Synthesis and antibacterial activity of some novel bis-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and bis-4-thiazolidinone derivatives from terephthalic dihydrazide

Article abstract of DOI:10.1016/j.ejmech.2009.07.023

A novel series of 1,4-bis(6-(substituted phenyl)-[1,2,4]-triazolo[3,4-b]-1,3,4-thiadiazoles (5a-b) and 4-bis(substituted phenyl)-4-thiazolidinone derivatives (7a-c) have been synthesized from terephthalic dihydrazide (1) through multistep reaction sequence. 1,4-Bis(5-aryl-1,3,4-oxadiazole-2yl) benzene derivatives (2a-f) and bis-substituted terephthalohydrazide (6a-e) were also synthesized from terephthalic dihydrazide by cyclization with various aromatic acids and aldehydes. Terephthalic dihydrazide (1) was obtained from poly(ethylene terephthalate) waste from reaction with hydrazine hydrate in good yield (86%). All the synthesized compounds were screened for their antibacterial activities against various bacteria and fungi strains. Several of these compounds showed potential antibacterial activity.

Full text of DOI:10.1016/j.ejmech.2009.07.023

European Journal of Medicinal Chemistry 44 (2009) 5112–5116
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antibacterial activity of some novel
bis-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and bis-4-thiazolidinone derivatives
from terephthalic dihydrazide
*
Vikrant S. Palekar, Amey J. Damle, S.R. Shukla
Department of Fibres and Textile Processing Technology, Institute of Chemical Technology (Autonomous), University of Mumbai, N. Parekh Marg, Matunga, Mumbai 400019,
Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 1,4-bis(6-(substituted phenyl)-[1,2,4]-triazolo[3,4-b]-1,3,4-thiadiazoles (5a–b) and 4-
bis(substituted phenyl)-4-thiazolidinone derivatives (7a–c) have been synthesized from terephthalic
dihydrazide (1) through multistep reaction sequence. 1,4-Bis(5-aryl-1,3,4-oxadiazole-2yl) benzene
derivatives (2a–f) and bis-substituted terephthalohydrazide (6a–e) were also synthesized from tereph-
thalic dihydrazide by cyclization with various aromatic acids and aldehydes. Terephthalic dihydrazide (1)
was obtained from poly(ethylene terephthalate) waste from reaction with hydrazine hydrate in good
yield (86%). All the synthesized compounds were screened for their antibacterial activities against
various bacteria and fungi strains. Several of these compounds showed potential antibacterial activity.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Received 24 October 2008
Received in revised form
16 July 2009
Accepted 23 July 2009
Available online 30 July 2009
Keywords:
Terephthalic dihydrazide
1,3,4-Oxadiazole/thiadiazoles
1,2,4-Triazole
Antibacterial activity
1. Introduction
high durability, non-biodegradability, crystal clear transparency
and non-toxic nature. On the other hand, this has led to problems of
Oxadiazole derivatives, an important group of heterocyclic
compounds, have been the subject of extensive study in the recent
past. Numerous reports have highlighted their chemistry and use
[1–3]. It has also been reported in literature that certain compounds
bearing 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole nucleus
possess significant anti-inflammatory activity [4–7]. 4-Thiazolidi-
none derivatives are also known to possess antibacterial [8–12],
antifungal [13–15], antiviral [16–20] and antituberculosis [11,21–
23] properties. 4-Thiazolidinones have been reported as novel
inhibitors of the bacterial enzyme [24]. The incidence of tubercu-
losis is increasing worldwide, partly due to poverty and inequity
and partly due to the HIV/AIDS pandemic, which greatly increase
the risk of infectious proceeding to overt disease. During recent
years, the microorganisms have developed increasing resistance
against drugs. Therefore, there is a need to develop new, potent,
fast-acting antimicrobial, antiviral and antimycobacterial drugs
with low toxicity.
