Synthesis of novel azetidinone derivatives as antitubercular agents

Article abstract of DOI:10.2174/157018012800673038

A series of twelve novel azetedinones 4a-l have been synthesized by cyclocondensation of various Schiff bases of amino thiadiazole with chloroacetyl chloride in the presence of triethylamine. Various novel Schiff bases 3a-l were synthesized by condensatio

Full text of DOI:10.2174/157018012800673038

Letters in Drug Design & Discovery, 2012, 9, 611-617
611
Synthesis of Novel Azetidinone Derivatives as Antitubercular Agents
M. Himajaa, Asif Karigar*,b, M.V. Ramanab, D. Munirajasekhara and Mukesh S. Sikarwarc
aPharmaceutical Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014, India;
bDepartment of Pharmaceutical chemistry, Maratha Mandal’s College of Pharmacy, Belgaum 590016, Karnataka,
India; cDepartment of Pharmacognosy, KLEU College of Pharmacy, Belgaum, Karnataka, India
Received March 14, 2012: Revised March 14, 2012: Accepted April 23, 2012
Abstract: A series of twelve novel azetedinones 4a-l have been synthesized by cyclocondensation of various Schiff bases
of amino thiadiazole with chloroacetyl chloride in the presence of triethylamine. Various novel Schiff bases 3a-l were
synthesized by condensation of 2-amino-5-aryl-5H-thiazolo[4,3-b]-l,3,4-thiadiazole with various aryl aldehydes. The
1
synthesized compounds were characterized by FTIR, H-NMR, 13C-NMR and mass spectra. The titled compounds 3a-l
and 4a-l were evaluated for anti-tubercular activity at a concentration of 0.1-100 µg/mL by Microplate Blue Alamar Assay
method. Azetedinones 4a-l showed very good inhibition against the growth of Mycobacterium tuberculosis compared to
compounds 3a-l and standard Streptomycin and Pyrazinamide.
Keywords: 2-amino-5-aryl-5H-thiazolo[4,3-b]-1,3,4-thiadiazoles, Antitubercular activity, Azetidin-2-ones, Schiff base.
1. INTRODUCTION
to synthesize some new congeners of β-lactam heterocycles
by incorporating the thiadiazole and azetidinone moieties in
a single molecular framework. The present work deals with
the synthesis of the title compounds followed by their
antitubercular screening.
The β -lactam heterocycles are still the most prescribed
antibiotics used in medicine. They are considered as an
important contribution of science to humanity [1]. The most
widely used antibiotics such as the penicillins,
cephalosporins, carumonam, aztreonam, thienamycine and
the nocardicins all contain β-lactam rings [2]. The long-term
use of β -lactam antibiotics exerts selective pressure on
bacteria and permits the proliferation of resistant organisms.
A comparative study of current antibiotics with those from
previous decades shows an alarming increase in bacterial
resistance to β - lactam antibiotics [3]. The development of
several synthetic and semi-synthetic β-lactam antibiotics by
the pharmaceutical industry was due to the growing
resistance of bacteria towards the β -lactam antibiotics and
the need for medicines with a more specific antibacterial
activity [4]. An interesting group of β -lactams are the
monocyclic β -lactams, which are molecules that do not
contain another ring fused to the β-lactam one.
2. RESULTS AND DISCUSSION
Compounds 3a-l, 4a-l were prepared as shown in Scheme
1. 2-amino-5-aryl-5H-thiazolo[4,3-b]-l,3,4-thiadiazole
required as the starting material was prepared according to
the literature procedure [19]. 2-amino-5-aryl-5H-
1
thiazolo[4,3-b]-l,3,4-thiadiazole 1 which on condensation
with various selected aromatic aldehydes furnished Schiff’s
bases,
5-(substituted)-N-[(1E)-(substituted)methylene]
[1,3]thiazolo[4,3-b][1,3,4]thiadiazol-2-amine 3a-l. The four
membered β-lactam ring was in compound 3 was introduced
by the cycloaddition of (compounds 3a-l) chloroacetyl
chloride in the presence of triethyl amine catalyst to give 3-
chloro-4-(substituted)-1-[5-(substituted)[1,3]thiazolo[4,3-
b][1,3,4]thiadiazol-2-yl]azetidin-2-one 4a-l. The purity of
the compounds was monitored by TLC and the structures of
all the derivatives (3a-l, 4a-l) were supported by spectral
data. The FTIR, 1H-NMR, 13C-NMR and mass spectra are in
agreement with the proposed structures. Physical and
analytical data of the synthesized compounds are reported in
Table 1.
Azetidinones, which are part of the antibiotic structure,
are known to exhibit interesting biological activities [5]. A
large number of 3-chloro monocyclic β -lactams possess
powerful antibacterial, antimicrobial, anti-inflammatory,
anticonvulsant and antitubercular activity [6-8]. They also
function as enzyme inhibitors and are effective on the central
nervous system [9]. Thiadiazole analogs deal with a variety
of bioactivities viz. antitumor [10], anti-HIV [11],
antimicrobial [12], anticonvulsant [13], antitubercular [14],
antioxidant [15], and anti-inflammatory [16]. Literature is
enriched with a lot of work on the synthesis of potent
3. BIOLOGICAL ACTIVITY
Antitubercular Activity
substituted
thiadiazole
derivatives
with
diverse
The antimycobacterial activity of all the synthesized
pharmacological activities [17, 18].
compounds 3a-l
& 4a-l were assessed against M.
