Synthesis, antimicrobial and nematicidal evaluation of a new class of triazolo[4,3-c]quinazolinylthiazolidinones

Article abstract of DOI:10.1007/s00044-016-1538-6

In an attempt to find a new class of antimicrobial and nematicidal agents, a series of 2-aryl/heteryl-3-(5-phenyl[1,2,4]triazolo[4,3-c]quinazolin-3-yl)-1,3-thiazolidin-4-ones 5a-k was prepared by one-pot three-component reaction, involving 5-phenyl[1,2,4]triazolo[4,3-c]quinazolin-3-amine 4, aryl/heteroaryl aldehydes and thioglycolic acid, and characterized by physicochemical as well as spectral means. All the newly synthesized compounds 5a-k were tested in vitro for their antimicrobial activity against three representative Gram-positive (Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus), Gram-negative (Proteus vulgaris, Salmonella typhimurium, Escherichia coli) bacteria and four fungal strains (Candida albicans, Aspergillus fumigatus, Trichophyton rubrum, Trichophyton mentagrophytes). These compounds 5a-k, were also evaluated for their nematicidal activity against two nematodes (Ditylenchus myceliophagus, Caenorhabditis elegans). Except phenyl substituted, all the ten aryl/heteroaryl substituted compounds 5b-k showed significant antimicrobial and nematicidal properties against tested microorganisms. Particularly, compounds 5b, 5c, 5g, 5h, 5j and 5k containing electron-withdrawing substituents like chlorophenyl, nitrophenyl, furyl and 1,3-benzodioxole exhibited promising activity comparable to employed standards Ampicillin, Amphotericin B and Levamisole, and emerged as potent antimicrobial and nematicidal agents.

Full text of DOI:10.1007/s00044-016-1538-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1538-6
ORIGINAL RESEARCH
Synthesis, antimicrobial and nematicidal evaluation of a new class
of triazolo[4,3-c]quinazolinylthiazolidinones
1
1
1
Cherkupally Sanjeeva Reddy
•
Gaddam Rajesh Kumar
•
Bommineni Sunitha
Received: 3 December 2014 / Accepted: 15 February 2016
Ó Springer Science+Business Media New York 2016
Abstract In an attempt to find a new class of antimi-
crobial and nematicidal agents, a series of 2-aryl/heteryl-3-
Keywords Triazolo[4,3-c]quinazolinylthiazolidinones Á
Synthesis Á Antimicrobial activity Á Nematicidal activity
(
5-phenyl[1,2,4]triazolo[4,3-c]quinazolin-3-yl)-1,3-thiazo-
lidin-4-ones 5a-k was prepared by one-pot three-compo-
nent reaction, involving 5-phenyl[1,2,4]triazolo[4,3-c]
quinazolin-3-amine 4, aryl/heteroaryl aldehydes and thio-
glycolic acid, and characterized by physicochemical as
well as spectral means. All the newly synthesized com-
pounds 5a–k were tested in vitro for their antimicrobial
activity against three representative Gram-positive
Introduction
Developing new, selective, potent and less toxic antimi-
crobial agents to combat against life threatening invasive
microbial infections and their ever growing multi-drug
resistant is a major concern to chemists. Quinazoline being
a core skeleton in many natural and synthetic heterocycles
possesses a wide range of biological and pharmacological
properties particularly, antimicrobial (Kumar et al., 2011),
anticancer (Kamal et al., 2011), COX-2 inhibitory (Kumar
et al., 2003) and antitumor (Abdel Gawad et al., 2010).
Thiazolidinone is also a core structure in various pharma-
ceuticals with a wide range of biological activities like
anticancer (Havrylyuk et al., 2010), anti-HIV (Rawal et al.,
2008) and antibacterial (Naceur et al., 2012). On the other
hand, the thiazolidinone moiety in heterocycles plays an
important role in exerting nematicidal action (Srinivas
et al., 2008). Azole heterocycles are able to bind easily
with the enzymes and receptors in organisms through weak
interactions such as coordination bonds, hydrogen bonds,
ion–dipole, cation–p, p–p stacking and hydrophobic effect
as well as van der Waals force etc (Zhou and Wang, 2012).
Many triazoles display prominent biological activities like
antimicrobial (Hacer et al., 2010), anti-inflammatory
(
Bacillus subtilis, Staphylococcus aureus, Micrococcus
luteus), Gram-negative (Proteus vulgaris, Salmonella
typhimurium, Escherichia coli) bacteria and four fungal
strains (Candida albicans, Aspergillus fumigatus, Tri-
chophyton rubrum, Trichophyton mentagrophytes). These
compounds 5a–k, were also evaluated for their nematicidal
activity against two nematodes (Ditylenchus myceliopha-
gus, Caenorhabditis elegans). Except phenyl substituted,
all the ten aryl/heteroaryl substituted compounds 5b–k
showed significant antimicrobial and nematicidal proper-
ties against tested microorganisms. Particularly, com-
pounds 5b, 5c, 5g, 5h, 5j and 5k containing electron-
withdrawing substituents like chlorophenyl, nitrophenyl,
furyl and 1,3-benzodioxole exhibited promising activity
comparable to employed standards Ampicillin, Ampho-
tericin B and Levamisole, and emerged as potent antimi-
crobial and nematicidal agents.
(Birsen et al., 2012), anticancer (Pramod et al., 2013) and
antiviral (Wu et al., 2013). The prevalence of azoles in
several natural products, and as drug candidates such as
Itraconazole, Voriconazole, Posaconazole and Fluconazole
inspired more research towards azole antimicrobial drugs.
Moreover, synthesis of triazoles fused/linked with another
heterocyclic ring has focused attention due to their diverse
&
Cherkupally Sanjeeva Reddy
chsrkuc@yahoo.co.in
1
Department of Chemistry, University College, Kakatiya
University, Warangal, Telangana 506 009, India
123

Med Chem Res
biological activities (Gang et al., 2005; Antipenko et al.,
009).
Nematodes are tiny worms and some of them are plant
thioglycolic acid (TGA) and ZnCl in dry toluene to obtain
2
2
the desired thiazolidinones 5a-k (Scheme 1) in good yield
(64–72 %).
parasites. These plant parasitic nematodes play an impor-
tant role in predisposition of the host plant to the invasion
by secondary pathogens (Jayasinghe et al., 2003). Plants
attacked by nematodes show retarded growth and devel-
opment, as well as loss in the quality and quantity of the
harvest. Due to environmental problems, the use of
nematicides such as dibromochloropropane (DBCP) and
ethylenedibromide (EDB) was slated and withdrawn from
the market. The highly toxic Aldicarb used to control
insects and nematodes has been detected in ground water
All the newly synthesized compounds were well char-
1
13
acterized by elemental analyses IR, H-NMR, C-NMR
and Electron Ionization (EI) mass spectral data. In IR
spectra of compounds 5a–k, disappearance of characteris-
-
1
tic absorption bands of NH2 (3423, 3363 cm ), and
appearance of a characteristic absorption band for C–S–C
-
1
at about 760 cm indicates the ring closure, involving
–NH group of the compound 4. Similarly, absence of
2
1
H-NMR signal of –NH protons at about d 5.38, and
2
presence of proton signals at about d 3.75 and d 5.86
corresponding to –CH –CO and –N–CH–S respectively of
(
Xaki et al., 1982). Hence, the use of commercial
2
nematicides is still limited due to their high degree of
toxicity. Hence there is a need to develop alternative
nematode control methods or less toxic nematicides (Nol-
ing and Becker, 1994).
the thiazolidinone ring, also support the ring closure
1
3
involving –NH . Further evidence was obtained from
2
C
NMR spectra. For all the compounds 5a–k, signals corre-
sponding to carbon atoms appeared at about 35.8, 70.0 and
171.6 ppm of thiazolidinone; 149.8 and 158.6 ppm of tri-
azole; 116.4, 128.1, 129.6, 131.4, 132.4, 138.6 and
163.8 ppm of quinazoline. In addition, the m/z values
Inspired by the biological profile of quinazoline, tria-
zole and thiazolidinone, and in continuation of our
research on the synthesis of biologically active hetero-
cycles (Sanjeeva Reddy et al., 2010, 2011a, b, 2012,
?