waste disposal [25]. One of the techniques to reduce PET waste
disposal problems is to follow chemical recycling through depoly-
merization and conversion of the products of the reaction into
value added materials. In our earlier study, depolymerization of PET
was carried through aminolysis using ethanolamine, to give
monomer bis-(2-hydroxy ethylene terephthalamide) having
terminal reactive hydroxyl group [26]. In the present study, we
have synthesized terephthalic dihydrazide from PET bottle waste
using excess hydrazine hydrate having terminal reactive NH2
groups. Five-membered heterocyclic compounds of terephthalic
acid derivatives were synthesized. We report herein the synthesis
of some potent analogs of bis-1,3,4-oxadiazole, bis-1,2,4-triazole
and 4-thiazolidinone derivatives, which have been tested for their
antibacterial activity.
2. Chemistry
Poly(ethylene terephthalate) (PET) is a thermoplastic polyester
produced in very large quantities since it finds major applications in
textile apparel, photographic films and soft drink bottles due to
The terephthalic dihydrazide 1 was prepared by aminolysis of
PET bottle waste with hydrazine hydrate at reflux condition in good
yield. Various 1,4-bis(5-aryl-1,3,4-oxadiazole-2yl) benzene (2a–f)
were prepared by treatment of dihydrazide with appropriate
aromatic acids in the presence of trifluoro acetic acid (Scheme 1).
The structures of compounds were established on the basis of their
* Corresponding author. Tel.: þ91 22 24145616; fax: þ91 22 24145614.
E-mail address: sanjeevrshukla@rediffmail.com (S.R. Shukla).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.07.023

V.S. Palekar et al. / European Journal of Medicinal Chemistry 44 (2009) 5112–5116
5113
O
C
NH
NH
NH2
C
NH2
O
1
TFA/
Ar-COOH
CS2 / KOH
Ar-CHO/Ethanol
Reflux
Ethanol
O
O
O
H
O
O
O
Ar'
NH
HC
N
Ar'
CH
N
HN
NH
N
+K-S
Ar
S-K+
Ar
HN
HN
NH
NH
S
S
N
N
N
N
(3)
2(a-f)
6(a-e)
NH2-NH2
Reflux
2
Ar
C6H5
SH-CH2-COOH
Benzene
a
b
c
d
e
4-NO2-C6H4
N
N
N
O
N
N
O
4-Cl-C6H4
Ar'
N
4-OH-C6H4
Ar'
N
NH
SH
HN
N
HS
4-OCH3-C6H4
4-NH2-C6H4
S
f
S
O
O
NH2
NH2
(4)
7(a-c)
POCl3
Ar-COOH
Reflux
Ar'
6,7
a
b
c
d
e
N
N
C6H5
N
N
2-Br-C6H4
2-Cl-C6H4
4-OH-C6H4
4-OCH3-C6H4
S
N
N
N
N
S
Ar
(5)
Ar
=Ar=2-Cl-C H
5a
6
5b=Ar=4-NO2-C64H4
Scheme 1.
spectral data. The required bis-dithiocarbazinate (3) was synthe-
sized by reacting dihydrazide with carbondisulfide and potassium
hydroxide in ethanol. This salt (3) underwent ring closure with an
excess of 99% hydrazine hydrate to give the 1,4-phenylene-
bis(4-amino-4H-1,2,4-triazole-3-thiol) (4). Thus resulted triazole
was then further converted to the title compounds (5a–b) in a one-
pot reaction, by condensation with aromatic acids in the presence
of POCl3. Hydrazones 6a–e were obtained from condensation
of compound 1 with aromatic aldehyde in ethanol. Another series
of 4-thiazolidinone (7a–c) were prepared by cyclocondensation of
some substituted hydrazones with thioglycolic acid in benzene. The
yield and physical data of synthesized compounds are summarized
in Table 1.