Hence, with a view to further assess the pharmacological
profile of this class of compounds, it was thought worthwhile
tuberculosis H37Rv (ATCC 2729411) using the Microplate
Alamar Blue Assay (MABA) [20, 21]. This methodology is
nontoxic, uses thermally stable reagent, and shows good
correlation with proportional and BACTEC radiometric
methods [22], and the activity expressed as the minimum
inhibitory concentration (MIC) in µg/mL. The final drug
*Address correspondence to this author at the Department of
Pharmaceutical chemistry, Maratha Mandal’s College of Pharmacy,
Belgaum 590016, Karnataka, India; Mob: 00919880219415; Fax:
00918312470717; E-mail: asifmpharm@yahoo.com
1875-628X/12 $58.00+.00
© 2012 Bentham Science Publishers

612 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 6
Himaja et al.
S
R2
O
H
S
N
N
+
NH2
(2)
(1)
R1
R1= -H, R= -H, (3a)
C2H5OH/HSO4
2
2
R1= -H, R = 2-Cl, (3b)
2
S
R1= -H, R= 4-Cl, (3c)
2
R2 R1= 4-CH , R2= H, (3d)
3
R1= 4-CH , R2= 2-CH, (3e)
3
3
R1= 4-CH , R2= 4-CH, (3f)
N
N
3
3
S
R1= 4-OH, R= -H, (3g)
2
R1
R1= 4-OH, R= 2-OH, (3h)
2
R1= 4-OH, R= 4-OH, (3i)
2
(3a-3l)
N
R1= 4-N(CH) , R2= H, (3j)
3 2
R1= 4-N(CH) , R2= 2-OCH, (3k)
3 2
3
ClCH COCl/ETN
2
3
R1= 4-N(CH) , R2= 4-OCH, (3l)
3 2
3
R1= -H, R = -H, (4a)
R2
2
R1= -H, R= 2-Cl, (4b)
2
S
R1= -H, R = 4-Cl, (4c)
2
S
R1= 4-CH, R2= H, (4d)
3
R1= 4-CH, R2= 2-CH , (4e)
N
3
3
R1= 4-CH, R2= 4-CH , (4f)
3
3
N
N
R1= 4-OH, R= -H, (4g)
2
R1= 4-OH, R= 2-OH, (4h)
2
Cl
R1= 4-OH, R= 4-OH, (4i)
2
R1
O
(4a-4l)
R1= 4-N(CH) , R2= H, (4j)
3 2
R1= 4-N(CH) , R2= 2-OCH, (4k)
3 2
3
R1= 4-N(CH) , R2= 4-OCH, (4l)
3 2
3
Scheme 1.
concentration tested was 0.1-100 µg/mL. A blue color in the
well was interpreted as no bacterial growth, and pink color
was scored as growth. The MIC (Minimal Inhibition
Concentration) was defined as the lowest drug concentration,
which prevented a color change from blue to pink. The MICs
of the compounds were depicted in Table 2 & Table 3.
Streptomycin and Pyrazinamide was used as standards. All
the tested compounds showed better in vitro activity against
Streptomycin and Pyrazinamide as standard drugs. A closer
look into the biological results of the above compounds
reveals that substitution on amino group of compound 1 with
methyl (3f), hydroxy (3h, 3i) functional groups substituted
aldehydes leads to increase in activity and further the para
substituent (3i) are more active than the ortho substituent
(3h) in a Schiff base series (3a-l). Cyclization of compounds
3a-l to 4a-l showed more potent in-vitro antitubercular
activity, perhaps due to increase in hydrophobicity resulting
into better penetration of the Mtb cell wall. Compounds 4e,
4f and 4i showed good antitubercular activity compared to
both standard drugs pyrazinamide and streptomycin and
compounds 3f, 3h, 3i, 4b-d, 4h, 4k and 4l are more active
than streptomycin and active as pyrazinamide.
4. EXPERIMENTAL
4.1. Materials and Methods
Analytical grade solvents and commercially available
reagents were used without further purification. All
chemicals were obtained from spectrochem Ltd (Mumbai,
India). The column chromatography was carried out over
silica gel (60-120 mesh), purchased from Sisco Research
Laboratories Pvt Ltd. Melting points were determined in
DBK, Prog, melting point apparatus Servewell Instruments
Pvt Ltd. FTIR spectra in KBr disk were recorded from 4000
to 400 cm-1 on Shimadzu FT-IR spectrometer. H NMR
1
spectra were recorded on 400-MHz and 500-MHz Bruker
spectrometer in DMSO-d6 or CDCl3 using tetramethylsilane
(TMS) as an internal standard. Chemical shifts are given in δ
relative to TMS, the coupling constants are given in Hz.
Mass spectra were recorded using Agilent 1100 MSD
spectrometer in electro spray mode.