?
obtained from M /(M ? 2) peaks fully supported the
structures assigned to compounds 5a-k.
2
013), it was thought worthwhile to synthesize a new
class of heterocycles confining quinazoline, triazole and
thiazolidinone pharmacophores in a single molecular
frame work, with expected potentiality against bacteria,
fungi and nematodes. In this context, we report herein the
synthesis of 2-aryl/heteryl-3-(5-phenyl[1,2,4]triazolo [4,3-
c]quinazolin-3-yl)-1,3-thiazolidin-4-ones 5a-k, with var-
ied electronic environment due to aryl moiety on 2nd
position of thiazolidinone. In a bid to come up with
effective chemotherapeutic agents, compounds 5a-k were
evaluated for their in vitro antimicrobial and nematicidal
activities.
Biological evaluation
Antibacterial activity
In-vitro antibacterial activity of the newly synthesized
compounds 5a–k was studied against three representative
Gram-positive bacteria, Bacillus subtilis (ATCC 6633),
Staphylococcus aureus (ATCC 6538p) and Micrococcus
luteus (IFC 12708), and Gram-negative bacteria, Proteus
vulgaris (ATCC 3851), Salmonella typhimurium (ATCC
14028) and Escherichia coli (ATCC 25922), by standard
Results and discussion
serial dilution method (Cappucino and Sherman, 1999),
using a stock solution of 100 lg/mL concentration.
Ampicillin was used as standard drug and minimum inhi-
bitory concentrations (MIC; inhibition of 100 % growth)
were determined (Table 1).
Chemistry
The synthesis of 2-aryl/heteryl-3-(5-phenyl[1,2,4]tria-
zolo[4,3-c]quinazolin-3-yl)-1,3-thiazolidin-4-ones
5a-k,
As evident from the Table 1, most of the newly syn-
nd
thesized compounds, with various substituents at 2
was commenced from the commercially available
anthranilamide 1, which on oxidative cyclocondensation
with benzaldehyde resulted 2-phenylquinazolin-4(3H)-one
position of thiazolidinone ring, showed potential antibac-
terial activity against the bacterial strains employed. Out of
11 screened compounds, 5j bearing 2-furyl substituent and
5k bearing 5-(1,3-benzodioxole) substituent, displayed
excellent activity almost equal/more than the standard drug
Ampicillin against all the tested strains. Further, many of
the chloro group or nitro group containing compounds 5b,
5c, 5g and 5h exhibited better activity than that containing
hydroxy, methoxy and methyl groups. Other compounds
showed moderate to least activity.
2
(Bakavoli et al., 2009). The compound 2 on reflux, for
h, with thionylchloride in presence of N,N-dimethyl
2
formamide (DMF) afforded 4-chloro-2-phenyl quinazoline
in 81 % yield. The intermediate 3 on treating with
3
thiosemicarbazide in ethanol afforded 5-phenyl [1,2,4]tri-
azolo[4,3-c]quinazolin-3-amine 4 in 68 % yield. The
compound 4 so obtained was subjected to one-pot three-
component reaction with various aryl/heteroaryl aldehydes,
1
23

Med Chem Res
O
O
N
Cl
N
NH2
NH
N
SOCl / DMF
PhCHO
I2 / EtOH
2
NH2
Ph
Ph
1
2
3
NH NHCSNH
2
2
EtOH
Ar
1
N
2
N
2'
S1'
N
N
1
0
10b
N
3
5'
4
'
3
'
9
8
NH2
N4
ArCHO
TGA
ZnCl / toluene
2
10a
N
6"
O
6
a
5
5"
N
7
1
"
N
Ph
6
2"
4"
4
5
a-k
3"
5a; Ar =
5b; Ar =
5c; Ar =
5d; Ar =
Cl
NO2
OH
'"
4
'"
4
4
'"
4'"
3'" OCH3
5
'"
'"
3'"
2'"
3
'"
3
'"
5
'"
'"
5'"
'"
5'"
6'"
1'"'
6
6
2'"
6
2'"
2'"
1
'"
1'"
1'"
1
'"
5e; Ar =
5f; Ar =
5g; Ar =
5h; Ar =
H C
CH3
1'"'
OH
3
4
'"
4'"
N
'"
3'" NO
2'"
1
'"'
4'"
2
3'"
5
'"
5'"
6'"
4
3
'"
5
'"
3
'"
2'"
Cl
5
'"
'"
6
'"
6
'"
2'"
6
2'"
1'"
1'"
1
'"
1
'"
5i; Ar =
5j; Ar =
5k; Ar =
4
'"
3'"
'"
4'"
'"
7'"
7
a'"O
1'"
2'"
O3'"
3
'"
6'"
5'"
5
'"
'"
2
5
2
'"
OH
O
1'"
6
3
a'"
1
'"
4
'"
Scheme 1 Schematic route for the synthesis of 2-aryl/heteryl-3-(5-phenyl[1,2,4]triazolo[4,3-c]quinazolin-3-yl)-1,3-thiazolidin-4-ones 5a-k
The structure–activity relationship (SAR) revealed that
thiazolidine ring is essential for antimicrobial activity
the oxygen of C=O group and positive charge of nitrogen
in NH contribute positively in favor of antibacterial
activity. It was hypothesized that difference in charges
between two heteroatoms of the same dipolar
(
Bonde and Gaikwad, 2004). From this perspective, studies
of the literature data revealed that the negative charge of
123

Med Chem Res
Table 1 Antimicrobial and nematicidal activity of the newly synthesized compounds 5a-k
Compounds
Minimum inhibitory concentration (MIC) in lg/mL
LD50 values (ppm)
Nematicidal activity
Antibacterial activity
Antifungal activity
B. S
S. A
M. L
P. V
S. T
E. C
C. A
A. F
T. R
T. M
D. M
C. E
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
50.00
3.12
1.56
6.25
12.50
3.12
6.25
1.56
12.5
1.56
1.56
1.56
–
12.50
1.56
6.25
12.50
6.25
25.00
1.56
3.12
1.56
1.56
1.56
1.56
–
25.00
1.56
3.12
25.00
3.12
1.56
3.12
1.56
25.0
1.56
1.56
1.56
–
50.00
6.25
1.56
6.25
25.00
12.50
3.12
1.56
3.12
3.12
1.56
3.12
–
12.50
1.56
6.25
1.56
12.50
3.12
1.56
1.56
6.25
1.56
3.12
3.12
–
50.0
12.50
12.50
25.00
12.50
25.00
12.50
6.25
12.50
12.50
6.25
12.50
–
50.00
3.12
6.25
25.00
12.5
25.00
6.25
6.25
25.00
6.25
3.12
–
25.00
6.25
3.12
3.12
6.25
12.50
6.25
3.12
6.25
3.12
1.56
–
12.50
3.12
3.12
6.25
6.25
25.00
3.12
6.25
12.5
3.12
3.12
–
25.00
3.12
6.25
3.12
25.00
25.00
6.25
6.25
12.50
3.12
3.12
–
740
210
190
320
360
510
210
200
320
170
160
–
610
190
220
200
450
270
220
210
360
180
170
–
g
h
i
j
k
Ampicillin
Amphotericin B
Levamisole
6.25
–
3.12
–
3.12
–
3.12
–
–
–
–
–
–
–
–
–
160
180
B. S, Bacillus subtilis; S. A, Staphylococcus aureus; M. L, Micrococcus luteus; P. V, Proteus vulgaris; S. T, Salmonella typhimurium; E. C,
Escherichia coli; C. A, Candida albicans; A. F, Aspergillus fumigatus; T. R, Trichophyton rubrum; T. M, Trichophyton mentagrophytes; D. M,
Ditylenchus myceliophagus; C. E, Caenorhabditis elegans
pharmacophore site (Xd-–Yd?) may facilitate the inhibi-
tion of bacteria. Additionally this is in good agreement
with the mode of antibacterial action of the compounds
bearing (Xd-–Yd?) pharmacophore site (Chohan et al.,
Antifungal assay
The newly synthesized compounds 5a-k were also
screened for their in vitro antifungal activity against four
fungal strains, Candida albicans (ATCC 10231), Asper-
gillus fumigatus (HIC 6094), Trichophyton rubrum (IFO
9185) and Trichophyton mentagrophytes (IFO 40996), by
standard serial dilution method (Cappucino and Sherman,
1999), using a stock solution of 100 lg/mL concentration.
