Hybrids of ravuconazole: Synthesis and biological evaluation

Article abstract of DOI:10.1016/j.ejmech.2012.05.010

In continuation of our work on antimicrobial agents, a number of hybrid molecules 4a-y containing thiazole and triazole pharmacophores were designed and synthesized. The structure of the compounds was established by IR, NMR, MS and CHN analysis. All the synthesized compounds were tested for qualitative (Zone of inhibition) and quantitative (MIC) antimicrobial activities against four pathogenic bacteria Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa and two pathogenic fungi Candida albicans and Aspergillus niger. Of all the synthesized compounds screened, most of them show potent antimicrobial activity against Gram positive and Gram negative bacteria as well as the fungi species.

Full text of DOI:10.1016/j.ejmech.2012.05.010

European Journal of Medicinal Chemistry 54 (2012) 295e302
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Hybrids of ravuconazole: Synthesis and biological evaluation
,
Nitin D. Gaikwad b, Sachin V. Patil a, Vivek D. Bobade a
*
a Department of Chemistry, H.P.T Arts & R.Y.K. Science College, College Road, Nashik 422005, India
b Department of Chemistry, K.T.H.M. College, Nashik 422005, India
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
< Thiazole substituted triazole hybrids
of ravuconazole were synthesized.
< Qualitative and quantitative anti-
microbial activity was screened.
< All the synthesized compounds
showed good to moderate anti-
fungal activity.
R3
O
S
Br
R4
N
N
N
N
N
H
R5
N
R3
R1
R2
R3
R1
R2
1
4a-y
a r t i c l e i n f o
a b s t r a c t
Article history:
In continuation of our work on antimicrobial agents, a number of hybrid molecules 4aey containing
thiazole and triazole pharmacophores were designed and synthesized. The structure of the compounds
was established by IR, NMR, MS and CHN analysis. All the synthesized compounds were tested for
qualitative (Zone of inhibition) and quantitative (MIC) antimicrobial activities against four pathogenic
bacteria Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa and two
pathogenic fungi Candida albicans and Aspergillus niger. Of all the synthesized compounds screened, most
of them show potent antimicrobial activity against Gram positive and Gram negative bacteria as well as
the fungi species.
Received 2 December 2011
Received in revised form
3 May 2012
Accepted 7 May 2012
Available online 15 May 2012
Keywords:
Thiazole
Triazole
Ó 2012 Elsevier Masson SAS. All rights reserved.
Hydrazone
Antimicrobial activity
MIC
1. Introduction
One of the most common class of antifungal agent is azole. For
over a decade, azoles have been a mainstay of the antifungal
The chemistry of carbonenitrogen double bond of hydrazone is
becoming the backbone of condensation reaction in benzo-fused N-
heterocycles [1]. Hydrazone (eNHeN]Ce)constitutes an impor-
tant class of compounds for new drug development [2]. Many
researchers have synthesized these compounds as target structures
and evaluated their biological activities. Hydrazones have been
reported to possess antimicrobial [3], anti-tubercular [4,5], anti-
convulsant [6], analgesic [7], anti-inflammatory [8], antiplatelet
[9,10] anticancer [10,11], antifungal [12], antiviral [13], antitumoral
[14], antibacterial [15] and antimalarial [16] activities.
therapy (Fig. 1). Triazole derivatives are known to exhibit various
pharmacological properties such as antimicrobial [17], anti-tuber-
cular [18], anticancer [19], anticonvulsant [20], anti-inflammatory,
analgesic [21] and antiviral [22]. Triazoles have also been incor-
porated in a wide variety of therapeutically interesting drugs
including H1/H2 histamine receptor blockers, CNS stimulants, anti-
anxiety agents and sedatives [23]. The most important use,
however, is as antimycotics in drugs such as fluconazole, itraco-
nazole and voriconazole [24]. Unfortunately, the broad use of azoles
has led to development of severe resistance, which significantly
reduced their efficacy [25]. Therefore there is a need to develop
novel and potent antimicrobial azoles to overcome resistance and
develop effective therapies.
On the other hand, thiazoles and their derivatives are found
to be associated with various biological activities including
* Corresponding author. Tel.: þ91 9970499527; fax: þ91 0253 2573097.
E-mail address: v_bobade31@rediffmail.com (V.D. Bobade).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.05.010

296
N.D. Gaikwad et al. / European Journal of Medicinal Chemistry 54 (2012) 295e302
O
OH
N
OH
N
N
N
N
N
N
N
O
N
N
F
N
N
O
N
O
N
F
F
O
N
N
Fluconazole
Posaconazole
F
N
F
N
CH3
N
O
OH
N
N
O
N
N
O
N
N
N
Cl
N
F
Cl
F
Voriconazole
Itraconazole
CH3
OH
Cl
O
CH3
OH
N
N
N
N
N
N
N
N
N
F
Epoxyconazole
Cl
Cl
Cyproconazole
Tebuconazole
CH3
OH
CN
N
N
N
F
Si
N
N
N
N
S
F
F
F
Fusilazole
Ravuconazole
Fig. 1. Structures of the antifungal agent fluconazole, itraconazole, miconazole voriconazole, posaconazole, cyproconazole, tebuconazole, epoxiconazole, flusilazole, ravuconazole.
antiprotozoal [26] and anticonvulsant activity [27], as well as
depressant effect on the central nervous system [28], antimicrobial
[29], antituberculosis [30], and anti-HIV [31] activities. (4-aryl-
thiazol-2-yl) hydrazines have been investigated for their significant
antimicrobial activity against a variety of clinically relevant fungal
strains [32,33]. In particular, these studies confirmed that thiazole
derivatives are good pharmacophores for the design of bioactive
molecules [34].
The upsurge of widespread multi-drug resistance microorgan-
isms such as Staphylococcus aureus, Pseudomonas aeruginosa,
Escherichia coli, Bacillus subtilis, Aspergillus niger and Candida
albicans among others, had been reported [35] as a major threat to
human health. In view of this occurrence of microorganisms,
resistance to drugs [36] currently in use and emergence of new
diseases [37], there is a continuous need for the synthesis of new
organic compounds as potential antimicrobial agents.
It was observed that, triazole and thiazole rings present in the
same molecule could be convenient models for investigation of
their biological activity. Literature revealed that syntheses of such
thiazolyl-triazole showed antimicrobial [38], anti-inflammatory
[39], anti-tubercular [40] and antifungal activity [41]. After exten-
sive literature search, it was observed that, till date enough efforts
have not been made to combine triazole and thiazole moieties as
a single molecular scaffold and to study its biological activity. In
continuation with our earlier work [42e44], we herein report the
synthesis of new triazole derivatives clubbed with thiazole moiety
in the form of ravuconazole analogues 4aey (Scheme 1) with the
aim of investigating their antimicrobial activity.
