Synthesis and biological activity studies of new hybrid molecules containing tryptamine moiety

Article abstract of DOI:10.1007/s00044-010-9531-y

The synthesis of N′-(4-substitutedphenylsulfonyl)-2-{4-[2-(1H-indol- yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl} acetohydrazides (3a-c), 2-{4-[2-(1H-indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo- 4,5-dihydro-1H-1,2,4-triazol-1-yl}-N

Full text of DOI:10.1007/s00044-010-9531-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:212–223
DOI 10.1007/s00044-010-9531-y
ORIGINAL RESEARCH
Synthesis and biological activity studies of new hybrid molecules
containing tryptamine moiety
•
•
•
Hakan Bektas Ahmet Demirbas Neslihan Demirbas
Sengul Alpay Karaoglu
Received: 17 June 2010 / Accepted: 2 December 2010 / Published online: 15 December 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The synthesis of N0-(4-substitutedphenylsul-
fonyl)-2-{4-[2-(1H-indol-yl)ethyl]-3-(4-chlorobenzyl)-5-
oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazides (3a–
c), 2-{4-[2-(1H-indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-
4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-aryl methylidene acet-
ohydrazides (4a–f) and 4-[2-(1H-indol-3-yl)ethyl]-5-(4-sub-
stitutedbenzyl)-2-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-
2,4-dihydro-3H-1,2,4-triazol-3-ones (5a, b) was performed
starting from the corresponding acid hydrazides (2a,
b) which was reported earlier. The treatment of 1,3,4-
oxadiazole derivatives (5a, b) with hydrazine hydrate
produced 4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl deriv-
atives (6a, b). Then, compound 6b was converted to
the corresponding Schiff base (7) by the treatment with
anisaldehyde. The synthesis of 5-(4-chlorobenzyl)-4-[2-
(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-
3-one (8) and 5-(4-methylbenzyl)-4-[2-(1H-indol-3-yl)
ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-
yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (10) was
carried out by the reaction of acid hydrazides (2a, b) with
aryl iso(thio)cyanates either via the formation of the
intermediates (9a, b) (for 10) or direct cyclization (for 8).
1,3-Oxa(thia)zol-2(3H)-ylidene]acetohydrazide derivatives
(11a, b) were obtained by the reaction of 9a, b with
4-chlorophenacyl bromide. All newly synthesized com-
pounds were screened for their antimicrobial activities and
some of which was found to be active against the test
microorganisms.
Keywords 1H-indole ꢀ 1,2,4-Triazole ꢀ Schiff base ꢀ
1,3-Oxadiazole ꢀ 1,3-Thiazole ꢀ Antimicrobial activity
Introduction
Research and development of potent and efficient antimi-
crobial agents possessing the activity not only on the
control of serious infections, but also for the prevention and
treatment of some infectious diseases constitutes a major
challenge in medicinal chemistry. Although these efforts
has resulted in the development of a wide variety of anti-
microbial agents, as a result of misuse and overuse of
antibiotics, pathogenic microorganisms have developed
resistance associated with an increase in mortality towards
number of antibiotics which have been using clinically as
significant drugs, such as b-lactam antibiotics, macrolides,
quinolones and vancomycin. Resistance has been defined
as the temporary or permanent ability of an organism and
its progeny to remain viable and/or multiply under condi-
tions that would destroy or inhibit other members of the
strain. Bacteria may be defined as resistant when they are
not susceptible to a concentration of antibacterial agent
used in practice. Traditionally, resistance refers to instan-
ces where the basis of increased tolerance is a genetic
change, and where the biochemical basis is known. Such
serious global health problem demands a renewed effort
seeking the development of new antimicrobial agents, and
H. Bektas
Department of Chemistry, Faculty of Sciences, Giresun
University, 28100
Giresun, Turkey
A. Demirbas ꢀ N. Demirbas (&)
Department of Chemistry, Faculty of Sciences,
Karadeniz Technical University, 61080 Trabzon, Turkey
e-mail: neslihan@ktu.edu.tr
S. A. Karaoglu
Department of Biology, Faculty of Sciences,
Rize University, 53100 Rize, Turkey
123