The compounds were dissolved in DMSO at concentration of
1 mg mlꢀ1. Antibacterial activity of DMSO against the test organ-
isms was investigated, and was found to be nil. Approximately
1 cm3 of a 24 h broth culture containing 106 cfu cmꢀ3 was placed in
sterile Petri dishes. Molten nutrient agar (15 cm3), kept at 45ꢁC, was
then poured into the Petri dishes and allowed to solidify. Six mil-
limetre diameter holes were then punched carefully using a sterile
cork borer and completely filled with the test solutions. The plates
were incubated for 24 h at 37ꢁC. After 24 h, the inhibition zone that
appeared around the holes in each plate was measured. Antibac-
terial activity was determined by measuring the diameter of
inhibition zone. Activity of each compound was compared with
ciprofloxacin and sulphametoxazol as standards [28,29]. These
results are summarized in Table 2.
3. Results and discussion
Compounds 2a–2e, showed comparatively good activity against
all the strains, which is attributed to the presence of groups having
inductively electron withdrawing but mesomerically electron
donating substituents on phenyl group. These were found to be the
most active compounds against the test microorganisms.
Compounds 2b and 2c have higher antibacterial activity against
E. coli and B. cereus than the compounds containing parallel polar
groups (OH, NH2). It has been observed that compound 4 having
1,2,4-triazole-3-thiol moiety has comparatively good activity
against all the fungal strains. In the 1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazole series, compounds 5a and 5b showed similar activities
as compared to compound 4. These results indicate that additional
3.1. Antibacterial activity
The antibacterial activities of the synthesized compounds were
determined by the well-diffusion method [27]. In this work,
Escherichia coli (ATTC-25922), Klebsiella pneumoniae (ATCC 10031),
Bacillus cereus (ATTC-10702), Salmonella typhimurium (ATTC-
23564) were used to investigate the antibacterial activities. The
prepared compounds were tested against the Gram þve bacteria
(B. cereus) and Gram ꢀve bacteria (E. coli). The bacterial liquid
cultures were prepared in infusion broth for their activity tests.

5114
V.S. Palekar et al. / European Journal of Medicinal Chemistry 44 (2009) 5112–5116
Table 1
and 6c show good activity against B. cereus and S. typhi. Compounds
7b and 7c, wherein electron withdrawing substituents Br and Cl are
attached ortho to phenyl group of thiazolidinone ring show
moderate biological activity. From these results it is clear that
substituents affect the activity of compounds in different series
such as chloro group present in 2c of oxadiazole system has good
activity while in case of 1,3,4-thiadiazole (compound 5b) and 4-
thiazolidinones (compound 7c) series activity varies. Also in case of
compound 2b in oxadiazole series has very good activity against all
the test organisms with NO2 substituent while same substituent in
thiadiazole system has moderate activity (compound 5b).
Yield and physical data of the synthesized compounds.