2. Chemistry
The synthetic route of compounds is outlined in Scheme 1. In
the present work substituted phenacyl bromides 1aee and
substituted 1-aryl-2-(1H-1,2,4-triazol-1-yl)ethanone 2aee were
obtained by literature method [45]. 1-(substitutedphenyl-2-
(1H-1,2,4-triazol-1-yl)ethylidene) thiosemicarbazide 3aee were
prepared by reacting 1-aryl-2-(1H-1,2,4-triazol-1-yl)ethanone
2aee with thiosemicarbazide in the presence of acetic acid. The
condensation of 3aee with appropriate phenacyl bromide resulted
in the formation of 2-(4-(4-substitutedphenyl)thiazol-2-yl)-1-(1-
(4-substitutedphenyl)-2-(1H-1,2,4-triazol-1-yl) ethylidene) hydra-
zine 4aey as shown in Scheme 1. Analytical and spectral data (IR,
1H NMR, 13C NMR and EIMS) confirmed the structures of the new
compounds.
The behaviour of thiocarbamoyl functional group in thio-
semicarbazone towards phenacyl bromide was investigated. Liter-
ature [46] reported three sets of experimental conditions used to
the reaction of thiosemicarbazone with phenacyl bromide using
pyridine as catalyst. In the literature [47] it was reported that thi-
osemicarbazone reacted with phenacyl bromide in absolute

N.D. Gaikwad et al. / European Journal of Medicinal Chemistry 54 (2012) 295e302
297
N
O
O
N
Br
N
N
N
N
H
R3
R1
R3
R1
Et3N
Ethanol
R2
R2
2
1
Thiosemicarbazide
Ethanol
R4
S
R5
B
S
N
N
N
N
N
H
Ethanol
N
N
NH2
R6
N
N
N
H
A
O
N
R4
R3
R1
R2
R3
R1
Br
R5
R2
4a-y
R6
3
R1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R2
F
F
F
F
R3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CF3
CF3
CF3
CF3
CF3
R4
H
H
H
H
CF3
H
H
H
H
CF3
H
H
H
H
CF3
H
H
H
H
CF3
H
H
R5
F
Cl
Br
NO2
H
F
Cl
Br
NO2
H
R6
H
H
H
H
CF3
H
H
H
H
CF3
H
H
H
H
CF3
H
H
H
H
Compound
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
F
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
NO2
NO2
NO2
NO2
NO2
H
F
Cl
Br
NO2
H
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
F
Cl
Br
NO2
H
CF3
H
H
H
H
CF3
CF3
CF3
CF3
CF3
F
H
H
H
H
Cl
Br
NO2
H
H
H
CF3
CF3
4y
Scheme 1. Synthetic route of 4aey.
ethanol in the presence of fused sodium acetate at room temper-
ature. We treated the thiosemicarbazones 3aee with phenacyl
bromide in anhydrous ethanol under 70 ꢀC for 15 min to obtain
corresponding compounds in good yields without using catalyst
(Scheme 1).
methylene protons and in the 13C NMR spectrum, CeCF3 carbon
showed quartet at
133.5, 133.0, 132.6, 132.1 with J ¼ 34 Hz, while
a quartet due to CF3 carbon appeared at 127.8, 124.9, 120.8 and
117.2 with J ¼ 273 Hz. In fluoro substituted benzene ring (C1eF)
carbon showed doublet at 163.5, 161.7 (J ¼ 244 Hz), while
a doublet due to ortho C2eF carbon appeared at 114.5, 116.4
(J ¼ 21 Hz) and doublet due to meta C3eF appeared at 129.6, 130.8
(J ¼ 7.7 Hz). The respective MS spectra, showed molecular ion
peaks of all title compounds, the presence of M þ 2 peaks was
characteristic for the compound with chlorine and bromine
substitution.
d
d
The structure of intermediate 3 was substantiated by IR and 1H
NMR. IR spectra of compounds 3 revealed in each case, absorption
band in the region 3395e3215 cmꢁ1, 1613e1604 cmꢁ1 and
1276e1275 cmꢁ1 corresponding to NeH, C]N and C]S stretching
frequencies, respectively. The structure of the title compounds
4aey was also confirmed by elemental analysis, IR, NMR and MS.
The IR spectra of these compounds revealed C]C/C]N absorp-
tion bands between 1610 and 1482 cmꢁ1 and a broad band at
3118e3104 cmꢁ1 due to NeH group absorption. In the 1H NMR,
3. Antimicrobial assay
title compounds exhibited broad singlet between
due to NeH proton, a multiplet at 6.96 to 7.87 for the
aromatic, thiazole protons and a singlet at 5.98e6.20 for
d 11.06e9.90
The in vitro antibacterial activity of all newly synthesized
compounds was done by the agar-well diffusion assay technique
[48,49] against the standard strains B. subtilis (2250), S. aureus
d
d

298
N.D. Gaikwad et al. / European Journal of Medicinal Chemistry 54 (2012) 295e302
Table 2
(2079), E. coli (2109) and P. aeruginosa (2036) and for their
antifungal activity against C. albicans (3471) and A. niger (545).
All the strains were obtained from microbial type culture
collection (MTCC) at the NCIM, Pune, India. Chloramphenicol,
Nystatin and Ravuconazole which served as positive controls
were obtained from their respective manufacturers. The
preliminary screening (zone of inhibition) and MIC against
microorganisms tested is reported in Table 1 and Table 2,
respectively.
The in vitro minimal inhibitory concentrations (MICs) of
compounds against Gram positive, Gram negative test bacteria as
well as fungi were determined by the method of National
Committee for Clinical Laboratory (NCCLS) [50]. The MIC90 was
defined as the first well with an approximate 90% reduction in
growth compared to the growth of the drug-free well. For assays,
the compounds to be tested were dissolved in dimethyl sulphoxide
(DMSO), serially diluted in growth medium, incubated at 37 ꢀC.
Growth MIC was determined at 24 h for all bacterial strains and
24e72 h for fungal strains. The in vitro preliminary screening values
and minimal inhibitory concentration values are summarized in
Table 1 and Table 2 respectively.
