H, J = 8.5 Hz, H-3 aromatic), 3.83 (s, 3H, OCH3); 13CNMR (DMSO, 100 MHz): 171.44 (C-1 benzothiazole),
166.89 (C=O), 160.11 (C=O, C-2 thiazolidinedione), 159.69
123
Med Chem Res (2014) 23:47894802
(C-2 aromatic), 158.15 (C-3, benzothiazole), 151.64 (C=O,

pyrimidine), 133.62 (C-4 aromatic), 132.38 (C-20 ,60 aromatic), 130.38 (C-6 aromatic), 128.34 (C-10 aromatic), 127.73
(C-5 benzothiazole), 127.38 (C-8 benzothiazole), 127.32
(C=O, C-4 thiazolidinedione), 126.69 (C-4 benzothiazole),
124.53 (C-7 benzothiazole), 123.52 (C-5 aromatic), 122.75
(C-6 benzothiazole), 121.64 (C-40 aromatic), 118.32 (C-1
aromatic), 112.68 (C-30 ,50 aromatic), 111.32 (C-3 aromatic),
110.26 (SCN), 82.25 (C-5 thiazolidinedione), 54.48 (OCH3),
52.37 (CH aliphatic ethylene); MS: m/z: 729[M?]; Anal. calcd
for C27H17BrN6O6S4: C 44.45, H 2.35, N 11.52 %; Found C
44.57, H 2.49, N 11.38 %.
3-(7-(4-(Dimethylamino)phenyl)-2,5-dioxo-2,3,4,5,6,7hexahydrothiazolo[4,5-d] pyrimidine-3-carbonyl)-4methoxy-N-(4-(5-methylbenzo[d]thiazol-2-yl)phenyl)
benzenesulfonamide (5f)
cm-1): 3419, 3310, 3219, 3049, 1739, 1692, 1684, 1348,
1329, 1185, 839; 1H-NMR (CDCl3, 400 MHz): 9.83 (s, 1H,
SO2NH), 9.28 (s, 1H, NH), 8.21 (s, 1H, NH), 7.967.21 (m,
8H, CH pyrimidine, benzothiazole H-4,6,7, H-2,6,30 ,50
(d, 2H, J = 8.6 Hz, H-300 ,500 aromatic), 7.05 (d, 1H,
J = 8.4 Hz, H-3 aromatic), 6.78 (d, 2H, J = 8.4 Hz,
H-200 ,6 aromatic), 3.39 (s, 3H, OCH3), 3.12 (s, 6H,
N(CH3)2), 2.55 (s, 3H, CH3); 13C-NMR (DMSO,
100 MHz): 169.35 (C-2 benzothiazole), 166.49 (C=O),
165.45 (C=O, C-2 thiazolidinedione), 161.11 (C-2 aromatic), 159.57 (C-9, benzothiazole), 152.22 (C=O, pyrimidine), 149.56 (C-40 aromatic), 137.22 (C-5 benzothiazole),
136.74 (C-4 aromatic), 133.45 (C-8 benzothiazole), 133.22
(C-6 aromatic), 128.65 (C-10 aromatic), 128.39 (C-300 ,500
aromatic), 127.76 (C-20 ,60 aromatic), 127.62 (C=O, C-4
thiazolidinedione), 126.44 (C-6 benzothiazole), 126.19 (C5 aromatic), 121.32 (C-7 benzothiazole), 121.12 (C-4
benzothiazole), 120.59 (C-400 aromatic), 119.45 (C-3 aromatic), 118.56 (C-1 aromatic), 118.23 (C-30 ,50 aromatic),
116.45 (C-200 ,600 aromatic), 83.44 (C-5 thiazolidinedione),
59.98 (OCH3), 53.09 (CH aliphatic ethylene), 43.52
(N(CH3)2), 19.69 (CH3); MS: m/z: 726[M?]; Anal. calcd
for C35H30N6O6S3: C 57.84, H 4.16, N 11.56 %; Found C
57.73, H 4.03, N 11.41 %.