Amphotericin B was used as standard drug and MIC values
were determined in terms of lg/mL (Table 1).
The perusal of antifungal activity data (Table 1) indi-
cated that most of the compounds exhibited good activity.
Compounds bearing electron-withdrawing groups such as
chloro and nitro (5b, 5c, 5g, 5h) were found to be more
active than the compounds bearing electron-donating
groups. Compounds 5j and 5k bearing 2-furyl and 5-(1,3-
benzodioxole) substituent respectively displayed high
activity comparable to reference drug Amphotericin B. In
brief, compounds 5b, 5c, 5g, 5h, 5j and 5k emerged as
potential antimicrobial agents.
2
010).
Further, the literature study revealed that the activity of
thiazolidinone ring increases, when substituted with aryl/
heteryl groups at N3 (3rd) and C2 (2nd) positions
(
Havrylyuk et al., 2010, 2012, 2013; Lesyk et al., 2011).
The substitution with heteryl at C2 position increases
polarity of the pharmacophore, and the presence of elec-
tron-withdrawing substitution on aromatic ring at C2
position of thiazolidinone displaying varied degree of
inhibition, against Gram-positive and Gram-negative bac-
teria, comparable to the employed standard drug.
The presence of nitro/chloro group on phenyl ring at C2
position of thiazolidinone played an important role in
activity. It was reported that the nitro/chloro group present
on the phenyl ring form complexes with metaloenzymes,
particularly those which are responsible in basic physiol-
ogy such as cytochrome oxidase. These compounds (5b,
5
c, 5g and 5h) may react with the peptidoglycan layer of
the bacterial cell wall and damage it by penetrating in such
a manner that the phenyl ring gets entered inside the cell by
puncturing it, followed by bacterial cell death (Kant et al.,
Nematicidal activity
The new compounds 5a–k were assayed for their nemati-
cidal activity (McBeth and Bergeson, 1953) against Dity-
lenchus myceliophagus and Caenorhabditis elegans. The
results were expressed in terms of median lethal dose
2
008). Sometimes these compounds when present in low
concentrations may cause bacteriostatic conditions, which
slow down the growth of bacteria.
1
23

Med Chem Res
(
LD ), at which 50 % nematodes became immobile/dead
5
spectrometer, operating at 300, 75 MHz, respectively. The
chemical shifts are reported as parts per million (d ppm)
down field using TMS as the internal standard and cou-
pling constants (J) are reported in Hz units. Mass spectra
were obtained on a VG micromass 7070H spectrometer.
Elemental analyses were performed on a Perkin-Elmer 240
CHN elemental analyzer.
0
and compared with standard Levamisole (Table 1). The
LD50 values of compounds screened revealed that, 5j and
5
k, bearing heteroaryl substituents are beneficial and dis-
played excellent nematicidal activity with LD50 values of
60–180 ppm, which are equal to standard Levamisole, and
1
emerged as most potent nematicidal agents. Compounds
bearing chloro and nitro groups (5b, 5c, 5g and 5h) favored
in displaying better nematicidal activity than the com-
pounds with electron-releasing groups (5d, 5e, 5f and 5i).
Finally, compounds 5b, 5c, 5g, 5h, 5j and 5k emerged as
potential nematicidal agents.
Synthesis of 4-chloro-2-phenylquinazoline (3) Compound
2
(5 mmol) was added in portions to a stirred thionyl
chloride (30 mL), followed by DMF (5 mL) and the mix-
ture was refluxed for 90 min at 80 °C. The reaction mixture
was cooled and the excess thionylchloride was removed
under reduced pressure. The residue thus obtained was
dissolved in dichloromethane (60 mL) and washed with a
saturated solution of sodium carbonate, brine and dried
over Na SO . The solvent was evaporated under reduced
Conclusions
2
4
In conclusion, a new series of 1,3-thiazoldin-4-ones linked
to the annealed triazolo-quinazoline 5a-k has been pre-
pared in good yields, through an easy, convenient and
economic one-pot three-component synthetic method. All
the newly synthesized compounds were well characterized
by IR, NMR, MS spectra and elemental analyses. The
in vitro antibacterial and antifungal evaluation showed that
most of the synthesized thiazolidinone analogs could
effectively inhibit the growth of the tested bacteria and
fungi. Particularly, compounds 5b, 5c, 5g, 5h, 5j and 5k
containing electron-withdrawing chloro, nitro groups and
heteroaryl substituents like furyl and 1,3-benzodioxole
exhibited prominent antimicrobial activity comparable to
standards Ampicillin and Amphotericin B. Further,
nematicidal screening revealed that compounds with furyl
pressure and the solid obtained was recrystallized from
ethanol to give pure compound 3 as pale brown solid; yield
1
-
8
1 %; mp 123–125 °C; IR (KBr, cm ): 3053 (Ar–H),
1
616 (C=N), 1603 (C=C), 689 (C–Cl); H-NMR
1
(
300 MHz, DMSO-d ): d 7.61–7.73 (m, 4H, ArH, H-7,
6
0
0
00
H-8, H-9, H-10), 7.89–7.93 (m, 2H, ArH, H-2 , H-6 ),
00 00 00
8
.17–8.22(m, 3H, ArH, H-3 , H-4 , H-5 ),; MS m/z: 240
?
M ), 242 (M ? 2). Anal. Calcd for C H ClN : C,
?
(
14 9 2
6
1
9.86; H, 3.77; N, 11.64. Found: C, 69.86; H, 3.68; N,
1.66.
Synthesis of 5-phenyl[1,2,4]triazolo[4,3-c]quinazolin-3-
amine (4) A mixture of compound 3 (2.82 g, 0.01 mol)
and thiosemicarbazide (0.01 mol) in ethanol (20 mL) was
refluxed for 8 h. The reaction mixture was cooled to room
temperature, the solid separated, was filtered off, dried and
purified by column chromatography (silica gel 60–120
mesh) using EtOAc: n-hexane (3:2) as eluent, to afford the
pure compound 4 as brown solid; yield 68 %; mp
5j and 1,3-benzodioxole 5k were equipotent to standard
Levamisole.
In brief, presence of heteroaryl substituents and elec-
tron-withdrawing groups are beneficial to improve the
antimicrobial and nematicidal properties than their analogs.
-
1
1
81–183 °C; IR (KBr, cm ): 3423, 3363 (NH ), 3038
2
1
Ar–H), 1622 (C=N), 1601 (C=C); H-NMR (300 MHz,
(
0
DMSO-d ): d 5.38 (bs, 2H, NH , H-3 ), 7.48–7.58 (m, 4H,
6
2
Experimental
Chemistry
0
0
ArH, H-7, H-8, H-9, H-10), 7.72–7.80 (m, 2H, ArH, H-2 ,
00
0
0
00
00
H-6 ), 7.99–8.15(m, 3H, ArH, H-3 , H-4 , H-5 ); MS m/z:
?