Antimicrobial screening of synthesized compounds 4aey Minimum inhibitory
concentration (MIC) in g/mL.
m
Compounds
Microorganisms
S. aureus E. coli B. subtilis P. aeruginosa A. niger C. albicans
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
64
64
e
32
>64
64
>64
>64
>64
>64
e
32
32
e
32
e
16
16
64
>64
64
32
32
64
>64
>64
>64
32
>64
e
64
32
64
e
32
e
e
e
e
e
32
e
e
32
64
64
e
64
e
32
32
e
16
32
e
e
>64
>64
e
>64
e
>64
32
64
64
>64
e
>64
64
>64
e
32
e
32
64
e
e
32
e
>64
>64
>64
e
e
e
e
e
e
e
>64
>64
e
>64
>64
e
e
>64
64
e
e
>64
e
e
e
>64
>64
e
64
64
64
16
32
32
e
e
e
e
e
e
e
64
64
e
e
e
e
e
>64
e
32
16
e
>64
32
e
4. Results and discussion
>64
>64
e
e
>64
e
As shown in Table 1 most of the compounds were active against
Gram positive and Gram negative bacteria as well as both the fungi
species. Careful analysis of the MICs in Table 2 provides some lead
molecules with good antibacterial and antifungal activity. Of the
compounds 4aey tested, compounds with F, Cl, Br, CF3 at the
phenyl ring expressed a moderate to good activity against most of
the tested pathogens, they inhibited the Gram negative and Gram
positive pathogens equally. Compounds 4aey required about
e
e
e
4y
e
e
e
e
32
32
16
NA
64
1
16
NA
Ravuconazole
Nystatin
Ciprofloxacin 16
e
e
e
e
NA
NA
16
NA
16
NA
16
Ravuconazole
reference.
NA ¼ Not Applicable; (e) ¼ Inactive.
(mg/mL), Nystatin (mg/mL), Ciprofloxacin (mg/mL), were used as
16e64
well as both the fungi species. Compound 4f showed better activity
against S. aureus and required 32 g/mL while compounds 4a, 4b,
4g, 4h, 4k, 4t, 4u required 64 g/mL and 4j, 4l, 4q required >64 g/
mL. Against E. coli compound 4a showed better activity with MIC of
32 g/mL whereas compounds 4b, 4d, 4e, 4f, 4g, 4i, 4j, 4m, 4n, 4o,
4r, 4s, 4v, 4w required >64 g/mL and 4c registered their MIC at
64 g/mL. Compounds 4a, 4b, 4k required 32 g/mL, 4f, 4l, 4q
required 64 g/mL and 4i, 4p, 4u, 4w showed MIC at >64 g/mL
against B. subtilis. Compounds 4g and 4u registered very good
activity at 16 g/mL, while 4a, 4c, 4e, 4h, 4j, 4l, 4v, 4w and 4r, 4s, 4t
mg/mL against Gram positive and Gram negative bacteria as
Table 1
Antimicrobial screening of synthesized compounds 4aey (zone diameter of growth
inhibition in mm).
m
m
m
Compounds
Microorganisms
S. aureus E. coli B. subtilis P. aeruginosa A. niger C. albicans
m
m
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
16.12
22.34
e
21.46 24.43
15.90 20.51
24.12
e
20.40
20.66
15.82
9.44
13.76
18.75
19.52
18.60
14.52
8.66
11.88
16.72
15.28
e
16.28
18.78
14.82
e
m
m
e
e
e
e
18.17
e
m
m
e
10.95
14.87
e
23.92
e
e
m
25.66
18.77
19.12
e
13.88 16.81
9.65
19.12
20.36
e
e
28.92
23.85
e
registered MIC at 32 and 64
respectively.
mg/mL against P. aeruginosa,
e
e
10.55 12.17
11.68
20.72
14.40
16.18
13.90
e
Table 2 describes the MIC of synthesized compounds for their
antifungal activity. The introduction of F, Cl, Br substituents on
phenyl ring exhibited moderate to good activity against C. albicans
and A. niger. Of the fluoro and chloro substituted compounds 4a, 4b,
11.23
15.5
13.10
e
15.60
e
e
26.15
e
20.27
17.26
e
e
21.71
e
10.87
13.97
11.38
e
e
e
e
4v registered excellent activity against A. niger at 16
two fold more than ravuconazole and comparable to nystatin.
Compounds 4f, 4g, 4l, 4u, 4y exhibited good activity at 32 g/mL
(which is comparable to ravuconazole), while 4c, 4e, 4h exhibited
moderate activity at 64 g/mL (which is fourfold lower than stan-
dard Nystatin) and 4d, 4j, 4k, 4o, 4i, 4m, 4p exhibited activity at
>64 g/mL. In addition compounds 4b, 4f, 4g, 4j, 4v exhibited
activity at 32 g/mL, while 4a, 4c, 4k, 4l, 4y registered the MIC at
64 g/mL and 4i, 4m, 4o, 4p, 4u registered the MIC at >64 g/mL
mg/mL which is
e
e
e
10.90
14.40
e
13.90
11.20
e
e
11.28
15.76
e
e
m
14.15
e
e
e
11.02
10.80
e
19.80
20.78
16.82
22.87
26.76
20.44
e
e
e
e
e
e
e
m
17.21
21.22
e
e
e
e
e
9.77
e
17.28
19.12
e
19.44
17.56
e
m
13.25
m
e
17.00 10.12
e
11.11
13.14
e
e
e
e
m
m
4y
e
e
e
15.21
20.18
21.60
NA
11.74
28.64
23.28
NA
against C. albicans.
Ravuconazole
Nystatin
Ciprofloxacin 28.43
e
e
e
NA
NA
NA
NA
30.88
5. Structure activity relationship
26.22 26.66
Ravuconazole (100 g/disc), Nystatin (100
used as reference; synthesized compounds (100
(ꢁ) ¼ Inactive.
m
m
g/disc) Ciprofloxacin (100
m
g/disc), were
From the in vitro antimicrobial activity data, preliminary
structure activity relationship of the synthesized compounds
m
g/disc); NA ¼ Not Applicable;

N.D. Gaikwad et al. / European Journal of Medicinal Chemistry 54 (2012) 295e302
299
(4aey) was studied. The introduction of various substituents F,
7. Experimental
Cl, Br, NO2, CF3 on the phenyl rings A (adjacent to triazole ring)
and B (thiazole ring) significantly improve the antimicrobial
activity. The electrostatic property of the substituents had little
effect on the antimicrobial activity. In general halo substituent (F,
Cl, Br) enhances the antimicrobial activity while NO2 and CF3
substituent shows moderate activity. A closer look into the
structure activity relationship of these compounds revealed
following points:
Chemicals were procured from Aldrich Chemical Co. Reactions
were monitored and purity of the products was checked by thin
layer chromatography (TLC). TLC was performed on Merck 60 F-
254 silica gel plates with visualization by UV-light. Melting
points were determined in capillary tubes in silicon oil bath
using a Veego melting point apparatus and are uncorrected. 1H
(300 MHz) NMR and 13C (75 MHz) NMR spectra were recorded
on Varian mercury XL-300 and Bruker at either 400 MHz (1H
1. The hybrid molecules 4aey exhibited moderate to good anti-
bacterial activity against four pathogenic bacteria B. subtilis,
S. aureus, E. coli, P. aeruginosa and excellent antifungal activity
against two pathogenic fungi C. albicans and A. niger due to
presence of triazole ring, thiazole ring, hydrazone and different
substituents on phenyl rings A and B. These results also suggest
that combination of certain substituent on both the phenyl
rings A and B is responsible for the antimicrobial activity.