4.2. Preparation of 2-Amino-5-aryl-5H-Thiazolo[4,3-b]-
l,3,4-Thiadiazole (1)
2-amino-5-aryl-5H-thiazolo[4,3-b]-l,3,4-thiadiazoles are
prepared according to literature procedure [25]. An aromatic

Synthesis of Novel Azetidinone Derivatives as Antitubercular Agents
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 6 613
Table 1. Physical Data of Synthesized Compounds 3a-3l & 4a-4l
Compd
R1
R2
Yield (%)
M.P. (oC)
Mol. Formula
3a
3b
3c
3d
3e
3f
-H
-H
-H
2-Cl
62
58
63
71
78
76
72
75
78
76
72
66
67
61
65
71
73
74
71
73
75
70
71
67
140
144
109
114
132
156
179
186
154
156
179
141
158
163
129
136
146
156
167
123
167
189
134
156
C17H13N3S2
C17H12ClN3S2
C17H12ClN3S2
C18H15N3S2
-H
4-Cl
4-CH3
4-CH3
4-CH3
4-OH
-H
2-CH3
4-CH3
-H
C19H17N3S2
C19H17N3S2
3g
3h
3i
C17H13N3OS2
C17H13N3O2S2
C17H13N3O2S2
C19H18N4S2
4-OH
2-OH
4-OH
-H
4-OH
3j
4-N(CH3)2
4-N(CH3)2
4-N(CH3)2
-H
3k
3l
2-OCH3
4-OCH3
-H
C20H20N4OS2
C20H20N4OS2
C19H14ClN3OS2
C19H13Cl2N3OS2
C19H13Cl2N3OS2
C20H16ClN3OS2
C21H18ClN3OS2
C21H18ClN3OS2
C19H14ClN3O2S2
C19H14ClN3O3S2
C19H14ClN3O3S2
C21H19ClN4OS2
C22H21ClN4O2S2
C22H21ClN4O2S2
4a
4b
4c
4d
4e
4f
-H
2-Cl
-H
4-Cl
4-CH3
4-CH3
4-CH3
4-OH
-H
2-CH3
4-CH3
-H
4g
4h
4i
4-OH
2-OH
4-OH
-H
4-OH
4j
4-N(CH3)2
4-N(CH3)2
4-N(CH3)2
4k
4l
2-OCH3
4-OCH3
Table 2. Antitubercular Activity of Synthesized Compounds 3a-3l
Sl No
R1
R2
MIC (µg/mL)
Compound
1
2
3a
-H
-H
-H
2-Cl
4-Cl
-H
12.5
6.25
6.25
12.5
6.25
3.125
12.5
3.125
3.125
6.25
6.25
6.25
6.25
3.12
3b
3
3c
-H
4
3d
4-CH3
4-CH3
4-CH3
4-OH
4-OH
4-OH
4-N(CH3)2
4-N(CH3)2
4-N(CH3)2
-
5
3e
2-CH3
4-CH3
-H
6
3f
7
3g
8
3h
2-OH
4-OH
-H
9
3i
10
11
12
13
14
3j
3k
2-OCH3
4-OCH3
-
3l
Streptomycin
Pyrazinamide
-
-
The MIC values were evaluated at concentration range, 0.1-100 µg/mL.
The figure in the table showed the value in µg/ml.

614 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 6
Himaja et al.
Table 3. Antitubercular Activity of Synthesized Compounds 4a-4l
Sl No
Compound
R1
R2
MIC (µg/mL)
1
2
4a
-H
-H
-H
2-Cl
4-Cl
-H
6.25
3.125
3.125
3.125
1.6
4b
3
4c
-H
4
4d
4-CH3
4-CH3
4-CH3
4-OH
4-OH
4-OH
4-N(CH3)2
4-N(CH3)2
4-N(CH3)2
-
5
4e
2-CH3
4-CH3
-H
6
4f
0.8
7
4g
6.25
3.125
1.6
8
4h
2-OH
4-OH
-H
9
4i
10
11
12
13
14
4j
4k
6.25
3.125
3.125
6.25
3.12
2-OCH3
4-OCH3
-
4l
Streptomycin
Pyrazinamide
-
-
The MIC values were evaluated at concentration range, 0.1-100 µg/mL.
The figure in the table showed the value in µg/ml.
aldehyde (0.02 moles) and thioglycolic acid (0.02 moles)
were mixed, and after 10-15 min. 0.022 moles of
thiosemicarbazide were added; then 10 mL of concentrated
H2SO4 was added in portions upon cooling. The mixture was
homogenized and left for 18-24 hours at -20 °C. The reaction
mass was treated with 30--50 g ice, the precipitated solid
was decanted, water was added, and the obtained suspension
was neutralized with 40% NaOH until a weak alkaline
reaction. Synthesized compounds were recrystallized from
aqueous dioxane solution.
H thiazole), 1598 (-N=CH), 682 (C-S-C); 1H NMR chemical
shifts at ( 400 MHz, CDCl3, δ ppm): 11.05 (s, 1H, CH); 8.04
(s, 1H, -N=CH); 7.86 (s, 1H, CH); 7.40-7.75 (m, 9H, Ar-H);
MS spectrum, m/z: 359[M+1] +.
4.3.3. N-[(1E)-(4-Chlorophenyl)Methylene]-5-Phenyl[1,3]
Thiazolo[4,3-b][1,3,4]Thiadiazol-2-Amine (3c)
The following spectral data were recorded for compound
3c: FTIR (KBr) cm-1: 3095 (Ar C-H); 2930 (C-H); 2820 (C-
H thiazole), 1582 (-N=CH), 710 (C-S-C); 1H NMR chemical
shifts at ( 400 MHz, CDCl3, δ ppm): 11.10 (s, 1H, CH), 8.20
(s, 1H, N=CH), 7.90 (s, 1H, CH), 7.15-7.72 (m, 9H, Ar-H);
MS spectrum, m/z: 358[M+1] +.
4.3. General Procedure for the Synthesis of Compounds
3a-3l
4.3.4. 5-(4-Methylphenyl)-N-[(1E)-Phenylmethylene][1,3]
Thiazolo[4,3-b][1,3,4]Thiadiazol-2-Amine (3d)
To a stirred solution of compound 1(0.01 mole) in
ethanol (50ml) containing sulphuric acid (2ml) was added
appropriate aromatic aldehyde (0.01 mole) and the mixture
refluxed for 4-6 hours on a water bath. The separated solid
was filtered and recrystallized from ethanol to give the title
compounds.