3-(7-(4-Fluorophenyl)-2,5-dioxo-2,3,4,5,6,7hexahydrothiazolo[4,5-d]pyrimidine-3-carbonyl)-4methoxy-N-(4-(5-methylbenzo[d]thiazol-2yl)phenyl)benzene sulfonamide (5g)
cm-1): 3470, 3242, 3177, 3043, 1758, 1698, 1674, 1356,
1332, 1179, 834; 1H-NMR (CDCl3, 400 MHz): 10.09 (s,
Med Chem Res (2014) 23:47894802
1H, SO2NH), 9.98 (s, 1H, NH), 9.55 (s, 1H, NH), 7.92-7.16
(m, 8H, CH pyrimidine, benzothiazole H-4,6,7, H-2,6,30 ,50
(d, 2H, J = 8.4 Hz, H-300 500 aromatic), 6.99 (d, 1H,
J = 8.3 Hz, H-3 aromatic), 6.67 (d, 2H, J = 8.1 Hz,
H-200 ,6 aromatic), 3.39 (s, 3H, OCH3), 2.55 (s, 3H, CH3);
13
C-NMR (DMSO, 100 MHz): 169.92 (C-2 benzothiazole), 166.67 (C=O), 165.96 (C-40 aromatic), 164.92 (C=O,
C-2 thiazolidinedione), 160.26 (C-2 aromatic), 159.21 (C9, benzothiazole), 151.91 (C=O, pyrimidine), 137.06 (C-5
benzothiazole), 136.55 (C-4 aromatic), 133.60 (C-8 benzothiazole), 133.47 (C-6 aromatic), 128.84 (C-10 aromatic),
128.68 (C-300 ,500 aromatic), 127.89 (C-20 ,60 aromatic),
127.78 (C=O, C-4 thiazolidinedione), 126.85 (C-6 benzothiazole), 126.76 (C-5 aromatic), 121.47 (C-7 benzothiazole), 121.01 (C-4 benzothiazole), 120.83 (C-400 aromatic),
119.61 (C-3 aromatic), 118.63 (C-1 aromatic), 118.47 (C30 ,50 aromatic), 116.67 (C-200 ,600 aromatic), 83.90 (C-5
thiazolidinedione), 59.38 (OCH3), 53.43 (CH aliphatic
ethylene), 19.9 (CH3); MS: m/z: 701[M?]; Anal. calcd for
C33H24FN5O6S3: C 56.48, H 3.45, N 9.98 %; Found C
56.37, H 3.29, N 9.78 %.
3-(2,5-Dioxo-7-(4-propylphenyl)-2,3,4,5,6,7hexahydrothiazolo[4,5-d]pyrimidine-3-carbonyl)-4methoxy-N-(4-(5-methylbenzo[d]thiazol-2yl)phenyl)benzene sulfonamide (5h)
(KBr, cm-1): 3439, 3354, 3217, 3039, 1732, 1695, 1679,
1363, 1342, 1171, 825; 1H-NMR (CDCl3, 400 MHz):
11.13 (s, 1H, SO2NH), 9.53 (s, 1H, NH), 8.87 (s, 1H, NH),
H-2,6,20 ,60 aromatic), 7.65 (d, 2H, J = 6.6 Hz, H-30 ,5 aromatic), 7.23 (d, 2H, J = 8.5 Hz, H-300 ,500 aromatic), 6.92
(d, 1H, J = 8.4 Hz, H-3 aromatic), 6.72 (d, 2H,
J = 8.3 Hz, H-200 ,6 aromatic), 3.42 (s, 3H, OCH3), 2.57
(t, 2H, CH2), 2.49 (s, 3H, CH3), 1.73 (m, 2H, CH2), 2.43 (t,
3H, CH3); 13C-NMR (DMSO, 100 MHz): 169.86 (C-2
aromatic), 137.56 (C-5 benzothiazole), 136.26 (C-4 aromatic), 133.87 (C-8 benzothiazole), 133.11 (C-6 aromatic),
(C-20 ,60 aromatic), 127.13 (C=O, C-4 thiazolidinedione),
126.84 (C-6 benzothiazole), 126.33 (C-5 aromatic), 121.86
(C-7 benzothiazole), 121.56 (C-4 benzothiazole), 120.34
(C-400 aromatic), 119.67 (C-3 aromatic), 118.48 (C-1 aromatic), 118.11 (C-30 ,50 aromatic), 116.85 (C-200 ,600 aromatic), 83.78 (C-5 thiazolidinedione), 59.23 (OCH3), 53.18
(CH aliphatic ethylene), 36.24 (CH2CH2CH3), 25.56
(CH2CH2CH3), 19.34 (CH3), 14.45 (CH2CH2CH3); MS:
4799
m/z: 754[M?]; Anal. calcd for C37H34N6O6S3: C 59.33, H

4.06, N 10.25 %; Found C 59.21, H 4.15, N 10.11 %.