Compound Ar
Crystallization m.p. (ꢁC) UV,
solvent
Yielda Mol formula/
lmax (%) mol wt
(nm)
2a
2b
C6H5
4-NO2-
C6H4
4-Cl-
C6H4
4-OH-
C6H4
Ethanol/H2O
Ethanol/H2O
335–336 301 90
354–356 245 87
C22H14N4O2/366
C22H12N6O6/458
2c
2d
2e
2f
Ethanol/H2O
Ethanol/H2O
370–372 245 83
353–355 246 75
327–329 245 85
276–278 252 70
312–314 314 82
267–268 336 76
324–326 343 72
365–366 314 88
346–348 313 86
C22H12N4O2Cl2/
435
C22H14N4O4/
398
C24H18N4O4/
428
C22H16N6O2/
396
C10H10N8S2/
306
C24H12Cl2N8S2/
546
C24H12N10O4S2/
568
C22H18N4O2/
370
C22H16N4O2Br2/
526
C22H16N4O2Cl2/
438
C22H18N4O4/
402
C24H22N4O4/
430
C26H22N4O4S2/
518
C26H20Br2N4O4S2/
674
C26H20Cl2N4O4S2/
586
4-OCH3- Ethanol/H2O
C6H4
4-NH2- Ethanol/H2O
C6H4
3.2. Spectroscopic data
4
–
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
The IR spectra of 1 showed absorption peak at 1630 cmꢀ1 due to
amide group and broad peak at 3254 cmꢀ1 due to NH. Its 1H
5a
5b
6a
6b
6c
6d
6e
7a
7b
7c
2-Cl
4-NO2
C6H5
spectrum revealed a singlet at
peaks at 9.87 and
4.55 due to the amide and NH protons. 13C
spectra of 1 shows peak at 126.9, 135.4 and 165.1 for aromatic CH,
d 7.86 for aromatic protons, broad
d
d
d
Ar–C–CO and CO groups respectively. These spectral values of
synthesized terephthalic dihydrazide are in good agreement with
those reported in the literature [30]. The IR spectrum of compound
2a showed absorption peak at 1676 cmꢀ1 due to C]N streching
vibrations. The absence of CO peak at 1630 cmꢀ1 confirms the
formation of oxadiazole ring. Its 1H NMR spectrum revealed
2-Br-
C6H4
2-Cl-
C6H4
4-OH-
C6H4
342
314 83
309 86
(decom)
348
(decom)
4-OCH3- DMF/H2O
C6H4
348–350 317 87
352–354 309 73
338–340 316 75
a multiplet at
d 7.7–7.9 due to aromatic protons. Physical and
spectral data of these compounds are in good agreement with those
reported in the literature [31].
C6H5
DMF/H2O
DMF/H2O
DMF/H2O
The IR spectrum of 4 displayed stretching bands at 3313 cmꢀ1
2-Br-
C6H4
2-Cl-
C6H4
due to NH. 1H NMR spectrum of this sample displayed a singlet at
355
314 72
d
9.88 and
d
5.55 which were accounted for SH and NH2, respec-
168.10 and 135.4
(decom)
tively. 13C NMR spectrum of 4 showed signals at
d
d
a
Isolated yield.
due to C]S of triazole and C5 carbon of triazole, respectively. The
mass spectrum of 4 displayed a molecular ion peak at m/z 306
which confirmed its molecular weight. Compounds 6(a–e) showed
carbonyl amide stretching at 1645 cmꢀ1 and N–H bands in 3200–
3228 cmꢀ1 region. 1H NMR and 13C NMR data were also in agree-
ment with the formation of hydrazones. 1H NMR spectra of 6a
bulky substituents deteriorate the antibacterial activity of these
triazole analogs. Compound 5a showed comparatively good activity
against B. cereus in which chloro group is present at ortho position
to the phenyl ring. Hydrazones 6a–6e show moderate activity
against all the bacterial strains. The compounds containing electron
withdrawing substituents at ortho position such as compounds 6b
showed two singlets at d 12.0 and d 8.4 which were attributed to the
CO–NH and N]CH protons, respectively. IR absorption bands due
to the 4-thiazolidiones 7(a–c) give C]O stretching at 1653 cmꢀ1
and at 3314 cmꢀ1 due to the –NH stretching. Their 1H NMR spectra
exhibited resonances at 5.86–6.35, 3.61–3.98 and 3.69–4.13 ppm
assigned for 4-thiazolidinone, –CH and S–CH2, respectively. The
structure of synthesized compounds was confirmed by spectral
data (IR, 1H NMR, 13C NMR and Mass). The characterization data of
all the compounds are summarized in Table 3.
Table 2
Results of antibacterial activity of the tested compounds.