The following spectral data were recorded for compound
3d: FTIR (KBr) cm-1: 3157 (Ar C-H), 2929 (C-H), 2850 (C-
H thiazole), 1598 (-N=CH), 705 (C-S-C); 1H NMR chemical
shifts at ( 400 MHz, CDCl3, δ ppm): 10.30 (s, 1H, CH), 8.37
(s, 1H, N=CH), 7.72 (s, 1H, CH), 6.86-7.52 (m, 9H, Ar-H),
1.45 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6 ): δ 32.65,
43.74, 130.60, 134.86, 140.93, 144.85, 150.86, 153.55,
160.17, 160.68, 163.23, 164.40;MS spectrum, m/z: 338
4.3.1.
5-Phenyl-N-[(1E)-Phenylmethylene][1,3]Thiazolo
[4,3-b][1,3,4]Thiadiazol-2-Amine (3a)
The following spectral data were recorded for compound
3a: FTIR (KBr) cm-1: 3115 (Ar C-H), 2960 (C-H), 2880 (C-
H thiazole), 1590 (-N=CH), 702 (C-S-C); 1H NMR chemical
shifts at ( 400 MHz, CDCl3, δ ppm): 11.14 (s, 1H, CH), 8.14
(s, 1H, -N=CH), 7.98 (s, 1H, CH), 7.30-7.68 (m, 10H, Ar-
H); MS spectrum, m/z: 324[M+1] +; Anal. Calcd for
C17H13N3S2: C(63.13), H(4.05), N(12.99). Found: C(63.11),
H(4.01), N(12.95).
+
[M+1] ; Anal. Calcd for C18H15N3S2: C(64.06), H(4.48),
N(12.45). Found: C(64.01), H(4.44), N(12.39).
4.3.5. 5-(4-Methylphenyl)-N-[(1E)-(2-Methylphenyl)Methy-
lene][1,3]Thiazolo[4,3-b][1,3,4]Thiadiazol-2-Amine (3e)
The following spectral data were recorded for compound
3e: FTIR (KBr) cm-1: 3108 (Ar C-H), 2950(C-H), 2870 (C-H
1
thiazole), 1585 (-N=CH), 712 (C-S-C); H NMR chemical
4.3.2. N-[(1E)-(2-Chlorophenyl)Methylene]-5-Phenyl[1,3]
Thiazolo[4,3-b][1,3,4]Thiadiazol-2-Amine (3b)
shifts at ( 400 MHz, CDCl3, δ ppm): 10.16 (s, 1H, CH), 8.39
(s, 1H, N=CH), 7.86 (s, 1H, CH), 7.25-7.63 (m, 8H, Ar-H),
2.45 (s, 6H, CH3); MS spectrum, m/z: 353 [M+1] +.
The following spectral data were recorded for compound
3b: FTIR (KBr) cm-1: 3110 (Ar C-H), 2890 (C-H), 2810 (C-

Synthesis of Novel Azetidinone Derivatives as Antitubercular Agents
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 6 615
4.3.12. 5-[4-(Dimethylamino)Phenyl]-N-[(1e)-(4-Methoxy-
phenyl)Methylene][1,3]Thiazolo[4,3-B][1,3,4] Thiadiazol-
2-Amine (3l)
4.3.6. 5-(4-Methylphenyl)-N-[(1E)-(4-Methylphenyl)Methy-
lene][1,3]Thiazolo[4,3-b][1,3,4]Thiadiazol-2-Amine (3f)
The following spectral data were recorded for compound
3f: FTIR (KBr) cm-1: 3005 (Ar C-H), 2890 (C-H), 2750 (C-
H thiazole), 1583 (-N=CH), 712 (C-S-C); 1H NMR chemical
shifts at ( 400 MHz, CDCl3, δ ppm): 10.14 (s, 1H, CH), 8.36
(s, 1H, N=CH), 7.81 (s, 1H, CH), 7.22-7.68 (m, 8H, Ar-H),
2.35 (s, 6H, CH3); MS spectrum, m/z: 352 [M+1] +.
The following spectral data were recorded for compound
3l: FTIR (KBr) cm-1: 3122 (ArC-H), 2972 (C-H), 2892 (C-H
1
thiazole), 1594 (-N=CH), 722 (C-S-C); H NMR chemical
shifts at ( 400 MHz, CDCl3, δ ppm): 9.80 (s, 1H, CH), 9.30
(s, 1H, N=CH), 6.43 (s, 1H, CH), 7.75-7.98 (m, 8H, Ar-H),
3.52 (s, 3H, -OCH3), 1.52-1.58(s, 6H, CH3); MS spectrum,
m/z: 397 [M+1] +.
4.3.7. 4-(2-{[(1E)-Phenylmethylene]Amino}[1,3]Thiazolo
[4,3-b][1,3,4]Thiadiazol-5-yl)Phenol (3g)
The following spectral data were recorded for compound
4.4. General Procedure for the Synthesis of Compounds
4a-4l
3g: FTIR (KBr) cm-1: 3545 (O-H), 3005 (ArC-H), 2955 (C-
1
H), 2875 (C-H thiazole), 1515 (-N=CH), 695 (C-S-C); H
To a stirred solution of the particular 5-phenyl-N-
[(substituted) phenylmethylene][1,3]thiazolo[4,3-b][1,3,4]
thiadiazol-2-amine 2a-2l (0.02 mole) and triethylamine (0.01
mole) in dioxan (50ml), chloroacetyl chloride (0.01 mole)
was added drop wise at 0-50C. The reaction mixture stirred
for 3hours and the separated solid was crystallized from
methanol to give the title compounds.