2
2
61 (M ). Anal. Calcd for C H N :C, 68.95; H, 4.24; N,
15 11 5
6.80. Found: C, 68.95; H, 4.22; N, 26.77.
Sigma–Aldrich chemicals were used as such without fur-
ther purification. Progress of reactions and purity of
compounds were checked by thin-layer chromatography
General procedure for the synthesis of 2-aryl/heteryl-3-(5-
phenyl[1,2,4]triazolo[4,3-c]quinazolin-3-yl)-1,3-thiazolidin-
4-ones (5a-k) To a stirred mixture of compound 4
(0.01 mol), aryl/heteroaryl aldehyde (0.01 mol) and TGA
(0.02 mol) in dry toluene (20 mL), was added ZnCl2
(0.01 mol) and refluxed for about 5 h. After cooling, the
reaction mixture was filtered, concentrated under reduced
pressure, and the residue was taken-up in ethyl acetate. The
ethyl acetate layer was washed with 5 % sodium bicar-
bonate solution and finally with brine. The organic layer
(
TLC) on pre-coated silica gel F-254 plates from Merck
and compounds visualized by exposure to UV light. Col-
umn chromatography was performed on silica gel 60–120
mesh. Melting points were determined with a Fisher–Johns
apparatus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer Fourier transform-infrared (FT-IR)
1
13
spectrometer, using KBr pellet. H and C NMR spectra
in DMSO-d ) were recorded on a Varian Gemini
(
6
123

Med Chem Res
-
1
was dried over Na SO4 and evaporated to dryness at
2
142–144 °C; IR (KBr, cm ): 3058 (Ar–H), 1610 (C=N),
1
1603 (C=C), 1349 (NO ), 757 (C–S–C); H-NMR
reduced pressure. The crude product thus obtained was
purified by column chromatography on silica gel (60–120
mesh) with hexane-ethylacetate as eluent to get the pure
compounds 5a-k.
2
0
(300 MHz, DMSO-d ): d 3.74 (s, 2H, CH –CO, H-5 ,
6
2
0
0
H-5 ), 5.84 (s, 1H, N–CH–S, H-2 ), 7.10–7.20 (m, 3H, ArH,
0
0
000
000
00
00
H-4 , H-2 , H-6 ), 7.50–7.60 (m, 4H, ArH, H-2 , H-6 ,
000
0
0
00
000
H-3 , H-5 ), 7.78–7.86 (m, 3H, ArH, H-3 , H-4 , H-9),
2
-Phenyl-3-(5-phenyl[1,2,4]triazolo[4,3-c]quinazolin-3-yl)-
,3-thiazolidin-4-one (5a) This compound was prepared
1
.15–8.22 (m, 3H, ArH, H-7, H-8, H-10); C NMR
3
8
1
0
0
(
75 MHz, DMSO-d ): d 35.4(CH , C-5 ), 70.1 (CH, C-2 ),
16.3 (C, C-10a), 122.6 (CH, C-3 , CH, C-5 ), 128.0
6
2
and purified by the above mentioned general procedure. It
was obtained as an orange solid; yield 72 %; mp
000 000
1
000 000 00
(
CH, C-10), 129.4 (CH, C-2 , CH, C-6 , CH, C-4 ),
000 000 00
30.4 (CH, C-9, CH, C-2 , CH, C-6 ), 131.4 (CH, C-3 ,
-
1
1
1
60–162 °C; IR (KBr, cm ) : 3061 (Ar–H), 1709 (C=O),
627 (C=N), 1602 (C=C), 757 (C–S–C); H-NMR
1
1
0
0
00
CH, C-5 ), 132.2 (CH, C-7, C, C-1 ), 133.8 (CH, C-8),
000
0
(
300 MHz, DMSO-d ): d 3.72 (s, 2H, CH –CO, H-5 ,
6
2
000
1
45.0 (C, C-1 ), 147.2 (C, C-4 ), 148.4 (C, C-3), 149.4
0
0
H-5 ), 5.82 (s, 1H, N–CH–S, H-2 ), 6.42–6.60 (m, 2H, ArH,
00
(
C, C-6a), 158.6 (C, C-10b), 163.4 (C, C-5), 172.4 (C,
?
C-4 ); MS m/z: 468 (M ); Anal. Calcd for C H N O S:C,
0
000
000
000
H-2 , H-6 ), 6.75–7.10 (m, 3H, ArH, H-3 , H-4 ,
00
0
0
00
00
00
24 16 6 3
H-5 ), 7.44–7.56 (m, 3H, ArH, H-3 , H-4 , H-5 ),
6
1
1.53; H, 3.44; N, 17.94. Found: C, 61.51; H, 3.42; N,
7.93.
00 00
7
3
.76–7.83 (m, 3H, ArH, H-2 , H-6 , H-9), 8.10–8.25 (m,
1
H, ArH, H-7, H-8, H-10); C NMR (75 MHz, DMSO-
3
0
0
d ): d 35.6 (CH , C-5 ), 69.6 (CH, C-2 ), 116.3 (C, C-10a),
6
2
2-(4-Hydroxy-3-methoxyphenyl)-3-(5-phenyl[1,2,4]triazolo
4,3-c]quinazolin-3-yl)-1,3-thiazolidin-4-one (5d) This
000 00 00
1
1
1
27.4 (CH, C-4 , CH, C-10), 128.3 (CH, C-2 , CH, C-6 ),
[
0
00
000
00
00
000
29.5 (CH, C-9, CH, C-3 , CH, C-5 ), 131.1 (CH, C-4 ),
000
compound was prepared and purified by the above men-
tioned general procedure. It was obtained as a white solid;
0
00
31.9 (CH, C-2 , CH, C-6 ), 132.4 (CH, C-7, CH, C-3 ,
0
0
00
-
1
CH, C-5 ), 133.8 (CH, C-8, C, C-1 ), 138.4 (C, C-1 ),
47.1 (C, C-3), 149.6 (C, C-6a), 158.8 (C, C-10b), 163.7
yield 68 %; mp 163–164 °C; IR (KBr, cm ): 3360–3280
–OH), 3056 (Ar–H), 1612 (C=N), 1605 (C=C), 1033 (C–
1
(
0
?
C, C-5), 172.0 (C, C-4 ); MS m/z: 423 (M ). Anal. Calcd
1
(
O–C), 757 (C–S–C); H-NMR (300 MHz, DMSO-d ): d
0000 0
3.64 (s, 3H, –OCH , H-1 ), 3.74 (s, 2H, CH –CO, H-5 ,
3 2
6
for C H N OS:C, 68.07; H, 4.05; N, 16.54. Found: C,
2
4
17
5
6
8.01; H, 3.99; N, 16.53.