Sample ID
Antibacterial activity (in mm/ conc. 1 mg/mlꢀ1
)
Escherichia
coli
Klebsiella
pneumoniae
Bacillus
cereus
Salmonella
typhi
2a
2b
8
9
7
8
8
9
7
8
4. Conclusion
2c
2d
2e
2f
4
5a
5b
6a
6b
6c
6d
6e
7a
7b
7c
8
6
7
6
7
6
5
6
6
5
5
6
8
7
7
12
20
4
6
5
5
6
6
5
5
5
6
5
6
6
7
6
10
21
8
5
6
6
5
7
5
4
5
8
6
6
8
7
6
10
18
6
4
4
5
6
6
5
4
6
7
5
4
7
6
6
11
23
In this report, an easy and useful method to synthesize anti-
bacterial active derivatives containing novel series of 1,4-bis(6-
(substituted phenyl)-[1,2,4]-triazolo[3,4-b]-1,3,4-thiadiazoles
(5a–b) and 4-bis(substituted phenyl)-4-thiazolidinone derivatives
(7a–c) from terephthalic dihydrazide which is being obtained from
PET waste. Bis-oxadiazole and bis-hydrazone derivatives have also
been synthesized. Most of these compounds show moderate anti-
bacterial activity comparable with to commercial compounds. And
therefore become lead molecules for further synthetic and bio-
logical evaluation. It can be concluded that this class of compounds
certainly holds great promise towards pursuit to discover novel
class of antibacterial agents. Further studies are being conducted to
acquire more information about quantitative structure–activity
relationships.
Sulphametoxazol
Ciprofloxacin

V.S. Palekar et al. / European Journal of Medicinal Chemistry 44 (2009) 5112–5116
5115
Table 3
Spectral data of compounds.
5. Experimental procedures
5.1. Chemical protocols
Compound Spectral values
no.
2a
2b
IR (cmꢀ1) ¼ 2923 (C–H), 1676 (C]N)
Chemicals were purchased from Merck Chemical Company, S.D.
Fine (India). Melting points was determined in an open capillary and
are uncorrected. IR spectra were recorded on a Shimadzu IR-470
spectrophotometer and reported in wave numbers (cmꢀ1). 1H and
13C NMR spectra were recorded on a Bruker DRX-400 spectrometer
at 400 and 100 MHz, respectively. NMR spectra were obtained in
solutions of DMSO (d6) and chemical shifts reported in parts per
million (ppm) and TMS as internal standard. Analytical TLC of all
reactions was performed on Merck prepared plates. Column chro-
matography was performed using silica gel (100–200 mesh).
1H NMR (DMSO-d6) (
d
ppm) ¼ 7.97 (m, 14H, Ar-H)
13C NMR (DMSO-d6) (
d
ppm) ¼ 163.5, 155.8, 155.5, 135.2, 127.6,
118,115.2
IR (cmꢀ1) ¼ 2921 (C–H), 1669 (C]N), 1519 (NO2)
1H NMR (DMSO-d6) (
d
ppm) ¼ 8.3 (d, J ¼ 9.2 Hz, Ar-H), 8.1
(d, J ¼ 8.8 Hz, Ar-H), 7.9 (s, 4H, Ar-H)
13C NMR (DMSO-d6) (
d
ppm) ¼ 166.2, 149.6, 130.5, 127.6, 123.6, 123.5
2c
2d
2e
2f
4
IR (cmꢀ1) ¼ 2929(C–H), 1668(C]N)
1H NMR (DMSO-d6) (
d
ppm) ¼ 8.01 (d, J ¼ 9.0 Hz, Ar-H), 7.9
(d, J ¼ 8.6 Hz, Ar-H), 7.5 (s, 4H, Ar-H)
IR (cmꢀ1) ¼ 3226 (O–H), 2935 (CH), 1662 (C]N)
1H NMR(DMSO-d6) (
d
ppm) ¼ 11.8(bs, –OH), 11.0(d, J ¼ 8.4 Hz,
Ar-H), 8.0(s, 4H, Ar-H), 7.5(d, J ¼ 8.4 Hz, 4H, Ar-H)
5.1.1. General procedure for the synthesis of 1,4-bis(5-aryl-1,3,4-
oxadiazole-2yl) benzene (2a–2f)
IR (cmꢀ1) ¼ 2925(C–H), 1672(C]N)
1H NMR (DMSO-d6) (
d
ppm) ¼ 8.01 (s, 4H, Ar-H), 7.9 (d, J ¼ 8.8 Hz,
A
mixture of terephthalic dihydrazide (1 mmol) and the
Ar-H), 7.0 (d, J ¼ 8.8 Hz, Ar-H), 3.8 (s, 3H, –OCH3)
IR (cmꢀ1) ¼ 3307 (N–H), 2991 (C–H), 1664 (C]N)
appropriate aromatic acid (2 mmol) in trifluoroacetic acid (10 ml)
was refluxed for 4–6 h. The reaction mixture was slowly poured
over crushed ice and kept overnight. The solid thus separated out
was neutralized with NaHCO3, filtered and washed with water and
recrystallized from ethanol.