2. The halo substituents on the phenyl ring A as well as B at 4-
position in compounds 4aey affected the antibacterial
activity to some extent. The F, Cl, Br substituents on these
phenyl rings exhibited good antibacterial activity, while the CF3
and NO2 substituent does not affect the antibacterial activity
appreciably.
3. The ravuconazole analogues 4aey exhibited antifungal activity
of varying degree. The compounds with F, Cl, Br substituents at
4 position on phenyl rings A and B exhibited good to excellent
antifungal activity against A. niger and C. albicans (4a, 4b, 4c, 4f,
4g, 4h, 4l, 4u, 4v) except (4c, 4h, 4k, 4m) which possess
moderate antifungal activity. While the analogues with 4-NO2
and 3,5-bis CF3 substituents on phenyl rings A and B exhibited
less or no antifungal activity against C. albicans and A. niger (4d,
4e, 4i, 4n, 4o, 4p, 4q, 4r, 4s, 4t, 4w, 4x) except 4j, 4u, 4v, 4y
which showed good antifungal activity.
NMR) and 100 MHz
Chemical shifts are reported from internal tetramethyl silane
standard and are given in units. The solvent for NMR spectra
(
13C NMR), spectrometer instruments.
d
was CDCl3. Infrared spectra were taken on Shimadzu FTIRe408 in
KBr. The mass spectra were recorded on Bruker daltonics 3.2
mass spectrometer with an ionization potential of 70 eV.
Elemental analysis was performed on
a Hosli CH-analyzer.
Column chromatography was performed on silica gel (230e400
mesh) supplied by Acme Chemical Co. The chemicals and
solvents used were laboratory grade and were purified as per
literature methods.
7.1. General procedure for the synthesis of 2-(1H [1,2,3]triazol-1-
yl)-1-(substituted phenyl) ethanone 2
A mixture of phenacyl bromide (0.01 mol) and 1,2,4-triazole
(0.01 mol) was stirred at room temperature in presence of
ethanol (15 mL) and catalytic amount of triethyl amine
(0.001 mol) for 15 min, the solid product appeared during stirring
was filtered and re-crystallized from methanol to give pure
product 2.
7.2. General procedure for the preparation of thiosemicarbazones 3
4. Introduction of F and Cl substituents at 4-position of phenyl
ring B possesses good (4f) to moderate antibacterial activity
(4a, 4b, 4g, 4k, 4l, 4q, 4u) against S. aureus. In case of E. coli
most of the synthesized compounds with F, Cl, Br substituents
at the phenyl ring A exhibited moderate activity (4a, 4b, 4c, 4d,
4e, 4f, 4g, 4i, 4j, 4m, 4n, 4o) except compounds 4h, 4k, 4l. In
case of B. subtilis F and Cl substituents present on both phenyl
rings A and B shows excellent activity (4a, 4b, 4k). In case of
P. aeruginosa F, Cl and CF3 substituents present at phenyl ring A
shows excellent activity (4a, 4c, 4e, 4g, 4h, 4j, 4u, 4v, 4w) as
compared to Br and NO2 substituents. It was interesting to note
that when F and Cl substituents present in phenyl ring A along
with Br, CF3 substituents in phenyl ring B shows good activity
(4g, 4u). In case of A. niger F and Cl substituents present in
either phenyl ring A and/or B possesses good to excellent
activity for (4ae4m, 4o, 4p, 4u, 4v). In case of C. albicans F, Cl,
Br, CF3 substituents present on phenyl ring A and/or B shows
moderate (4a, 4c, 4i, 4k, 4l, 4m, 4o, 4p, 4u, 4y) to good (4b, 4f,
4g, 4j, 4v) antifungal activity.
A
mixture of compound 2 (0.01 mol), thiosemicarbazide
(0.01 mol), ethanol (15 mL) and acetic acid (1 mL) was refluxed for
60 min, then allowed to cool at room temperature. The solid
product 3 collected was re-crystallized from ethanol/DMF.
7.3. General procedure for the preparation of substituted ethanone
hydrazone 4aey
A mixture of 1-phenyl-2-(1H-1,2,4 azole-1-yl) ethane-1-one
thiosemicarbazone
(0.1 mmol) was refluxed in ethanol (20 mL) for 15 min. The solid
product 4aey appeared during reflux were filtered after cooling
and were purified by silica gel column chromatography (ethyl
acetate: hexane, 1:1).
3
(0.1 mmol) and phenacyl bromide
7.3.1. 1-(1-(4-Fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2-(4-(4-fluorophenyl)thiazol-2-yl)hydrazine (4a)
Yield: 62% mp: 198 ꢀC, 1H NMR (300 MHz, CDCl3):
d 6.10 (s, 2H,
CH2), 6.91 (s, 1H, thiazole), 7.1 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz, AreH),
7.4 (dd, 2H, J ¼ 8.5 Hz and 5.5 Hz, AreH), 7.7 (dd, 2H, J ¼ 9.2 Hz and
8.5 Hz, AreH), 8.0 (dd, 2H, J ¼ 8.5 Hz and 5.5 Hz, AreH), 8.01 (s, 1H,
triazole), 8.44 (s, 1H, triazole), 10.80 (bs, 1H, eNH); 13C NMR
(75 MHz, CDCl3): 48.5 (CH2), 100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF),
129.6, 130.8 (d, J ¼ 7.7 Hz, C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF),
115.6, 116.0 (d, J ¼ 21 Hz, C2eF), 128.1, 129.6 (d, J ¼ 7.7 Hz, C3eF),
162.9, 165.2 (d, J ¼ 244 Hz, C1eF), 129.6, 143.6, 148.2, 151.3, 155.6,
171.8; Anal. Calcd for: C19H14F2N6S: C, 57.57; H, 3.56; N, 21.20;
Found: C, 57.62; H, 3.72; N, 21.38; (m/z): 397.1 (M þ 1), 398.1
(M þ 2), 393.1 (M þ 3).