0
0
000
H-5 ), 4.87 (s, 1H, –OH, H-4 ), 5.84 (s, 1H, N–CH–S,
000
000
000
H-2 ), 6.84–7.16 (m, 3H, ArH, H-2 , H-5 , H-6 ),
2-(4-Chlorophenyl)-3-(5-phenyl[1,2,4]triazolo[4,3-c]quina-
00 00 00
7
3
.42–7.63 (m, 3H, ArH, H-3 , H-4 , H-5 ), 7.76–7.83 (m,
0
zolin-3-yl)-1,3-thiazolidin-4-one (5b) This compound was
prepared and purified by the above mentioned general
procedure. It was obtained as a white solid; yield 70 %; mp
0
00
H, ArH, H-2 , H-6 , H-9), 8.13–8.21 (m, 3H, ArH, H-7,
3
1
H-8, H-10); C NMR (75 MHz, DMSO-d ): d 35.9 (CH ,
6
2
0 0000 0
C-5 ), 54.4 (OCH , C-1 ), 68.8 (CH, C-2 ), 115.1 (CH,
3
-
1
1
1
58–160 °C; IR (KBr, cm ) : 3058 (Ar–H), 1610 (C=N),
603 (C=C), 1034 (Ar–Cl), 769 (C–S–C) H-NMR
0
0
0
0
0
0
1
C-2 ), 116.2 (C, C-10a), 117.6 (CH, C-5 ), 124.1 (CH,
000 00 00
C-6 ), 128.1 (CH, C-10, CH, C-2 , CH, C-6 ), 129.5 (CH,
0
(
300 MHz, DMSO-d ): d 3.74 (s, 2H, CH -CO, H-5 ,
6
2
0
0
0
0
0
0
0
0
C-4 ), 131.0 (CH, C-9), 131.8 (CH, C-3 , CH, C-5 ),
H-5 ), 5.83 (s, 1H, N–CH–S, H-2 ), 6.70 (d, J = 8.2 Hz,
000 000
00
132.6 (CH, C-7, C, C-1 ), 134.0 (CH, C-8), 136.2 (C,
2
H, ArH, H-2 , H-6 ), 7.32 (d, J = 8.2 Hz, 2H, ArH,
0
000 000
00
000
00
00
00
C-1 ), 147.8 (C, C-4 ), 148.5 (C, C-3), 149.8 (C, C-6a),
H-3 , H-5 ), 7.46–7.55 (m, 3H, ArH, H-3 , H-4 , H-5 ),
000
154.2, (C, C-3 ), 158.8 (C, C-10b), 163.5 (C, C-5), 171.9
00 00
7
3
.76–7.83 (m, 3H, ArH, H-2 , H-6 , H-9), 8.16–8.24(m,
3
H, ArH, H-7, H-8, H-10); C NMR (75 MHz, DMSO-
0
(C, C-4 ); MS m/z: 469 (M ); Anal. Calcd for C H N
25 19 5
?
1
0
0
O S:C, 63.95; H, 4.08; N, 14.92. Found: C, 63.91; H, 4.05;
3
d ): d 35.8 (CH , C-5 ), 69.8 (CH, C-2 ), 116.4 (C, C-10a),
6
2
00 00 00
N, 14.90.
1
28.1 (C, C-10, CH, C-2 , CH, C-6 ), 129.3 (CH, C-4 ,
0
00
000
000
CH, C-3 , CH, C-5 ), 130.9 (CH, C-9, CH, C-2 , CH,
0
2-(4-(Dimethylamino)phenyl)-3-(5-phenyl[1,2,4]triazolo[4,3-
00
00
00
C-6 ), 131.8 (CH, C-3 , CH, C-5 ), 132.2 (CH, C-7, C,
000
c]quinazolin-3-yl)-1,3-thiazolidin-4-one (5e) This com-
pound was prepared and purified by the above mentioned
0
0
000
C-1 ), 133.8 (CH, C-8), 136.2 (C, C-4 ), 138.6 (C, C-1 ),
48.1 (C, C-3), 149.6 (C, C-6a), 158.7 (C, C-10b), 163.6
1
general procedure. It was obtained as a white solid; yield
0
?
C, C-5), 172.2 (C, C-4 ); MS m/z: 457 (M ), 459
(
-1
6
1
9 %; mp 159–161 °C; IR (KBr, cm ): 3059 (Ar–H),
610 (C=N), 1606 (C=C), 757 (C–S–C); H-NMR
?
M ? 2). Anal. Calcd for C H ClN OS:C, 62.95; H,
(
1
2
4
16
5
3
.52; N, 15.29. Found: C, 62.94; H, 3.49; N, 15.25.
0000
(
300 MHz, DMSO-d ): d 2.94 (s, 6H, –N(CH ) , H-1 ),
6
3 2
0
0
2
-(4-Nitrophenyl)-3-(5-phenyl[1,2,4]triazolo[4,3-c]quina-
3.74 (s, 2H, CH
0
2
–CO, H-5 , H-5 ), 5.84 (s, 1H, N–CH–S,
000
000
zolin-3-yl)-1,3-thiazolidin-4-one (5c) This compound
was prepared and purified by the above mentioned general
procedure. It was obtained as a red solid; yield 65 %; mp
H-2 ), 6.88 (d, J = 8.4 Hz, 2H, ArH, H-2 , H-6 ), 7.28
0
00
000
(d, J = 8.4 Hz, 2H, ArH, H-3 , H-5 ), 7.52–7.63 (m, 3H,
00
0
0
00
00
ArH, H-3 , H-4 , H-5 ), 7.76–7.83 (m, 3H, ArH, H-2 ,
1
23

Med Chem Res
0
0
13
H-6 , H-9), 8.13–8.21 (m, 3H, ArH, H-7, H-8, H-10);
0
C
61.53; H, 3.44; N, 17.94. Found: C, 61.53; H, 3.39; N,
17.91.
NMR (75 MHz, DMSO-d ): d 35.5 (CH , C-5 ), 44.6 (N–
CH , C-1 , N–CH , C-1 ), 69.6 (CH, C-2 ), 116.4 (C,
3
6
2
0
000
0000
0
3
0
00
000
00
000
00
2-(2-Chlorophenyl)-3-(5-phenyl[1,2,4]triazolo[4,3-c]quina-
zolin-3-yl)-1,3-thiazolidin-4-one (5h) This compound was
prepared and purified by the above mentioned general pro-
cedure. It was obtained as a white solid; yield 65 %; mp
C-10a, CH, C-3 , CH, C-5 ), 128.1 (C, C-10, CH, C-2 ,
0
0
000
00
CH, C-6 ), 128.8 (C, C-1 ), 129.9 (CH, C-4 , CH, C-2 ,
0
00
00
CH, C-6 ), 130.8 (C, C-9), 131.9 (CH, C-3 , CH, C-5 ),
00
1
32.4 (CH, C-7, C, C-1 ), 133.6 (CH, C-8), 146.4(C,
0
-
1
00
170–172 °C; IR (KBr, cm ): 3059 (Ar–H), 1610 (C=N),
1606 (C=C), 757 (C–S–C); H-NMR (300 MHz, DMSO-
C-4 ), 148.6 (C, C-3), 149.6 (C, C-6a), 158.8 (C, C-10b),
1
0
?
63.4 (C, C-5), 171.8 (C, C-4 ); MS m/z: 466 (M ); Anal.
1
0
0
d ): d 3.76 (s, 2H, CH –CO, H-5 , H-5 ), 5.88 (s, 1H, N–CH–
6
2
Calcd for C H N OS:C, 66.93; H, 4.75; N, 18.01. Found:
26 22 6
0
000
000
000
S, H-2 ), 7.04–7.16 (m, 4H, ArH, H-3 , H-4 , H-5 ,
0
C, 66.91; H, 4.73; N, 17.97.
-(4-Hydroxyphenyl)-3-(5-phenyl[1,2,4]triazolo[4,3-c]quina-
00
00
00
00
H-6 ), 7.55–7.61 (m, 3H, ArH, H-3 , H-4 , H-5 ),
2
00 00
7
3
.74–7.86 (m, 3H, ArH, H-2 , H-6 , H-9), 8.12–8.19 (m,
1
3
H, ArH, H-7, H-8, H-10); C NMR (75 MHz, DMSO-d6):
zolin-3-yl)-1,3-thiazolidin-4-one (5f) This compound was
prepared and purified by the above mentioned general
procedure. It was obtained as an orange solid; yield 64 %;
0
0
000
d 35.6 (CH , C-5 ), 62.8 (CH, C-2 ), 110.5 (C, C-1 ), 116.6
(
2
000 00 00
C, C-10a), 124.2 (CH, C-5 ), 127.8 (CH, C-2 , CH, C-6 ),
-
1
mp 171–173 °C; IR (KBr, cm ): 3380–3310 (–OH), 3059
000 00 000
28.4 (CH, C-10, CH, C-4 ), 129.4 (CH, C-4 , CH, C-3 ),
1
1
1
Ar–H), 1610 (C=N), 1606 (C=C), 757 (C–S–C); H-NMR
(
000
00
30.2 (CH, C-6 ), 131.0 (CH, C-9), 131.8 (CH, C-3 , CH,
00
0
(
300 MHz, DMSO-d ): d 3.74 (s, 2H, CH –CO, H-5 ,
00
6
2
C-5 ), 132.4 (CH, C-7, C, C-1 ), 134.1 (CH, C-8), 139.0 (C,
000
0
00
H-5 ), 5.24 (s, 1H, –OH, H-4 ), 5.84 (s, 1H, N–CH–S,
000
C-2 ), 148.3 (C, C-3), 149.6 (C, C-6a), 158.9 (C, C-10b),
0
000
0
?