1H NMR (DMSO-d6) (
d
ppm) ¼ 11.4 (bs, –NH), 8.0 (s, 4H, Ar-H),
7.9 (d, J ¼ 8.2 Hz, 4H, Ar-H), 7.8 (d, J ¼ 8.0 Hz, 4H, Ar-H)
IR (cmꢀ1) ¼ 3313 (N–H), 2935 (CH), 2554 (SH), 1604 (C]N)
1H NMR (DMSO-d6) (
d
ppm) ¼ 9.88 (bs, 1H, SH), 7.8 (s, 4H, Ar-H),
ppm) ¼ 165.1, 135.4, 126.8
4.57 (bs, NH2)
13C NMR (DMSO-d6) (
d
MS(m/z) ¼ 307(Mþ), 261, 163, 146
5.1.2. Synthesis of bis-potassium dithiocarbazinate (3)
5a
IR (cmꢀ1) ¼ IR (cmꢀ1) ¼ 2925(C-H), 1672(C]N)
1H NMR (DMSO-d6) (
d
ppm) ¼ 8.1 (s, Ar-H), 8.0 (d, 2H, Ar-H), 7.9
Potassium hydroxide (3 mmol) was dissolved in absolute
ethanol (25 mL). The solution was cooled in ice bath and tereph-
thalic dihydrazide (1 mmol) was added with stirring. To this car-
bondisulfide (5 mmol) was added in small portions with constant
stirring. The reaction mixture was agitated continuously for 12 h at
room temperature. The precipitated potassium dithiocarbazinate
was collected by filtration, washed with cold ethanol (50 mL) and
dried in vacuum. The potassium salt thus obtained was used in the
next step without further purification.
(d, 2H, Ar-H), 7.75-7.5(m, Ar-H)
13C NMR (DMSO-d6) (
d
ppm) ¼ 165, 131.5, 131, 129.7, 128.6,
127.8, 126.4, 125.6, 124.5
MS (m/z) ¼ 546(Mþ), 382, 284, 164
5b
6a
IR (cmꢀ1) ¼ 2954 (C–H), 1656 (C]N)
1H NMR (DMSO-d6) (
d
ppm) ¼ 10.9 (d, 4H, Ar-H), 8.4 (s, 4H, Ar-H),
8.1 (d, 4H, Ar-H)
MS (m/z) ¼ 569 (Mþ), 526, 164, 101
IR (cmꢀ1) ¼ 3201 (N–H), 2837 (C–H), 1645 (amide C]O)
1H NMR (DMSO-d6) (
d
ppm) ¼ 12.0 (s, 1H, CO–NH), 8.4
(s, 2H, –CH]N), 8.0 (d, 4H, Ar-H), 7.75 (d, J ¼ 8.1 Hz, 4H, Ar-H),
5.1.3. Synthesis of bis-4-amino-1,2,4-triazole-3-thiol (4)
7.46 (s, 6H, Ar-H)
13C NMR (DMSO-d6) (
d
ppm) ¼ 162.4, 148.3, 136.1, 134.2, 130.2,
A suspension of potassium dithiocarbazinate (1 mmol) in water
(5 mL) and hydrazine hydrate (99%, 3 mmol) was heated for 18–
20 h at 100 ꢁC with occasional shaking. The colour of the reaction
mixture changed to green with the evolution of hydrogen sulfide
gas. A homogeneous reaction mixture was obtained during the
reaction process. The reaction mixture was cooled to room
temperature and diluted with cold water (20 mL). On acidification
with HCl the required triazole was precipitated out, which was
recrystallized with DMF–water mixture.