3-(2,5-Dioxo-7-phenyl-2,3,4,5,6,7-hexahydrothiazolo[4,5d]pyrimidine-3-carbonyl)-4-methoxy-N-(4-(5methylbenzo[d]thiazol-2-yl)phenyl)benzenesulfonamide
(5i)
cm-1): 3392, 3267, 3189, 3048, 1737, 1689, 1665, 1339,
1322, 1138, 858; 1H-NMR (CDCl3, 400 MHz): 10.48 (s,
1H, SO2NH), 9.57 (s, 1H, NH), 8.85 (s, 1H, NH),
H-2,6,40 ,30 ,50 aromatic), 7.62 (d, 2H, J = 6.6 Hz, H-20 ,60
aromatic), 7.25 (d, 2H, J = 8.6 Hz, H-300 ,500 aromatic),
6.94 (d, 1H, J = 8.5 Hz, H-3 aromatic), 6.69 (d, 2H,
(s, 3H, CH3); 13C-NMR (DMSO, 100 MHz): 169.19 (C-2
benzothiazole), 136.23 (C-4 aromatic), 133.86 (C-8 benzothiazole), 133.39 (C-6 aromatic), 128.86 (C-10 aromatic),
128.23 (C-300 ,500 aromatic), 127.70 (C-20 ,60 aromatic),
127.42 (C=O, C-4 thiazolidinedione), 126.55 (C-40 aromatic), 126.42 (C-6 benzothiazole), 126.03 (C-5 aromatic),
120.16 (C-400 aromatic), 119.75 (C-3 aromatic), 118.86 (C1 aromatic), 118.22 (C-30 ,50 aromatic), 116.25 (C-200 ,600
aromatic), 83.11 (C-5 thiazolidinedione), 59.93 (OCH3),
53.56 (CH aliphatic ethylene), 19.56 (CH3); MS: m/z:
683[M?]; Anal. calcd for C33H25N5O6S3: C 59.57, H 4.30,
N 9.65 %; Found C 59.42, H 4.23, N 9.57 %.
3-(7-(4-Bromophenyl)-2,5-dioxo-2,3,4,5,6,7hexahydrothiazolo[4,5-d]pyrimidine-3-carbonyl)-4methoxy-N-(4-(5-methylbenzo[d]thiazol-2yl)phenyl)benzene sulfonamide (5j)
cm-1): 3382, 3276, 3192, 3033, 1752, 1691, 1664, 1346,
1337, 1154, 842; 1H-NMR (CDCl3, 400 MHz): 11.34 (s,
1H, SO2NH), 10.29 (s, 1H, NH), 9.98 (s, 1H, NH),
aromatic), 7.19 (d, 2H, J = 8.3 Hz, H-300 ,500 aromatic),
6.96 (d, 1H, J = 8.4 Hz, H-3 aromatic), 6.69 (d, 2H,
(s, 3H, CH3); 13C-NMR (DMSO, 100 MHz): 168.97 (C-2
benzothiazole), 136.81 (C-4 aromatic), 133.38 (C-8
123
4800
benzothiazole), 133.11 (C-6 aromatic), 128.71 (C-10 aromatic), 128.39 (C-300 ,500 aromatic), 127.46 (C-20 ,60 aromatic), 127.23 (C=O, C-4 thiazolidinedione), 126.55 (C-6
benzothiazole), 126.18 (C-5 aromatic), 121.59 (C-7 benzothiazole), 121.23 (C-40 aromatic), 121.09 (C-4 benzothiazole), 120.63 (C-400 aromatic), 119.41 (C-3 aromatic),
(C-200 ,600 aromatic), 83.76 (C-5 thiazolidinedione), 59.53
(OCH3), 53.22 (CH aliphatic ethylene), 19.9 (CH3); MS:
m/z: 761[M?]; Anal. calcd for C33H24BrN5O6S3: C 51.97,
H 3.17, N 9.18 %; Found C 51.83, H 3.03, N 9.10 %.