63.7 (C, C-5), 171.8 (C, C-4 ); MS m/z: 457 (M ), 459
H-2 ), 6.92 (d, J = 8.6 Hz, 2H, ArH, H-3 , H-5 ), 7.24
000 000
1
?
M ? 2); Anal. Calcd for C H ClN OS:C, 62.95; H,
(
d, J = 8.6 Hz, 2H, ArH, H-2 , H-6 ), 7.52–7.63 (m, 3H,
00
(
24 16 5
0
0
00
00
ArH, H-3 , H-4 , H-5 ), 7.76–7.83 (m, 3H, ArH, H-2 ,
13
3.52; N, 15.29. Found: C, 62.88; H, 3.49; N, 15.24.
0
0
H-6 , H-9), 8.13–8.21 (m, 3H, ArH, H-7, H-8, H-10);
0
C
NMR (75 MHz, DMSO-d ): d 35.4 (CH , C-5 ), 69.5 (CH,
2-(2-Hydroxyphenyl)-3-(5-phenyl[1,2,4]triazolo[4,3-c]quina-
zolin-3-yl)-1,3-thiazolidin-4-one (5i) This compound was
prepared and purified by the above mentioned general
procedure. It was obtained as a white solid; yield 68 %; mp
6
2
0
000
000
C-2 ), 116.6 (C, C-10a), 118.1(CH, C-3 , CH, C-5 ),
00 00 00
1
1
28.1 (CH, C-10, CH, C-2 , CH, C-6 ), 129.6 (CH, C-4 ),
0
00
000
00
00
31.0 (CH, C-9, CH, C-2 , CH, C-6 ), 131.8 (CH, C-3 ,
0
0
-1
CH, C-5 ), 132.7 (CH, C-7, C, C-1 ), 133.4 (CH, C-8),
0
166–169 °C; IR (KBr, cm ): 3376–3305 (–OH), 3059
(Ar–H), 1610 (C=N), 1606 (C=C), 757 (C–S–C); H-NMR
00
1
1
34.2 (C, C-1 ), 148.6 (C, C-3), 149.8 (C, C-6a), 156.9 (C,
0
00
0
0
C-4 ), 158.7(C, C-10b), 163.9 (C, C-5), 171.9 (C, C-4 );
(300 MHz, DMSO-d
0
6
): d 3.74 (s, 2H, CH
2
–CO, H-5 ,
?
MS m/z: 439 (M ); Anal. Calcd for C H N O S:C,
0
H-5 ), 5.84 (s, 1H, N–CH–S, H-2 ), 6.22 (s, 1H, –OH,
2
4 17 5 2
000 000 000 000
6
1
5.59; H, 3.90; N, 15.94. Found: C, 65.55; H, 3.88; N,
5.91.
H-4 ), 6.82–7.12 (m, 4H, ArH, H-3 , H-4 , H-5 ,
0
00
00
00
00
H-6 ), 7.52–7.63 (m, 3H, ArH, H-3 , H-4 , H-5 ),
0
0
13
00
7
.76–7.83 (m, 3H, ArH, H-2 , H-6 , H-9), 8.13–8.21 (m,
2
-(3-Nitrophenyl)-3-(5-phenyl[1,2,4]triazolo[4,3-c]quina-
3
H, ArH, H-7, H-8, H-10); C NMR (75 MHz, DMSO-
zolin-3-yl)-1,3-thiazolidin-4-one (5g) This compound
was prepared and purified by the above mentioned general
procedure. It was obtained as a brown solid; yield 67 %;
0
0
000
d ): d 35.4 (CH , C-5 ), 63.2 (CH, C-2 ), 114.2 (C, C-2 ),
1
6
2
00 000
16.6 (C, C-10a), 118.4(C, C-1 ), 122.4 (CH, C-5 ), 128.2
00 00 00
(
CH, C-10, CH, C-2 , CH, C-6 ), 129.6 (CH, C-4 , CH,
0
-
1
mp 168–171 °C; IR (KBr, cm ): 3046 (Ar–H), 1620
00
000
00
C-4 ), 130.8 (CH, C-9, CH, C-6 ),131.4 (CH, C-3 , CH,
00
1
C=N), 1606 (C=C), 1342 (NO ), 759 (C–S–C); H-NMR
(
2
00
C-5 ), 132.0 (CH, C-7), 132.9 (C, C-1 ), 134.3 (CH, C-8),
000
0
(
300 MHz, DMSO-d ): d 3.74 (s, 2H, CH -CO, H-5 ,
6
2
1
48.5 (C, C-3), 149.4 (C, C-6a), 154.2 (CH, C-2 ), 158.6
0
0
0
H-5 ), 5.84 (s, 1H, N–CH–S, H-2 ), 7.48–7.62 (m, 7H, ArH,
0
(
C, C-10b), 163.8 (C, C-5), 172.0 (C, C-4 ); MS m/z: 439
0
00
00
000
000
000
H-3 , H-4 , H-5 , H-1 , H-5 ), 7.74–7.82 (m, 3H, ArH,
0
?
M ); Anal. Calcd for C H N O S:C, 65.59; H, 3.90; N,
(
2
4 17 5 2
00
H-9, H-2 , H-4 ,), 8.12–8.21 (m, 3H, ArH, H-7, H-8,
3
15.94. Found: C, 65.56; H, 3.88; N, 15.90.
1
0
000
00
000
00
000
H-10); C NMR (75 MHz, DMSO-d ): d 35.9 (CH , C-5 ),
6
2
0
0
6
1
1
1
1
1
7.8 (CH, C-2 ), 116.4 (C, C-10a), 120.2 (CH, C-4 ),
00
2-(Furan-2-yl)-3-(5-phenyl[1,2,4]triazolo[4,3-c]quinazolin-
3-yl)-1,3-thiazolidin-4-one (5j) This compound was pre-
pared and purified by the above mentioned general proce-
dure. It was obtained as a pale brown solid; yield 67 %; mp
00
0
0
26.2 (CH, C-2 ), 128.2 (CH, C-10, CH, C-2 , CH, C-6 ),
0
29.6 (CH, C-4 ), 130.1 (CH, C-9), 131.0 (CH, C-5 ),
0
00
31.8 (CH, C-3 , CH, C-5 ), 132.6 (CH, C-7, CH, C-1 ),
0
00
-1
33.4 (CH, C-8), 134.6 (CH, C-6 ), 138.6 (C, C-1 ),
0
170–172 °C; IR (KBr, cm ): 3061 (Ar–H), 1709 (C=O),
1627 (C=N), 1602 (C=C), 1462 (C=C), 1082 (C–O), 757
00
000
41.1 (CH, C-5 ), 148.4 (C, C-3, C, C-3 ), 149.8 (C,
0
1
C-6a), 158.6 (C, C-10b), 163.6 (C, C-5), 172.0 (C, C-4 );
(C–S–C); H-NMR (300 MHz, DMSO-d ): d 3.72 (s, 2H,
6
?