128.8, 127.7, 127.1
6b
6c
IR (cmꢀ1) ¼ 3220 (N–H), 2864 (C–H), 1642 (amide C]O)
1H NMR (DMSO-d6) (
d
ppm) ¼ 12.2 (s, 2H, C0-NH), 8.8
(s, 2H, –CH]N), 8.09 (s, 4H, Ar-H), 7.73 (d, J ¼ 8Hz, 2H, Ar-H),7.50
(d, J ¼ 7.2 Hz, 2H, Ar-H), 7.41(d, J ¼ 7.8 Hz, 2H, Ar-H)
IR (cmꢀ1) ¼ 3201(N–H), 2837(C-H), 1645 (amide C]O)
1H NMR(DMSO-d6) (
d
ppm) ¼ 12.2(s, 2H, CO–NH), 8.9
(s, 2H, –CH]N), 8.09(s, 4H, Ar-H), 7.56(d, J ¼ 8 Hz, 2H, Ar-H),
7.46(d, J ¼ 7.2 Hz, 2H, Ar-H), 7.41(d, J ¼ 8.0 Hz, 2H, Ar-H)
13C NMR (DMSO-d6) (
d
ppm) ¼ 163, 144.1, 138.2, 133.2, 131.5,
129.9, 127.8, 127.6, 126.9
6d
6e
7a
IR (cmꢀ1) ¼ 3210 (O–H, N–H), 2995 (C-H), 1641 (amide C]O)
5.1.4. Synthesis of 1,4-bis(6-substituted-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazoles (5a–b)
1H NMR (DMSO-d6) (
d
ppm) ¼ 11.80 (s, 1H, C0-NH), 9.91
(s, 1H, O-H), 8.37 (s, 1H,-CH]N), 8.03 (s, 2H, Ar-H), 7.60
(d, J ¼ 8.4 Hz, 2H, Ar-H), 6.8 (d, J ¼ 8 Hz, 2H, Ar-H)
IR (cmꢀ1) ¼ 3228(N–H), 2985(C–H), 1647(amide C]O)
An equimolar mixture of 1,4-bis(6-substituted-[1,2,4]tri-
azolo[3,4-b][1,3,4] thiadiazoles
4
(1 mmol), aromatic acids
1H NMR (DMSO-d6) (
d
ppm) ¼ 11.86(s, 2H, CO–NH), 8.42
(2 mmol) in phosphorus oxychloride (5 mL) was refluxed for 5 h.
The reaction mixture was cooled to room temperature and then
gradually poured onto crushed ice with stirring. The mixture was
neutralized with NaHCO3 solution and allowed to stand overnight.
The solid separated out was filtered and washed thoroughly with
cold water.