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 9.63 (s,
1H, CH), 7.83 (s, 1H, CH), 8.19 (s, 1H, N=CH), 7.18-7.34
(m, 9H, Ar-H), 5.28 (s, 1H, OH); MS spectrum, m/z: 341
[M+1] +.
4.3.8.
2-[(E)-{[5-(4-Hydroxyphenyl)[1,3]Thiazolo[4,3-b]
[1,3,4]Thiadiazol-2-yl]Imino}Methyl]phenol (3h)
4.4.1. 3-Chloro-4-Phenyl-1-(5-Phenyl[1,3]Thiazolo[4,3-b]
[1,3,4]Thiadiazol-2-yl)Azetidin-2-one (4a)
The following spectral data were recorded for compound
3h: FTIR (KBr) cm-1: 3515 (O-H), 3005 (ArC-H), 2965 (C-
1
H), 2885 (C-H thiazole), 1550 (-N=CH), 702 (C-S-C); H
The following spectral data were recorded for compound
4a: FTIR (KBr) cm-1: 3118 (Ar C-H), 2973 (C-H), 2884 (C-
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 9.82 (s,
1H, CH), 7.95 (s, 1H, CH), 8.22 (s, 1H, N=CH), 7.05-7.45
(m, 8H, Ar-H), 5.20 (s, 2H, OH); MS spectrum, m/z: 356
[M+1] +.
1
H thiazole), 1695 (-C=O), 708 (C-S-C), 766 (-C-Cl); H
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 11.12 (s,
1H, CH), 7.92 (s, 1H, CH), 7.28-7.60 (m, 10H, Ar-H), 4.14
(s, 1H, -N-CH), 5.15 (s, 1H, -CH-Cl); MS spectrum, m/z:
401[M+1] +; Anal. Calcd for C19H14ClN3OS2: C(57.06),
H(3.53), N(10.51). Found: C(57.01), H(3.48), N(10.44).
4.3.9.
4-(2-{[(1E)-(4-Hydroxyphenyl)Methylene]amino}
[1,3]Thiazolo[4,3-b][1,3,4]Thiadiazol-5-yl)Phenol (3i)
The following spectral data were recorded for compound
3i: FTIR (KBr) cm-1: 3530 (O-H), 3005 (ArC-H), 2955 (C-
4.4.2. 3-Chloro-4-(2-Chlorophenyl)-1-(5-Phenyl[1,3]Thia-
zolo[4,3-b][1,3,4]Thiadiazol-2-yl)Azetidin-2-One (4b)
1
H), 2875 (C-H thiazole), 1535 (-N=CH), 780 (C-S-C); H
The following spectral data were recorded for compound
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 9.85 (s,
1H, CH), 7.98 (s, 1H, CH), 8.30 (s, 1H, N=CH), 7.10-7.38
(m, 8H, Ar-H), 5.18 (s, 2H, OH); MS spectrum, m/z: 357
[M+1] +.
4b: FTIR (KBr) cm-1: 3122 (Ar C-H), 2975 (C-H), 2888 (C-
1
H thiazole), 1689 (-C=O), 702 (C-S-C), 755 (-C-Cl); H
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 11.14 (s,
1H, CH), 7.98 (s, 1H, CH), 7.30-7.68 (m, 9H, Ar-H), 4.11 (s,
1H, -N-CH), 5.18 (s, 1H, -CH-Cl); MS spectrum, m/z:
434[M+1] +.
4.3.10. 5-[4-(Dimethylamino)phenyl]-N-[(1E)-Phenylmeth-
ylene][1,3]Thiazolo[4,3-b][1,3,4]Thiadiazol-2-Amine (3j)
The following spectral data were recorded for compound
4.4.3. 3-Chloro-4-(4-Chlorophenyl)-1-(5-Phenyl[1,3]Thia-
zolo[4,3-b][1,3,4]Thiadiazol-2-yl)Azetidin-2-One (4c)
3j: FTIR (KBr) cm-1: 3111 (ArC-H), 2962 (C-H), 2875 (C-H
1
thiazole), 1583 (-N=CH), 714 (C-S-C); H NMR chemical
The following spectral data were recorded for compound
shifts at ( 400 MHz, CDCl3, δ ppm): 9.86 (s, 1H, CH), 9.39
(s, 1H, N=CH), 6.34 (s, 1H, CH), 7.17-7.72 (m, 9H, Ar-H),
1.42-1.47(s, 6H, CH3); MS spectrum, m/z: 368 [M+1] +.
4c: FTIR (KBr) cm-1: 3115 (Ar C-H), 2960 (C-H), 2890 (C-
1
H thiazole), 1696 (-C=O), 710 (C-S-C), 775 (-C-Cl); H
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 11.17 (s,
1H, CH), 7.82 (s, 1H, CH), 7.15-7.72 (m, 9H, Ar-H), 4.12 (s,
1H, -N-CH), 5.24 (s, 1H, -CH-Cl); MS spectrum, m/z:
435[M+1] +.
4.3.11.
5-[4-(Dimethylamino)Phenyl]-N-[(1E)-(2-Metho-
xyphenyl)Methylene][1,3]Thiazolo[4,3-b][1,3,4] Thiadiazol
-2-Amine (3k)
4.4.4.