MS m/z: 468 (M ); Anal. Calcd for C H N O S:C,
0 0 0
CH –CO, H-5 , H-5 ), 5.91 (s, 1H, N–CH–S, H-2 ), 6.16 (d,
2
2
4
16
6
3
123

Med Chem Res
0
00
J = 7.7 Hz, 1H, ArH, H-3 ), 6.55–7.14 (m, 2H, ArH,
0
50.00–1.56 lg/mL and than incubated with 100 lL of sus-
pension of selected microorganism in sterile saline. The
inoculated test tubes were incubated at 37 °C for 24 h.
Amphicillin was used as a standard drug and was also tested
under identical conditions for comparison with the newly
synthesized compounds.
00
000
00
00
00
H-4 , H-5 ), 7.44–7.56 (m, 3H, ArH, H-3 , H-4 , H-5 ),
00 00
1
7
3
.80–7.85 (m, 3H, ArH, H-2 , H-6 , H-9), 8.10–8.21(m,
3
H, ArH, H-7, H-8, H-10); C NMR (75 MHz, DMSO-
0
0
000
d ): d 34.6 (CH , C-5 ), 64.3 (CH, C-2 ), 103.6 (CH, C-3 ),
6
2
000
1
10.8 (CH, C-4 ), 116.8 (C, C-10a), 128.0 (CH, C-10, CH,
0
0
00
00
C-2 , CH, C-6 ), 129.6 (CH, C-4 ), 131.4 (CH, C-9, CH,
00
0
0
00
C-3 , CH, C-5 ), 132.7 (CH, C-7, C, C-1 ), 133.8 (CH,
0
00
Antifungal activity
C-8), 144.2 (CH, C-5 ), 148.9 (C, C-3), 149.8 (C, C-6a),
000
1
58.2 (C, C-2 ), 161.7 (C, C-10b), 162.9 (C, C-5), 171.8
0
C, C-4 ); MS m/z: 413 (M ); Anal. Calcd for C H N
22 15 5
?
The in vitro antifungal activity was evaluated against Can-
dida albicans (ATCC 10231), Aspergillus fumigatus (HIC
(
O S:C, 63.91; H, 3.66; N, 16.94. Found: C, 63.88; H, 3.61;
2
6094), Trichophyton rubrum (IFO 9185) and Trichophyton
N, 16.92.
mentagrophytes (IFO 40996) by standard serial dilution
method using a stock solution of 100 lg/mL concentration.
Sabouraud dextrose broth was employed as culture media
and DMSO as a solvent control. The stock solutions of the
test compounds were serially diluted in test tubes containing
1 mL of the sterile medium to get the concentration of
50.00–1.56 lg/mL and then inoculated with 100 lL of sus-
pension of the respective organisms in sterile saline. The
inoculated test tubes were incubated at 28 °C for 48 h.
Antifungal activity was determined by measuring MIC.
Amphotericin B was also assessed under identical conditions
for comparison with the newly synthesized compounds.
2
-(1,3-Benzodioxol-5-yl)-3-(5-phenyl[1,2,4]triazolo[4,3-c]
quinazolin-3-yl)-1,3-thiazolidin-4-one (5k) This com-
pound was prepared and purified by the above mentioned
general procedure. It was obtained as a brown solid; yield
-
1
6
6 %; mp 161–163 °C; IR (KBr, cm ): 3061 (Ar–H),
1
709 (C=O), 1627 (C=N), 1602 (C=C), 1130 (C–O), 757
1
(
C–S–C); H-NMR (300 MHz, DMSO-d ): d 3.72 (s, 2H,
6
0
0
000
CH –CO, H-5 , H-5 ), 5.54 (s, 2H, O–CH –O, H-2 ,
2
2
0
00
0
H-2 ), 5.84 (s, 1H, N–CH–S, H-2 ), 6.55–6.72 (m, 3H,
0
00
000
000
00
ArH, H-4 , H-6 , H-7 ), 7.44–7.56 (m, 3H, ArH, H-3 ,
0
0
00
00
00
H-4 , H-5 ), 7.75–7.84 (m, 3H, ArH, H-2 , H-6 , H-9),
1
.18–8.25(m, 3H, ArH, H-7, H-8, H-10); C NMR
3
8
0
0
(
75 MHz, DMSO-d ): d 35.6 (CH , C-5 ), 69.4 (CH, C-2 ),
6
2
0
00
000
1
00.1 (CH , C-2 ), 116.3 (C, C-10a, CH, C-4 ), 118.2
2
Nematicidal assay
000 000
(
CH, C-7 ), 122.4 (CH, C-6 ), 128.2 (CH, C-10, CH,
00
0
0
00
C-2 , CH, C-6 ), 129.5 (CH, C-4 ), 131.2 (CH, C-9),
All the compounds 5a–k were assayed for their nematicidal
activity by aqueous in vitro screening technique (McBeth and
Bergeson, 1953) at various concentrations. For the nemati-
cidal assay the Ditylenchus myceliophagus was extracted
from the cultivated mushrooms (Agaricus bisporus) infected
with the nematode. The Caenorhabditis elegans was grown
on 10 cm 8P plates on a E. coli NA22 bacteria diet, which
grow in a very thick layer and constitute an abundant food
source for large quantities on nematode. The nematode water
suspension was collected in petridishes. Suspension of adult
worms from five-day old culture was diluted with approxi-
mately 100–250 nematodes/mL of water, 100 lL of the
nematode suspension was introduced into a solution of each
test compound at various concentrations in a well of 24-well
plates and incubated at 25 °C. The percentage of immobile
(dead) nematodes was recorded after 2 days. The results
have been expressed in terms of LD50 i.e. median lethal dose
at which 50 % nematodes become immobile and compared
with the standard Levamisole.
00 00 00
1
1
31.9 (CH, C-3 , CH, C-5 ), 132.4 (CH, C-7, C, C-1 ),
0
00
000
33.9 (CH, C-8), 136.2 (C, C-5 ), 146.4(C, C-7a ), 148.6
000
(
C, C-3a ), 147.2 (C, C-3), 149.8 (C, C-6a), 158.7 (C,
0
C-10b), 163.9 (C, C-5), 172.2 (C, C-4 ); MS m/z: 467
?
(
M ); Anal. Calcd for C H N O S:C, 64.23; H, 3.67; N,
25 17 5 3
1
4.98. Found: C, 64.21; H, 3.63; N, 14.94.
Antimicrobial assay
Antibacterial
All the newly synthesized compounds 5a–k were tested
in vitro for their antibacterial activity against three Gram-
positive bacteria, Bacillus subtilis (ATCC 6633), Staphylo-
coccus aureus (ATCC 6538p) and Micrococcus luteus (IFC
1
2708), and three Gram-negative bacteria, Proteus vulgaris
(
ATCC 3851), Salmonella typhimurium (ATCC 14028) and
Escherichia coli (ATCC 25922), by standard serial dilution
method using a stock solution of 100 lg/mL concentration.
Double strength broth was used as culture media and DMSO
was used as a solvent control. The stock solutions of the test
compounds were serially diluted in test tubes containing
Acknowledgments The authors are grateful to the UGC, New
Delhi, India, for providing financial assistance in the form of UGC-
BSR, One-Time Research Grant and to the Director, Indian Institute
of Chemical Technology (IICT), Hyderabad, India for providing
spectral data.
1
mL of serial medium to get the concentration of
1
23

Med Chem Res
Compliance with ethical standards
Kumar A, Sharma S, Archana A, Bajaj K, Sharma S, Panwar H, Singh
T, Srivastava KV (2003) Some new 2,3,6-trisubstituted quina-
zolinones as potent anti-inflammatory, analgesic and COX-II
inhibitors. Bioorg Med Chem 11:5293–5299
Conflict of interest The authors have declared no conflict of
interest.