6. Conclusion
A series of hybrids of ravuconazole 4aey were synthesized and
their antimicrobial activities was screened against four pathogenic
bacteria B. subtilis, S. aureus, E. coli and P. aeruginosa and two
pathogenic fungi C. albicans and A. niger. Most of the synthesized
compounds exhibited moderate to good activity towards Gram
positive and Gram negative bacteria as well as both the fungi
species. The present study therefore would be very useful to get
lead antimicrobial agents.

300
N.D. Gaikwad et al. / European Journal of Medicinal Chemistry 54 (2012) 295e302
7.3.2. 2-(4-(4-Chlorophenyl)thiazol-2-yl)-1-(1-(4-fluorophenyl)-2-
(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4b)
Calcd for: C19H14ClFN6S: C, 55.27; H, 3.42; N, 20.36; Found: C,
55.41; H, 3.46; N, 20.28; m/z (70 eV): 413.07 [M þ 1], 414.07
[M þ 2].
Yield: 63%; mp: 220 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 6.8 (s, 1H, thiazole), 7.1 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz, AreH),
7.3 (d, 2H, J ¼ 8.5 Hz, AreH), 7.6 (d, 2H, J ¼ 8.5 Hz, AreH), 7.7 (dd,
2H, J ¼ 8.5 Hz and 5.5 Hz, AreH), 7.95 (s, 1H, triazole), 8.42 (s, 1H,
triazole), 11.13 (bs, 1H, eNH); 13C NMR (75 MHz, CDCl3): 48.5 (CH2),
100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF), 129.6, 130.8 (d, J ¼ 7.7 Hz,
C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF), 128.9, 129.6, 130.5, 131.2,
134.3, 143.6, 148.2, 155.6, 151.3, 171.8; Anal. Calcd for: C19H14ClFN6S:
C, 55.27; H, 3.42; N, 20.36; Found: C, 55.60; H, 3.56; N, 20.18; m/z
(70 eV): 413.07 (M þ 1), 414.07 (M þ 2), 411.07 (M ꢁ 1).
7.3.7. 1-(1-(4-Chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazine (4g)
Yield: 71%; mp: 253 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 6.8 (s, 1H, thiazole), 7.3 (d, 4H, J ¼ 8.5 Hz, AreH), 7.6 (d, 4H,
J ¼ 8.5 Hz, AreH), 8.0 (s, 1H, triazole), 8.5 (s, 1H, triazole), 10.0 (bs,
1H, eNH); Anal. Calcd for: C19H14Cl2N6S: C, 53.15; H, 3.29; N, 19.57;
Found: C, 53.96; H, 3.78; N, 19.45; m/z (70 eV): 429.05 [M þ 1],
430.07 [M þ 2].
7.3.3. 2-(4-(4-Bromophenyl)thiazol-2-yl)-1-(1-(4-fluorophenyl)-2-
(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4c)
7.3.8. 2-(4-(4-Bromophenyl)thiazol-2-yl)-1-(1-(4-chlorophenyl)-2-
(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4h)
Yield: 65%; mp: 234 ꢀC; 1H NMR (300 MHz, CDCl3):
d
5.8 (s, 2H,
Yield: 68%; mp: 269 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 6.8 (s, 1H, thiazole), 7.2 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz, AreH),
7.6 (d, 2H, J ¼ 8.5 Hz, AreH), 7.7 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (dd,
2H, J ¼ 5.5 Hz and 8.5 Hz, AreH), 8.01 (s, 1H, triazole), 8.44 (s, 1H,
triazole), 10.0 (bs, 1H, eNH); 13C NMR (75 MHz, CDCl3): 48.5(CH2),
100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF), 129.6, 130.8 (d, J ¼ 7.7 Hz,
C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF), 123.1, 129.7, 130.4, 132.1,
132.2, 143.6, 148.2, 151.3, 155.6, 171.8; Anal. Calcd for:
C19H14BrFN6S: C, 49.90; H, 3.09; N, 18.38; Found: C, 50.18; H, 2.88;
N, 18.53; m/z (70 eV): 457.02 (M þ 1), 458.02 (M þ 2), 455.02
(M ꢁ 1).
CH2), 6.8 (s, 1H, thiazole), 7.3 (d, 2H, J ¼ 8.5 Hz, AreH), 7.6 (d, 2H,
J ¼ 8.5 Hz, AreH), 7.7 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (d, 2H,
J ¼ 8.5 Hz, AreH), 8.0 (s, 1H, triazole), 8.4 (s, 1H, triazole), 10.45 (bs,
1H, eNH); Anal. Calcd for: C19H14BrClN6S: C, 48.17; H, 2.98; N,
17.74; Found: C, 48.32; H, 2.89; N, 17.83; m/z (70 eV): 472.9 [M þ 1],
473.7 [M þ 2].
7.3.9. 1-(1-(4-Chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine (4i)
Yield: 64%; mp: 265 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 6.9 (s, 1H, thiazole), 7.3 (d, 2H, J ¼ 8.5 Hz, AreH), 7.6 (d, 2H,
J ¼ 8.5 Hz, AreH), 7.8 (d, 2H, J ¼ 8.5 Hz, AreH), 8.2 (d, 2H,
J ¼ 8.5 Hz, AreH), 8.1 (s, 1H, triazole), 8.4 (s, 1H, triazole), 10.3 (bs,
1H, eNH); 13C NMR (75 MHz, CDCl3): 48.5 (CH2), 100.0, 121.6,
128.4, 129.0, 130.6, 132.1, 136.6, 139.2, 143.6, 148.2, 148.4, 151.3,
155.6, 171.8; Anal. Calcd for: C19H14ClN7O2S: C, 51.88; H, 3.21; N,
22.29; Found: C, 51.90; H, 3.32; N, 22.10; m/z (70 eV): 440.06
[M þ 1], 441.1 [M þ 2].