In vitro evaluation of antimicrobial activity
The MICs of synthesized compounds were carried out by
the broth microdilution method (Rattan, 2000). DMSO was
used as diluents to get desired concentration of drugs to test
upon standard bacterial strains. Serial dilutions were prepared in primary and secondary screening. The control tube
containing no antibiotic was immediately sub cultured
(before inoculation) by spreading a loop evenly over a
quarter of plate of medium suitable for the growth of the
test organism and put for incubation at 37 C overnight.
The tubes were then incubated overnight. The MIC of the
control organism was read to check the accuracy of the
drug concentrations. The lowest concentration inhibiting
growth of the organism was recorded as the MIC. All the
tubes not showing visible growth (in the same manner as
control tube described above) were subcultured and incubated overnight at 37 C. The amount of growth from the
control tube before incubation (which represents the original inoculum) was compared. Subcultures might show
similar number of colonies indicating bacteriostatic activity; a reduced number of colonies indicate a partial or slow
bactericidal activity and no growth if the whole inoculum
has been killed. The test must include a second set of the
same dilutions inoculated with an organism of known
sensitivity. Each synthesized drug was diluted obtaining
2,000 lg/ml concentration, as a stock solution. In primary
screening, 500, 250, and 125 lg/ml concentrations of the
synthesized drugs were taken. The active synthesized drugs
found in this primary screening were further tested in a
second set of dilution against all microorganisms. The
drugs found active in primary screening were similarly
diluted to obtain 100, 50, 25, 12.5, 6.250, 3.125, and
1.5625 lg/ml concentrations. The highest dilution showing
at least 99 % inhibition is taken as MIC.
In vitro evaluation of antitubercular activity
Drug susceptibility and determination of MIC of the test
compounds against M. tuberculosis H37Rv were performed
by L. J. agar (MIC) method (Rattan, 2000) where primary
123
Med Chem Res (2014) 23:47894802
1000, 500, and 250 lg/ml and secondary 200, 100, 62.5, 50,
25, 12.5, 6.25, and 3.25 lg/ml dilutions of each test compound were added liquid L. J. Medium and then media were
sterilized by inspissations method. A culture of M. tuberculosis H37Rv growing on LowensteinJensen medium was
harvested in 0.85% saline in bijou bottles. All test compounds starting from a stock solution of 2,000 lg/ml concentration of compounds were prepared in DMSO. These
tubes were then incubated at 37 C for 24 h followed by
streaking of M. tuberculosis H37Rv (5 9 104 bacilli per
tube). These tubes were then incubated at 37 C. Growth of
bacilli was seen after 12 days, 22 days, and finally 28 days
of incubation. Tubes having the compounds were compared
with control tubes where medium alone was incubated with
M. tuberculosis H37Rv. The concentration at which no
development of colonies occurred or\20 colonies noted was
taken as MIC concentration of test compound. The standard
strain M. tuberculosis H37Rv was tested with known drug
rifampicin.
Conclusion
Two series of thiazolopyrimidine analogs were synthesized
and screened as new potential antitubercular and antimicrobial agents against wide range of pathogenic bacteria,
fungi, and mycobacteria. All the synthesized compounds
have been investigated for their antimicrobial and antimycobacterial activities. Most of the synthesized compounds
show significant activity against gram-positive bacteria
S. aureus, especially 5b, 5f having F and N(CH3)2 moieties,
respectively, exhibited the highest activity. Compounds 5a
and 5b having N(CH3)2 and F-substituted thiocyanato
benzathiazole compounds also show promising activity
against E.coli. Compound 5a bearing N(CH3)2 displays the
highest activity against S. pyogenes, and only compounds
5e, 5g, 5j show comparable activity against P. aeruginosa.
The antitubercular results reveal that compounds 5a and 5f
bearing N(CH3)2 and benzothiazole moieties showed better
antitubercular activity compared to rifampicin.
Acknowledgments The authors are thankful to Department of
Chemistry, VNSGU, Surat for providing necessary research facilities.
One of the authors Amit C. Purohit is also thankful to Maa Foundation for providing research scholarship. We also thank CDRI
Lucknow for elemental analysis and SAIF Chandigarh for spectral
analysis of the compounds.
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