Kumar A, Sharma P, Kumari P, Lal Kalal B (2011) Exploration of
antimicrobial and antioxidant potential of newly synthesized 2,3-
disubstituted quinazoline-4(3H)-ones. Bioorg Med Chem Lett
References
2
1:4353–4357
Lesyk RB, Zimenkovsky BS, Kaminskyy DV, Kryshchyshyn AP,
Havryluk DY, Atamanyuk DV, Subtel’na IY, Khyluk DV (2011)
Thiazolidinone motif in anticancer drug discovery. Experience
of DH LNMU medicinal chemistry scientific group. Biopolym
Cell 27:107–117
Abdel Gawad MN, Georgey HH, Youssef MR, El Sayed AN (2010)
Synthesis and antitumor activity of some 2,3-disubstituted
quinazolin-4(3H)-ones and 4,6-disubstituted- 1,2,3,4-tetrahydro-
quinazolin-2H-ones. Eur J Med Chem 45:6058–6067
Antipenko L, Karpenko A, Kovalenko S, Katsev A, Komarovska-
Porokhnyavets E, Novikov V, Chekotilo A (2009) Synthesis of
new 2-thio-[1,2,4]triazolo[1,5-c]quinazoline derivatives and its
antimicrobial activity. Chem Pharm Bull 57:580–585
Bakavoli M, Rahimizadeh M, Shiri A, Ebrahimpour Z (2009)
Molecular iodine oxidative cyclocondesation of ortho-aminoben-
zamide with arylaldehydes: a new and efficient access to
quinazolin-4(3H)-ones. Iranian J Org Chem 1:39–42
Birsen T, Peri AS, G u¨ rsoy S, G o¨ knur A (2012) Design and synthesis
of some thiazolotriazolyl esters as anti-inflammatory and anal-
gesic agents. Med Chem Res 21:191–201
Bonde CG, Gaikwad NJ (2004) Synthesis and preliminary evaluation
of some pyrazine containing thiazolines and thiazolidinones as
antimicrobial agents. Bioorg Med Chem 12:2151–2161
McBeth CW, Bergeson GB (1953) Methods of assaying nematicides.
Phytopathology 43:264–267
Naceur H, Abdullah SA, Ridha BS, Fabienne A (2012) Synthesis and
characterization of new thiazolidinones containing coumarin
moieties and their antibacterial and antioxidant activities.
Molecules 17:9321–9334
Noling JW, Becker JO (1994) The challenge of research and
extension to define and implement alternatives to methyl
bromide. J Nematol 26:573–586
Pramod PK, Ravindra RK, Mahadevappa YK, Atukuri D, Raveendra
KH (2013) Synthesis, characterization and in vitro anticancer
evaluation of novel 1,2,4-triazolin-3-one derivatives. Eur J Med
Chem 62:232–240
Rawal RK, Tripathi R, Katti SB, Pannecouque C, Clercq ED (2008)
Design and synthesis of 2-(2,6-dibromophenyl)-3-heteroaryl-1,3-
thiazolidin-4-ones as anti-HIV agents. Eur J Med Chem
Cappucino JG, Sherman N (1999) Microbiology: a laboratory manual,
4
th edn. Addison Wesley Longman Inc, Harlow, p 263
Chohan ZH, Youssoufi MH, Jarrahpour A, Ben Hadda T (2010)
Identification of antibacterial and antifungal pharmacophore
sites for potent bacteria and fungi inhibition: indolenyl sulfon-
amide derivatives. Eur J Med Chem 45:1189–1199
4
3:2800–2806
Sanjeeva Reddy Ch, Srinivas A, Nagaraj A (2010) Synthesis and
in vitro study of methylene bis-tetrahydro[1,3]thiazolo[4,5-
c]isoxazoles as potential nematicidal agents. Eur J Med Chem
Gang Y, Serajul H, Li S, Gnanasambandam K, Joy W, Thomas ME,
Eric TW, Patrick RC, Hexi C, William FK, Russell CP (2005)
Synthesis of alkyne derivatives of a novel triazolopyrazine as
A2A adenosine receptor antagonists. Bioorg Med Chem Lett
4
5:2353–2358
Sanjeeva Reddy Ch, Chandrashekar Rao D, Yakub V, Nagaraj A
2011a) Synthesis of some novel bis-[1,2,4]triazolo[3,4-
(
b][1,3,4]thiadiazine derivatives for antimicrobial evaluation.
Acta Chem Slov 58:582–589
1
5:511–516
Hacer B, Ahmet DI, Hakan B, Seng u¨ l AK, Neslihan DI (2010)
Synthesis and antimicrobial activities of some new 1,2,4-triazole
derivatives. Turk J Chem 34:835–846
Havrylyuk D, Mosula L, Zimenkovsky B, Vasylenko O, Gzella A,
Lesyk R (2010) Synthesis and anticancer activity evaluation of
4-thiazolidinones containing benzothiazole moiety. Eur J Med
Chem 45:5012–5021
Havrylyuk D, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R
Sanjeeva Reddy Ch, Vani Devi M, Rajesh Kumar G, Sanjeeva Rao L,
Nagaraj A (2011b) Synthesis and antimicrobial activity of novel
2-(aryl)-3-[5-(2-oxo-2H-3-chromenyl)-1,3-oxazol-2-yl]-1,3-thia-
zolan-4-ones. J Heterocycl Chem 48:176–182
Sanjeeva Reddy Ch, Sanjeeva Rao L, Vani Devi M, Nagaraj A (2012)
Synthesis and antimicrobial activity of linked heterocyclics
containing pyrazole and oxadiazoles.
9:1038–1043
J Heterocycl Chem
4
(
2012) Synthesis of new 4-thiazolidinone, pyrazoline and isatin
based conjugates with promising antitumor activity. J Med Chem
5:8630–8641
Sanjeeva Reddy Ch, Vani Devi M, Rajesh Kumar G, Sunitha M,
Nagaraj A (2013) Synthesis and biological evaluation of novel
bis-[1,2,4]-triazolo[3,4-b][1,3,4]oxadizoles. J Heterocycl Chem
5
Havrylyuk D, Zimenkovsky B, Vasylenko O, Lesyk R (2013)
Synthesis and anticancer and antiviral activities of new 2-pyra-
5
0:557–562
Srinivas A, Nagaraj A, Sanjeeva Reddy Ch (2008) Synthesis and
biological evaluation of novel methylene-bis-thiazolidinone
derivatives as potential nematicidal agents. J Heterocycl Chem
zoline-substituted 4-thiazolidinones.
0:55–62
J
Heterocycl Chem
5
Jayasinghe ULB, Kumarihamy BMM, Bandara AGD, Vasquez EA,
Kraus W (2003) Nematicidal activity of some Sri Lankan plants.
Nat Prod Res 17:259–262
Kamal A, Bharathi VE, Reddy SJ, Ramaiah JM, Dastagiri D, Reddy
KM, Viswanath A, Reddy LT, Shaik BT, Pushpavali NS, Bhadra
PM (2011) Synthesis and biological evaluation of 3,5-diaryl
isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids
as anticancer agents. Eur J Med Chem 46:691–703
4
Wu J, Yu W, Fu L, He W, Wang Y, Chai B, Song C, Chang J (2013)
:999–1003
0
0
Design, synthesis, and biological evaluation of new 2 -deoxy-2 -
0
fluoro-4 -triazole cytidine nucleosides as potent antiviral agents.
Eur J Med Chem 63:739–745
Xaki MH, Moran D, Harris D (1982) Pesticides in groundwater: the
aldicarb story in Suffolk County, NY. Am J Public Health
7
2:1391–1395
Kant R, Amresh G, Chandrashekar K, Anil KKS (2008) Synthesis and
biological activity on some organoantimony (III) compounds.
Phosphorus Sulfur Silicon 183:1410–1419
Zhou CH, Wang Y (2012) Recent researches in triazole compounds as
medicinal drugs. Curr Med Chem 19:239–280
123