3-Chloro-1-[5-(4-Methylphenyl)[1,3]Thiazolo[4,3-
The following spectral data were recorded for compound
3k: FTIR (KBr) cm-1: 3120 (ArC-H), 2965 (C-H), 2892 (C-
H thiazole), 1585 (-N=CH), 718 (C-S-C); 1H NMR chemical
shifts at ( 400 MHz, CDCl3, δ ppm): 9.92 (s, 1H, CH), 9.28
(s, 1H, N=CH), 6.37 (s, 1H, CH), 7.80-7.95 (m, 8H, Ar-H),
3.15 (s, 3H, -OCH3), 1.42-1.47(s, 6H, CH3); MS spectrum,
m/z: 398 [M+1] +.
b][1,3,4]Thiadiazol-2-yl]-4-Phenylazetidin-2-One (4d)
The following spectral data were recorded for compound
4d: FTIR (KBr) cm-1: 3120 (Ar C-H), 2960 (C-H), 2880 (C-
1
H thiazole), 1689 (-C=O), 702 (C-S-C), 766 (-C-Cl); H
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 10.16 (s,
1H, CH), 7.86 (s, 1H, CH), 7.25-7.63 (m, 9H, Ar-H), 2.34 (s,
3H, CH3), 4.14 (s, 1H, -N-CH), 5.15 (s, 1H, -CH-Cl); 13C

616 Letters in Drug Design & Discovery, 2012, Vol. 9, No. 6
Himaja et al.
4.4.10. 3-Chloro-1-{5-[4-(Dimethylamino)phenyl][1,3]Thi-
NMR (75 MHz, DMSO-d6 ): δ 21.72, 29.28, 32.87, 129.24,
129.35, 130.65, 131.26, 131.71, 132.30, 133.83, 153.17,
153.68, 156.23,157.40, 175.10;MS spectrum, MS spectrum,
m/z: 415 [M+1] +; Anal. Calcd for C20H16ClN3OS2: C(58.03),
H(3.90), N(10.15). Found: C(57.98.11), H(3.85), N(10.09).
azolo[4,3-b][1,3,4]Thiadiazol-2-yl}-4-Phenyl
One (4j)
Azetidin-2-
The following spectral data were recorded for compound
4j: FTIR (KBr) cm-1: 3094 (ArC-H), 2989 (C-H), 2892 (C-H
1
thiazole), 1679 (-C=O), 709 (C-S-C), 762 (-C-Cl); H NMR
4.4.5. 3-Chloro-4-(2-Methylphenyl)-1-[5-(4-Methylphenyl)
[1,3]Thiazolo[4,3-b][1,3,4]Thiadiazol-2-yl] Azetidin-2-One
(4e)
chemical shifts at ( 400 MHz, CDCl3, δ ppm): 9.82 (s, 1H,
CH), 6.38 (s, 1H, CH), 7.17-7.72 (m, 9H, Ar-H), 1.42-1.47(s,
6H, CH3), 4.19 (s, 1H, -N-CH), 5.23 (s, 1H, -CH-Cl); MS
spectrum, m/z: 444 [M+1] +.
The following spectral data were recorded for compound
4e: FTIR (KBr) cm-1: 3090 (Ar C-H), 2955 (C-H), 2894 (C-
1
4.4.I1. 3-Chloro-4-(2-Methoxyphenyl)-1-{5-[4-(Dimethyl-
H thiazole), 1685 (-C=O), 669 (C-S-C), 760 (-C-Cl); H
amino)Phenyl][1,3]Thiazolo[4,3-b][1,3,4]
yl}Azetidin-2-One (4k)
Thiadiazol-2-
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 10.18 (s,
1H, CH), 7.92 (s, 1H, CH), 7.18-7.58 (m, 8H, Ar-H), 2.45 (s,
6H, CH3), 4.08 (s, 1H, -N-CH), 5.08 (s, 1H, -CH-Cl); MS
spectrum, m/z: 429 [M+1] +.
The following spectral data were recorded for compound
4k: FTIR (KBr) cm-1: 3093 (ArC-H), 2948 (C-H), 2872 (C-
1
H thiazole), 1695 (-C=O), 672 (C-S-C), 768 (-C-Cl); H
4.4.6. 3-Chloro-4-(4-Methylphenyl)-1-[5-(4-Methylphenyl)
[1,3]Thiazolo[4,3-b][1,3,4]Thiadiazol-2-yl] Azetidin-2-One
(4f)
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 9.92 (s,
1H, CH), 6.46 (s, 1H, CH), 7.74-7.98 (m, 8H, Ar-H), 3.15 (s,
3H, -OCH3), 1.42-1.48(s, 6H, CH3), 4.06 (s, 1H, -N-CH),
5.32 (s, 1H, -CH-Cl); MS spectrum, m/z: 474 [M+1] +.
The following spectral data were recorded for compound
4f: FTIR (KBr) cm-1: 3105 (Ar C-H), 2960 (C-H), 2896 (C-
4.4.12. 3-Chloro-4-(4-Methoxyphenyl)-1-{5-[4-(Dimethyl-
1
H thiazole), 1748 (-C=O), 713 (C-S-C), 767 (-C-Cl); H
amino)Phenyl][1,3]Thiazolo[4,3-b][1,3,4]
yl}Azetidin-2-One (4l)
Thiadiazol-2-
NMR chemical shifts at ( 400 MHz, CDCl3, δ ppm): 10.16 (s,
1H, CH), 7.86 (s, 1H, CH), 7.25-7.63 (m, 8H, Ar-H), 2.35 (s,
6H, CH3), 4.10 (s, 1H, -N-CH), 5.10 (s, 1H, -CH-Cl); MS
spectrum, m/z: 428 [M+1] +.