7.3.4. 1-(1-(4-Fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine (4d)
Yield: 72%; mp: 242 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 7.1 (s, 1H, thiazole), 7.2 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz, AreH),
7.7 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (dd, 2H, J ¼ 5.5 Hz and 8.5 Hz,
AreH), 8.2 (d, 2H, J ¼ 8.5 Hz, AreH), 8.0 (s, 1H, triazole), 8.46 (s, 1H,
triazole), 10.5 (bs, 1H, eNH); 13C NMR (75 MHz, CDCl3): 48.5 (CH2),
100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF), 129.6, 130.8 (d, J ¼ 7.7 Hz,
C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF), 121.6, 128.4, 129.6, 139.2,
143.6, 151.3, 148.2, 148.4, 155.6, 171.8; Anal. Calcd for: C19H14FN7O2S
: C, 53.89; H, 3.33; N, 23.16; Found: C, 53.66; H, 3.39; N, 23.04; m/z
(70 eV): 424.09 (M þ 1), 425.09 (M ꢁ 1).
7.3.10. 2-(4-(3,5-Bis(trifluoromethyl)phenyl)thiazol-2-yl)-1-(1-(4-
chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4j)
Yield: 62%; mp: 261 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.1 (s, 2H,
CH2), 7.1 (s, 1H, thiazole), 7.3 (d, 2H, J ¼ 8.5 Hz, AreH), 7.6 (d, 2H,
J ¼ 8.5 Hz, AreH), 7.7 (s, 2H, AreH), 8.0 (s, 1H, triazole), 8.5 (s, 1H,
triazole), 8.6 (s, 1H, AreH), 10.7 (bs, 1H, eNH); Anal. Calcd for:
C21H13ClF6N6S: C, 47.51; H, 2.47; N, 15.83; Found: C, 47.51; H, 2.39;
N, 15.62; m/z (70 eV): 531.05 [M þ 1], 532.1 [M þ 2].
7.3.5. 2-(4-(3,5-Bis(trifluoromethyl)phenyl)thiazol-2-yl)-1-(1-(4-
fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4e)
Yield: 77%; mp: 237 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 7.1 (s, 1H, thiazole), 7.2 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz, AreH),
7.7 (s, 2H, AreH), 7.8 (dd, 2H, J ¼ 5.5 Hz and 8.5 Hz, AreH), 8.0 (s,1H,
triazole), 8.2 (d, 2H, J ¼ 8.5 Hz, AreH), 8.4 (s, 1H, triazole), 8.6 (s, 1H,
AreH), 11.5 (bs, 1H, eNH); 13C NMR (75 MHz, CDCl3): 48.5 (CH2),
100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF), 129.6, 130.8 (d, J ¼ 7.7 Hz,
C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF), 115.6, 117.2, 120.8, 124.9,
127.8 (q, J ¼ 273 Hz, CeCF3), 132.1, 132.6, 133.0, 133.5 (q, J ¼ 33 Hz,
CF3), 128.9, 129.6, 134.6, 143.6, 148.2, 151.3, 155.2, 171.8; Anal. Calcd
for: C21H13F7N6S: C, 49.03; H, 2.55; N, 16.34; Found: C, 49.03; H,
2.78; N, 16.63; m/z (70 eV): 515.08 [M þ 1], 516.08 [M þ 2], 513.08
[M ꢁ 1].
7.3.11. 1-(1-(4-Bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2-(4-(4-fluorophenyl)thiazol-2-yl)hydrazine (4k)
Yield: 69%; mp: 248 ꢀC; 1H NMR (300 MHz, CDCl3):
d 5.8 (s, 2H,
CH2), 6.8 (s, 1H, thiazole), 7.2 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz, AreH),
7.6 (d, 2H, J ¼ 8.5 Hz, AreH), 7.7 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (dd,
2H, J ¼ 5.5 Hz and 8.5 Hz, AreH), 8.0 (s, 1H, triazole), 8.4 (s, 1H,
triazole), 10.0 (bs, 1H, eNH); 13C NMR (75 MHz, CDCl3): 48.5 (CH2),
100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF), 129.6, 130.8 (d, J ¼ 7.7 Hz,
C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF), 125.4, 128.9, 131.8, 131.4,
133.0,143.6, 148.2, 151.3, 155.6, 171.8; Anal. Calcd for: C19H14BrFN6S:
C, 49.90; H, 3.09; N, 18.38; Found: C, 49.77; H, 2.98; N, 18.42; m/z
(70 eV): 457.02 [M þ 1], 478.1 [M þ 2].
7.3.6. 1-(1-(4-Chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2-(4-(4-fluorophenyl)thiazol-2-yl)hydrazine (4f)
Yield: 68%; mp: 220 ꢀC; 1H NMR (300 MHz, CDCl3):
d
6.1 (s,
7.3.12. 1-(1-(4-Bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2H, CH2), 6.8 (s, 1H, thiazole), 7.1 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz,
AreH), 7.3 (d, 2H, J ¼ 8.5 Hz, AreH), 7.6 (d, 2H, J ¼ 8.5 Hz, AreH),
7.7 (dd, 2H, J ¼ 5.5 Hz and 8.5 Hz, AreH), 8.1 (s, 1H, triazole), 8.5
(s, 1H, triazole), 10.53 (bs, 1H, eNH); 13C NMR (75 MHz, CDCl3):
48.5 (CH2), 100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF), 129.6, 130.8
(d, J ¼ 7.7 Hz, C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF), 129.1,
130.6, 131.8, 132.1, 136.6, 143.6, 148.2, 151.3, 155.6, 171.8; Anal.
2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazine (4l)
Yield: 68%; mp: 265 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 6.8 (s, 1H, thiazole), 7.3 (d, 2H, J ¼ 8.5 Hz, AreH), 7.6 (d, 2H,
J ¼ 8.5 Hz, AreH), 7.7 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (d, 2H, J ¼ 8.5 Hz,
AreH), 7.9 (s, 1H, triazole), 8.4 (s, 1H, triazole), 9.45 (bs, 1H, eNH);
Anal. Calcd for: C19H14BrClN6S: C, 48.17; H, 2.98; N, 17.74; Found: C,
48.33; H, 2.86; N, 17.68; m/z (70 eV): 472.9 [M þ 1], 473.6 [M þ 2].

N.D. Gaikwad et al. / European Journal of Medicinal Chemistry 54 (2012) 295e302
301
7.3.13. 1-(1-(4-Bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
J ¼ 8.5 Hz, AreH), 8.2 (d, 4H, J ¼ 8.5 Hz AreH), 8.0 (s, 1H, triazole),
8.4 (s, 1H, triazole), 10.3 (bs, 1H, eNH); Anal. Calcd for:
C19H14N8O4S: C, 50.66; H, 3.13; N, 24.88; Found: C, 50.32; H, 3.19; N,
24.98; m/z (70 eV): 451.09 (M þ 1), 450.1 (M ꢁ 1).