(s, 2H, -CH]N), 8.03(s, 4H, ArH), 7.71(d, J ¼ 8.8 Hz, 4H, Ar-H),
7.05(d, J ¼ 8.4 Hz, 4H, Ar-H)
IR (cmꢀ1) ¼ 3213 (N–H), 2914 (C–H), 1627 (thiazolidinone C]O),
1606(amide C]O)
1H NMR (DMSO-d6) (
d
ppm) ¼ 11.8 (s, 2H, C0-NH), 8.3
(s, 4H, Ar-H), 7.4 (m, 10 H, Ar-H), 5.1 (s, 2H, C-H), 3.8
(d, J ¼ 7.2 Hz, 4H),
7b
7c
IR (cmꢀ1) ¼ 3314 (N–H), 2965 (C–H), 1653 (thiazolidinone C]O),
1628 (amide C]O)
5.1.5. Synthesis of N0,N0-bis(substituted benzylidene)
terephthalohydrazide (6a–e)
1H NMR (DMSO-d6) (
d
ppm) ¼ 12.2(s, 2H, CO–NH), 8.8(s, 4H, Ar-H),
7.4–8.0(m, 8H, Ar-H), 5.2(s, 2H, C–H), 3.9(d, J ¼ 7.2 Hz, 4H),
IR (cmꢀ1) ¼ 3201 (N–H), 2835 (C–H), 1643 (thiazolidinone C]O),
1606 (amide C]O)
Equimolar quantities of terephthalic dihydrazide (1 mmol) and
different aromatic aldehydes (2 mmol) was refluxed in alcohol for
4 h in the presence of few drops of glacial acetic acid. The reaction
mixture on cooling was poured into cold water, filtered and dried.
The crude solid was recrystallized in DMF–water mixture to give
the products.
1H NMR (DMSO-d6) (
7.4–7.6 (m, 8H, Ar-H),
5.2 (s, 2H, C–H), 3.9 (d, 4H, J ¼ 7.2 Hz)
d
ppm) ¼ 8.9 (s, 2H, CO–NH), 8.1 (s, 4H, Ar-H),

5116
V.S. Palekar et al. / European Journal of Medicinal Chemistry 44 (2009) 5112–5116
[11] S.G. Kucukguzel, E.E. Oruc, S. Rollas, F. Sahin, A. Ozbek, Eur. J. Med. Chem. 37
(2002) 197.
[12] C.G. Bonde, N.J. Gaikwad, Bioorg. Med. Chem. 12 (2004) 2151.
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Pharm. (Weinheim) 327 (1994) 271.
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[15] H.T.Y. Fahmy, Boll.Chim. Farmaco 140 (2001) 422.
[16] M.L. Barreca, A. Chimirri, L.D. Luca, A.M. Monforte, P. Monforte, A. Rao,
M. Zappala, J. Balzarini, E. De Clercq, C. Pannecouque, M. Witvrouw, Bioorg.
Med. Chem. Lett. 11 (2001) 1793.
5.1.6. Synthesis of 4-bis(substituted phenyl)-4-thiazolidinone
derivatives (7a–c)
A mixture of hydrazone (1 mmol) and thioglycolic acid (2 mmol)
was refluxed in dry benzene (25 ml) for 8–10 h. After completion of
reaction excess benzene was evaporated in vacuo. The resulting
residue was neutralized with saturated NaHCO3 solution until CO2
evolution ceased. The solid product was washed with water, dried
and recrystallized from DMF–water mixture.
[17] A. Rao, A. Carbone, A. Chimirri, E.D. Clercq, A.M. Monforte, P. Monforte,
C. Pannecouque, M. Zappala, Farmaco 57 (2002) 747.
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C. Pannecouque, M. Zappala, Farmaco 58 (2003) 115.
Acknowledgement
[19] M.L. Barreca, A. Chimirri, E.D. Clercq, L.D. Luca, A.M. Monforte, P. Monforte,
A. Rao, M. Zappala, Farmaco 58 (2003) 259.
[20] A. Rao, J. Balzarini, A. Carbone, A. Chimirri, E.D. Clercq, A.M. Monforte,
P. Monforte, C. Pannecouque, M. Zappala, Farmaco 59 (2004) 33.
[21] L. Bukowski, M. Janowiec, Z. Zwolska-Kwiek, Z. Andrezejczyk, Pharmazie 53
(1998) 373.
The authors express their thanks to University Grants
Commission, New Delhi, India for the financial support.
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