The following spectral data were recorded for compound
4l: FTIR (KBr) cm-1: 3098 (ArC-H), 2975 (C-H), 2892 (C-H
1
thiazole), 1692 (-C=O), 701 (C-S-C), 769 (-C-Cl); H NMR
4.4.7. 3-Chloro-1-[5-(4-Hydroxyphenyl)[1,3]Thiazolo[4,3-
b][1,3,4]Thiadiazol-2-yl]-4-Phenylazetidin-2-One (4g)
chemical shifts at ( 400 MHz, CDCl3, δ ppm): 9.83 (s, 1H,
CH); 6.37 (s, 1H, CH); 7.82-7.99 (m, 8H, Ar-H); 3.52 (s, 3H,
-OCH3), 1.40-1.47(s, 6H, CH3), 4.10 (s, 1H, -N-CH), 5.22 (s,
1H, -CH-Cl); MS spectrum, m/z: 473 [M+1] +.
The following spectral data were recorded for compound
4g: FTIR (KBr) cm-1: 3545 (O-H), 3005 (ArC-H), 2955 (C-
H), 2875 (C-H thiazole), 1738 (-C=O), 675 (C-S-C), 780 (-
1
C-Cl). H NMR chemical shifts at ( 400 MHz, CDCl3,
δ
CONCLUSION
ppm): 9.63 (s, 1H, CH), 7.83 (s, 1H, CH), 7.18-7.34 (m, 9H,
Ar-H), 5.28 (s, 1H, OH), 4.14 (s, 1H, -N-CH), 5.11 (s, 1H, -
CH-Cl); MS spectrum, m/z: 417 [M+1] +.
In the present paper, we reported the synthesis, spectral
studies and antitubercular activity of a new series of 5-
(Substituted)
phenyl-N-[(1E)-(
substituted)
4.4.8.
3-Chloro-4-(2-Hydroxyphenyl)-1-[5-(4-Hydroxy-
phenylmethylene][1,3]thiazolo[4,3 b][1,3,4] thiadiazol-2-
amine 3a-l, 3-chloro-4-(substituted)phenyl-1-[5-(substituted)
phenyl [1,3]thiazolo[4,3-b][1,3,4] thiadiazol-2-yl]azetidin-2-
one 4a-l in good yield. In Schiff base series 3a-3l, compound
3f, 3h and 3i showed good antitubercular activity compared
to standard streptomycin. Compounds 4e, 4f and 4i showed
good antitubercular activity compared to both standard drugs
pyrazinamide and streptomycin and compounds 3f, 3h, 3i,
4b-d, 4h, 4k and 4l are more active than streptomycin and
active as pyrazinamide. The overall outcome of these results
revealed that the Azetidinone ring is a satisfactory backbone
for antitubercular activity. These preliminary encouraging
results of biological screening of the tested compounds could
offer an excellent framework in this field that may lead to
the discovery of potent antitubercular agent.
phenyl)[1,3]Thiazolo[4,3-b][1,3,4]
din-2-one (4h)
Thiadiazol-2-yl]Azeti-
The following spectral data were recorded for compound
4h: FTIR (KBr) cm-1: 3515 (O-H), 3010 (ArC-H), 2966 (C-
H), 2888 (C-H thiazole), 1750 (-C=O), 705 (C-S-C), 762 (-
1
C-Cl); H NMR chemical shifts at (400 MHz, CDCl3,
δ
ppm): 9.69 (s, 1H, CH), 7.91 (s, 1H, CH), 7.11-7.37 (m, 8H,
Ar-H), 5.20 (s, 2H, OH), 4.12 (s, 1H, -N-CH), 5.15 (s, 1H, -
CH-Cl); MS spectrum, m/z: 431 [M+1] +.
4.4.9.
3-Chloro-4-(4-Hydroxyphenyl)-1-[5-(4-Hydroxy-
phenyl)[1,3]Thiazolo[4,3-b][1,3,4]Thiadiazol-2-yl]
Azetidin-2-One (4i)
The following spectral data were recorded for compound
4i: FTIR (KBr) cm-1: 3530 (O-H), 3008 (ArC-H), 2962 (C-
CONFLICT OF INTEREST
H), 2881 (C-H thiazole), 1738 (-C=O), 715 (C-S-C), 766 (-
1
C-Cl); H NMR chemical shifts at ( 400 MHz, CDCl3,
δ
None declared.
ppm): 9.68 (s, 1H, CH), 7.88 (s, 1H, CH), 7.20-7.41 (m, 8H,
Ar-H), 5.21 (s, 2H, OH), 4.08 (s, 1H, -N-CH), 5.12 (s, 1H, -
CH-Cl); MS spectrum, m/z: 432 [M+1] +.
ACKNOWLEDGEMENTS
Authors are thankful to the VIT University, Vellore and
Maratha Mandal’s college of Pharmacy Belgaum for

Synthesis of Novel Azetidinone Derivatives as Antitubercular Agents
Letters in Drug Design & Discovery, 2012, Vol. 9, No. 6 617
[13]
[14]
[15]
Gupta, A.; Mishra, P.; Pandeya, S. N.; Kashaw, S. K.; Kashaw V.;
Stables, J. P. Synthesis and anticonvulsant activity of some
substituted 1,2,4-thiadiazoles, Eur. J. Med. Chem., 2009, 44, 1100-
1105.
providing facilities to carry out the research work and
Maratha mandal’s Nathajirao G. Halgekar Institute of Dental
Sciences and Research Centre, Belgaum for antitubercular
activity.
Gadad, A. K.; Noolvi, M. N.; Karpoormath, R. V. Synthesis and
anti-tubercular activity of
a series of 2-sulfonamido/trifluoro
methyl-6-substituted imidazo[2,1-b]-1,3,4-thiadiazole derivatives.
Bioorg Med Chem., 2004, 12, 5651–5659.