2-(4-(4-bromophenyl)thiazol-2-yl)hydrazine (4m)
Yield: 62%; mp: 270 ꢀC; 1H NMR (300 MHz, CDCl3):
d
Yield: 80%;
6.0 (s, 2H,
mp: 230 ꢀC; IR: 1600 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
CH2), 6.8 (s, 1H, thiazole), 7.6 (d, 4H, J ¼ 8.5 Hz, AreH), 7.8 (d, 4H,
J ¼ 8.5 Hz, AreH), 8.1 (s, 1H, triazole), 8.5 (s, 1H, triazole), 9.45 (bs,
1H, eNH); Anal. Calcd for: C19H14Br2N6S: C, 44.04; H, 2.72; N, 16.22;
Found: C, 44.28; H, 2.66; N, 16.44; m/z (70 eV): 516.9 [M þ 1], 517.1
[M þ 2].
7.3.20. 2-(4-(3,5-Bis(trifluoromethyl)phenyl)thiazol-2-yl)-1-(1-(4-
nitrophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4t)
Yield: 73%; mp: 288 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.1 (s, 2H,
CH2), 6.9 (s, 1H, thiazole), 7.6 (d, 4H, J ¼ 8.5 Hz, AreH), 7.8 (s, 2H,
AreH), 8.3 (d, 4H, J ¼ 8.5 Hz, AreH), 8.6 (s, 1H, AreH), 8.1 (s, 1H,
triazole), 8.5 (s, 1H, triazole), 10.7 (bs, 1H, eNH); Anal. Calcd for:
C21H13F6N7O2S: C, 46.58; H, 2.42; N, 18.11; Found: C, 46.41; H, 2.46;
N, 18.28; m/z (70 eV): 542.08 [M þ 1], 540.1 [M ꢁ 1].
7.3.14. 1-(1-(4-Bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine (4n)
Yield: 68%; mp: 285 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 6.9 (s, 1H, thiazole), 7.6 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (d, 2H,
J ¼ 8.5 Hz, AreH), 8.0 (d, 2H, J ¼ 8.5 Hz, AreH), 8.3 (d, 2H, J ¼ 8.5 Hz,
AreH), 8.0 (s, 1H, triazole), 8.5 (s, 1H, triazole), 9.6 (bs, 1H, eNH);
13C NMR (75 MHz, CDCl3): 48.5 (CH2), 100.0, 121.6, 125.4, 128.4,
131.8, 131.4, 133.0, 139.2, 143.6, 148.2, 148.4, 151.3, 155.6, 171.8; Anal.
Calcd for: C19H14BrN7O2S: C, 47.12; H, 2.91; N, 20.24; Found: C,
47.58; H, 3.05; N, 20.60; m/z (70 eV): 484.03 [M þ 1], 485.4 [M þ 2].
7.3.21. 1-(1-(3,5-Bis(trifluoromethyl)phenyl)-2-(1H-1,2,4-triazol-1-
yl)ethylidene)-2-(4-(4-fluorophenyl)thiazol-2-yl)hydrazine (4u)
Yield: 72%; mp: 267 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 7.1 (s, 1H, thiazole), 7.2 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz, AreH),
7.4e7.7 (s, 2H, AreH), 7.8 (dd, 2H, J ¼ 5.5 Hz and 8.5 Hz, AreH), 8.2
(d, 2H, J ¼ 8.5 Hz, AreH), 8.6 (s,1H, AreH), 8.0 (s,1H, triazole), 8.5 (s,
1H, triazole), 11.5 (bs, 1H, eNH); 13C NMR (75 MHz, CDCl3): 48.5
(CH2), 100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF), 129.6, 130.8 (d,
J ¼ 7.7 Hz, C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF), 116.0, 117.2,
120.8,124.9,127.8 (q, J ¼ 273 Hz, CeCF3),132.1,132.6,133.0,133.5 (q,
J ¼ 33 Hz, CF3), 128.7, 129.3, 134.5, 143.6, 148.2, 151.3, 155.6, 171.8;
Anal. Calcd for: C21H13F7N6S: C, 49.03; H, 2.55; N, 16.34; Found: C,
49.41; H, 2.46; N, 16.28; m/z (70 eV): 515.08 [M þ 1], 516.8 [M þ 2],
517.8 [M þ 3].
7.3.15. 2-(4-(3,5-Bis(trifluoromethyl)phenyl)thiazol-2-yl)-1-(1-(4-
bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4o)
Yield: 65%; mp: 277 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.1 (s, 2H,
CH2), 6.9 (s, 1H, thiazole), 7.6 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (d, 2H,
J ¼ 8.5 Hz, AreH), 7.9 (s, 2H, AreH), 8.6 (s, 1H, AreH), 7.9 (s, 1H,
triazole), 8.4 (s, 1H, triazole), 10.7 (bs, 1H, eNH); Anal. Calcd for:
C21H13BrF6N6S: C, 43.84; H, 2.28; N, 14.61; Found: C, 43.73; H, 2.16;
N, 14.82; m/z (70 eV): 575.02 [M þ 1], 676.2 [M þ 2].
7.3.22. 1-(1-(3,5-Bis(trifluoromethyl)phenyl)-2-(1H-1,2,4-triazol-
1-yl)ethylidene)-2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazine (4v)
7.3.16. 2-(4-(4-Fluorophenyl)thiazol-2-yl)-1-(1-(4-nitrophenyl)-2-
(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4p)
Yield: 66%; mp: 279 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.1 (s, 2H,
Yield: 67%; mp: 256 ꢀC; 1H NMR (300 MHz, CDCl3):
d
6.0 (s, 2H,
CH2), 7.1 (s, 1H, thiazole), 7.3 (d, 2H, J ¼ 8.5 Hz, AreH), 7.6 (d, 2H,
J ¼ 8.5 Hz, AreH), 7.7 (s, 2H, AreH), 8.6 (s, 1H, AreH), 8.0 (s, 1H,
triazole), 8.4 (s, 1H, triazole), 9.7 (bs, 1H, eNH); 13C NMR (75 MHz,
CDCl3): 48.5 (CH2), 100.0, 117.2, 120.8, 124.9, 127.8 (q, J ¼ 273 Hz,
CeCF3), 132.1, 132.6, 133.0, 133.5 (q, J ¼ 33 Hz, CF3), 129.3, 134.5,
128.9, 129.4, 130.2, 131.4,134.3,143.6,148.2,151.3, 155.6,171.8; Anal.