Kus, C.; Kilcigil, G. A.; Ozbey, S.; Kaynak, F. B.; Kaya, M.;
Coban, T.; Eke, B. C. Synthesis and antioxidant properties of novel
N-methyl-1,3,4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-
3(4H)-thione derivatives of benzimidazole class, Bioorg. Med.
Chem., 2008, 16, 4294-4303.
Karegoudar, P.; Prasad, D. J.; Ashok, M.; Mahalinga, M.; Poojary,
B.; Holla, B. S. Synthesis, antimicrobial and anti-inflammatory
activities of some 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles and 1,2,4-
triazolo[3,4-b][1,3,4]thiadiazines bearing trichlorophenyl moiety,
Eur. J. Med. Chem, 2008, 43, 808-815.
Siddiqui, N.; Ahuja, P.; Waquar, A.; Pandeya, S. N.; Alam, M. S.
Thiadiazoles: Progress report on biological activities, J. Chem. and
Pharm. Res., 2009, 1, 19-30.
REFERENCES
[1]
Southgate, R. The synthesis of natural β-lactam antibiotics.
Contemp. Org. Synth., 1994. 1, 417-431.
[2]
Mata, E. G.; Fraga, M. A.; Delpiccolo, C. M. L. An Efficient,
Stereoselective Solid-Phase Synthesis of β-Lactams Using
Mukaiyama’s Salt for the Staudinger Reaction. J. Comb. Chem.,
2003, 5, 208-210.
[16]
[3]
[4]
Niccolai, D.; Trasi, L.; Thomas, R. J. The renewed challenge of
antibacterial chemotherapy. Chem. Commun., 1997, 4, 2333-2342.
Van der Steen, F. H.; Van Koten, G. Synthesis of 3-amino-2-
azetidinones: A literature survey. Tetrahedron 1991, 47, 7503-
7524.
[17]
[18]
[5]
Durckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H.
Recent Developments in the Field of β-Lactam Antibiotics. Angew.
Chem. Int. Ed. Engl. 1985, 24, 180-202.
Karabasanagouda, T.; Adhikari, A.V.; Shetty, N. S. Synthesis and
antimicrobial activities of some novel 1,2,4-triazolo [3,4-b]-1,3,4-
thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines carrying
thioalkyl and sulphonyl phenoxy moieties, Eur. J. Med. Chem.,
2007, Vol. 42, 521-529.
[6]
[7]
Abdulla, R. F.; Fuhr, K. H. Monocyclic antibiotic beta-lactams. J.
Med. Chem. 1975, 18, 625-627.
Khalafallah, A. K.; Selim, M. A.; El-Hamd, R. M. A.; Elmaghraby,
M. A.; Soleiman, H. A.; Raslan, M. A. Novel synthesis of some
new fused/spiro heterocyclic compounds and their biological
activity. Indian J. Chem. 1995, 34B, 1066-1070.
[19]
[20]
Karigar, A. A.; Himaja, M.; Mali, S. V.; Jagadeesh, K. P.;
Sikarwar, M. S. One-Pot Synthesis and Antitubercular activity of
2-Amino-5-Aryl-5H-Thiazolo
[4,3-b]-1,3,4-Thiadiazoles,
[8]
[9]
Parikh, K. A.; Oza, P. S.; Parikh, A. R. Synthesis of some new 2-
azetidinones as potential antitubercular agents. Indian J. Chem.
2000, 39B, 716.
Vashi, B. S.; Mehta, D. S.; Shah, V. H. Synthesis and biological
activity of 4-thiazolidinones, 2-azetidinones, 4-imidazolinone
derivatives having thymol moiety. Indian J. Chem., 1995, 34B,
802-808.
International Research Journal of Pharmacy., 2011, 2(1), 153-158.
Franzblau, S. G.; Witzig, R. S.; McLaughlin, J. C.; Torres, P.;
Madico, G.; Hernandez, A.; Degnan, M. T.; Cook, M. B.; Quenzer,
V. K.; Ferguson, R. M.; Gilman, R. H. Rapid, Low-Technology
MIC Determination with Clinical Mycobacterium tuberculosis
Isolates by Using the Microplate Alamar Blue Assay. J. Clin.
Microbiol., 1998, 36, 362-366.
[10]
[11]
Matysiak, J.; Opolski, A. Synthesis and antiproliferative activity of
N-substituted 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles.
Bioorg. Med. Chem., 2006, 14, 4483-4489.
Giri, S. N.; Srivastava, U. C. Synthesis of some N-(5-
aryl/aryloxymethyl-1,3,4-thiadiazol-2-yl)-glyoxyla-mide
thiosemicarbazones as potential antiviral and antifungal agents,
Agric. Biol. Chem., 1983, 47, 103-105.
Padmavathi, V.; Reddy, G. S.; Padmaja, A.; Kondaiah, P.; Shazia,
A. Synthesis, antimicrobial and cytotoxic activities of 1,3,4-
oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles, Eur. J. Med.
Chem., 2009, 44, 2106-2112.
[21]
[22]
Carvalho, S. A.; Edson, F. D.; Marcus, V.N.; Maria, C.S.; Felipe,
R. V. Synthesis and antimycobacterial evaluation of new trans-
cinnamic acid hydrazide derivatives, Bioorganic & Medicinal
Chemistry Letters., 2008, 18, 538-541.
Reis, R. S.; Neves, Jr. I.; Lourenço, S. L. S.; Fonseca, L. S.;
Lourenço, M. C. S. Comparison of Flow Cytometric and Alamar
Blue Tests with the Proportional Method for Testing Susceptibility
of Mycobacterium tuberculosis to Rifampin and Isoniazid. J. Clin.
Microbiol., 2004, 42, 2247-2248.
[12]