Calcd for: C21H13ClF6N6S: C, 47.51; H, 2.47; N,15.83; Found: C, 47.96;
H, 2.78; N, 15.45; m/z (70 eV): 531.05 [M þ 1], 532.7 [M þ 2].
CH2), 7.1 (s, 1H, thiazole), 7.2 (dd, 2H, J ¼ 9.2 Hz, J ¼ 8.5 Hz, AreH),
7.7 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (dd, 2H, J ¼ 5.5 Hz and 8.5 Hz,
AreH), 8.2 (d, 2H, J ¼ 8.5 Hz, AreH), 8.0 (s, 1H, triazole), 8.4 (s, 1H,
triazole), 10.5 (bs, 1H, eNH); 13C NMR (75 MHz, CDCl3): 48.5 (CH2),
100.0, 114.5, 116.4 (d, J ¼ 21 Hz, C2eF), 129.6, 130.8 (d, J ¼ 7.7 Hz,
C3eF), 161.7, 163.5 (d, J ¼ 244 Hz, C1eF), 121.2, 130.1, 128.1, 140.1,
143.6,148.2,150.7,151.3,155.6,171.8; Anal. Calcd for: C19H14FN7O2S:
C, 53.89; H, 3.33; N, 23.16; Found: C, 53.66; H, 3.57; N, 23.62; m/z
(70 eV): 424.09 [M þ 1], 425.6 [M þ 2].
7.3.23. 1-(1-(3,5-Bis(trifluoromethyl)phenyl)-2-(1H-1,2,4-triazol-
1-yl)ethylidene)-2-(4-(4-bromophenyl)thiazol-2-yl)hydrazine (4w)
7.3.17. 2-(4-(4-Chlorophenyl)thiazol-2-yl)-1-(1-(4-nitrophenyl)-2-
Yield: 70%; mp: 285 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.1 (s, 2H,
(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4q)
CH2), 6.9 (s, 1H, thiazole), 7.8 (s, 2H, AreH), 8.6 (s, 1H, AreH), 8.0 (s,
1H, triazole), 8.4 (s, 1H, triazole), 10.7 (bs, 1H, eNH); Anal. Calcd for:
C21H13BrF6N6S: C, 43.84; H, 2.28; N, 14.61; Found: C, 43.74; H, 2.15;
N, 14.78; m/z (70 eV): 575.2 [M þ 1], 676.2 [M þ 2].
Yield: 71%; mp: 263 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.0 (s, 2H,
CH2), 6.9 (s, 1H, thiazole), 7.3 (d, 2H, J ¼ 8.5 Hz, AreH), 7.6 (d, 2H,
J ¼ 8.5 Hz, AreH), 7.8 (d, 2H, J ¼ 8.5 Hz, AreH), 8.2 (d, 2H, J ¼ 8.5 Hz,
AreH), 8.0 (s, 1H, triazole), 8.4 (s, 1H, triazole), 11.3 (bs, 1H, eNH);
Anal. Calcd for: C19H14ClN7O2S: C, 51.88; H, 3.21; N, 22.29; Found: C,
51.92; H, 3.36; N, 22.12; m/z (70 eV): 440.06 [M þ 1], 441.8 [M þ 2].
7.3.24. 1-(1-(3,5-Bis(trifluoromethyl)phenyl)-2-(1H-1,2,4-triazol-
1-yl)ethylidene)-2-(4-(4-nitrophenyl) thiazol-2-yl) hydrazine (4x)
Yield: 63%; mp: 271 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.1 (s,
7.3.18. 2-(4-(4-Bromophenyl)thiazol-2-yl)-1-(1-(4-nitrophenyl)-2-
2H, CH2), 6.9 (s, 1H, thiazole), 7.6 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8
(s, 2H, AreH), 8.3 (d, 2H, J ¼ 8.5 Hz, AreH), 8.6 (s, 1H, AreH), 8.1
(s, 1H, triazole), 8.4 (s, 1H, triazole), 11.7 (bs, 1H, eNH); Anal.
Calcd for: C21H13F6N7O2S: C, 46.58; H, 2.42; N, 18.11; Found: C,
46.76; H, 2.56; N, 18.58; m/z (70 eV): 542.08 [M þ 1], 540.1
[M ꢁ 1].
(1H-1,2,4-triazol-1-yl)ethylidene)hydrazine (4r)
Yield: 68%; mp: 270 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.1 (s, 2H,
CH2), 6.9 (s, 1H, thiazole), 7.6 (d, 2H, J ¼ 8.5 Hz, AreH), 7.8 (d, 2H,
J ¼ 8.5 Hz, AreH), 8.0 (d, 2H, J ¼ 8.5 Hz, AreH), 8.3 (d, 2H, J ¼ 8.5 Hz,
AreH), 8.0 (s, 1H, triazole), 8.5 (s, 1H, triazole), 10.6 (bs, 1H, eNH);
Anal. Calcd for: C19H14BrN7O2S: C, 47.12; H, 2.91; N, 20.24; Found: C,
47.12; H, 3.04; N, 20.30; m/z (70 eV): 484.01 [M þ 1], 485.01 [M þ 2].
7.3.25. 1-(1-(3,5-Bis(trifluoromethyl)phenyl)-2-(1H-1,2,4-triazol-
1-yl)ethylidene)-2-(4-(3,5-bis(trifluoromethyl)phenyl)thiazol-2-yl)
hydrazine (4y)
7.3.19. 1-(1-(4-Nitrophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene)-
2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine (4s)
Yield: 68%; mp: 280 ꢀC; 1H NMR (300 MHz, CDCl3):
d 6.1 (s, 2H,
Yield: 65%; mp: 278 ꢀC; 1H NMR (300 MHz, CDCl3):
d
1H NMR
CH2), 6.9 (s, 1H, thiazole), 7.8 (s, 4H, AreH), 8.6 (s, 2H, AreH), 8.0 (s,
1H, triazole), 8.4 (s, 1H, triazole), 10.3 (bs, 1H, eNH); Anal. Calcd for:
(300 MHz, CDCl3): d 6.0 (s, 2H, CH2), 6.9 (s, 1H, thiazole), 7.6 (d, 4H,

302
N.D. Gaikwad et al. / European Journal of Medicinal Chemistry 54 (2012) 295e302
(b) K. Shalini, N. Kumar, S. Drabu, P.K. Sharma Beilstein, J. Org. Chem. 7 (2011)
C23H12F12N6S: C, 43.68; H,1.91; N,13.29; Found: C, 43.51; H, 2.09; N,
13.62; m/z (70 eV): 633.07 [M þ 1], 631.5 [M ꢁ 1].
668e677.
ꢀ
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