Med Chem Res (2012) 21:212–223
213
much attention has been focused on addressing the problem
of multi-drug resistant (MDR) bacteria and fungi resulting
from the widespread use and misuse of classical antimi-
crobial agents (Ozdemir et al., 2007; Tuncbilek et al.,
2009; Giraud et al., 2008, 2009; Hester and Nesnow, 2008;
Ezabadi et al., 2008).
polar hydrogen or hydroxy mimic. Substitution of hydro-
gen by halogen atom has been a strategy in designing
molecules having biological activity. Although triazole and
imidazole nuclei act by the same mechanism of action,
triazoles have been possess advantages over imidazoles,
which have slow metabolic rate, oral bioavailability, and
less effect on human sterol synthesis. For these reasons,
imidazoles have slowly being replaced by triazole mole-
cules (Rostom et al., 2009; Sahoo et al., 2010).
In order to search and synthesize of combinational
chemotherapeutic drugs with different mechanisms of
action and with low side effects constitute an important
part of the methods that aims to overcome the antimicro-
bial resistance. Beside the development of completely new
agents possessing chemical characteristics that clearly
differ from those of existing ones, there is another approach
containing to combine two or more pharmacophores each
with different mode of action, into a single molecule. These
merged pharmacophore may be addressing the active site
of different targets and offer the possibility to overcome
drug resistance. In addition, this approach can also reduce
unwanted side effects (Rawal et al., 2005; Bonde and
Gaikwad, 2004; Rawal et al., 2007; Dixit et al., 2006;
Kaplancikli et al., 2008, Solomon et al., 2010).
Ribavirin (antiviral), Rizatriptan (antimigraine) and
Alprazolam (anxiolytic) are the other examples of drugs
containing triazole moiety (Cai et al., 2007; Rao et al.,
2006; Hancu et al., 2007). Other therapeutic effects of
1,2,4-triazole derivatives have been reported on inflam-
mation, cancer, pain, tuberculosis or hypertension
(Kuc¸ukguzel et al., 1999; Yuksek et al., 1997; Tozkoparan
et al., 2000; Ikizler et al., 2000; Demirbas et al., 2002;
Turan-Zitouni et al., 2001). Moreover, a number of triazole
derivatives containing an imine bond have intensively been
synthesized due to their biological activities (Demirbas
et al., 1996, 2009; Bayrak et al., 2009a, b; Bektas et al.,
2010a, b; Isloor et al., 2009; Karthikeyan et al., 2006).
Oxazolidinones are the other important azole derivatives
incorporated into new class of totally synthetic antibiotics,
such as Linezolid, Eperezolid, AZD2564 and the thi-
omorpholine analogue of linezolide, PNU-100480 (Das
et al., 2005; Cui et al., 2005). Also Eperezolid derivatives
containing five-membered heterocycles have been found to
be active. Moreover, the tryptamine sub-structure is present
in numerous naturally occurring and synthetic compounds,
many of which exhibit important pharmacological activi-
ties. For example, a number of 5-alkyltryptamine deriva-
tives which are known as triptans collectively, e.g.
sumatriptan, have been using as antimigraine drugs. Some
N,N-disubstituted tryptamines have been reported to show
psychotomimetic activity, although there is evidence to
suggest that the tryptamine derivatives are metabolized
in vivo to more active forms. In addition, some tryptamine-
based sulfonamides have been reported as human
b3-adrenergic receptor agonists (Kobeci et al., 2005;
Sawa et al., 2005; Yamazaki et al., 2009; Jenkins et al.,
2008).
Among the important pharmacophores responsible for
antimicrobial activity, the azole scaffold is still considered
a viable lead structure for the synthesis of more efficacious
and broad spectrum antimicrobial agents. Among azole-
based drugs, which have been using for the treatment of
fungal infections, Conazoles, such as Itraconazole, Fluco-
nazole, Voriconazole and Ravuconazole are widely used
and studied class of antimicrobial therapeutics due to their
safety profile and high therapeutic index (Yu et al., 2007;
Gupta et al., 2007; Schiller and Fung, 2007; Ashok et al.,
2007; Rostom et al., 2009). In addition, it has been
reported that remarkable antibacterial activity against
methicillin-resistant strains of Staphylococcus aureus
(MRSA) has been ascribed to some azoles, particularly
miconazole.
It has been reported that the primary structural
requirement for the antimicrobial azole class is a weak
basic azole nucleus bonded by a nitrogen–carbon linkage to
the rest of the structure. In this connection, the amidine
nitrogen (in imidazole or triazole) is believed to bind the
heme iron of enzyme-bound cytochrome P450 to prevent
oxidation of steroidal substrates by the enzyme. Azoles
containing aromatic substituents have been believed to
mimic the corresponding non-polar steroidal portion of the
substrate for the enzyme. The non-polar functionality leads
to high degree of lipophilicity to the antifungal azoles. On
the other hand, it was reported that incorporation of various
halo substituents into the heterocyclic ring systems aug-
ments biological activities considerably. Furthermore,
introduction a chloro-substituted benzene moiety into tri-
azole scaffold results in increase of broad spectrum of
antimicrobial activity due to the ability of halogen to act as
Synthetic organic chemistry has always been a vital part
of the highly integrated and multidisciplinary process of
various drug developments. Hydrazides and their deriva-
tives have been in generally used as the starting materials
for the synthesis of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles,
1,2,4-triazoles, 1,3-oxazolidin-2-ones, 1,3-thiazolidin-2-
ones (Weidinger-Wells et al., 2002; Demirbas et al., 2005,
2007). Furthermore, heterocyclic hydrazides are generally
utilized as intermediates for the synthesis of several con-
densed systems containing triazoles and other moieties
(Demirbas et al., 2005; Holla et al., 2002).
123

214
Med Chem Res (2012) 21:212–223
Motivated by these findings and in continuation of our
corresponding Schiff bases (4a–f) in good yields. This
idea originated from the need to incorporate an sulfon-
amide or imine moiety to molecule, because, so far, the
antimicrobial properties of sulfonamides or imine com-
pounds were well documented. The synthesis of 4-[2-(1H-
indol-3-il)ethyl]-5-(4-substitutedbenzyl)-2-[(4-amino-5-
sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,
4-triazol-3-ones (6a, b) has been performed starting from
hydrazides (2a, b) via the formation of 4-[2-(1H-indol-3-
yl)ethyl]-5-(4-substitutedbenzyl)-2-[(5-sulfanyl-1,3,4-oxa-
diazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones
(5a, b). Then, the 4-amino group on 1,2,4-triazol-3-yl
moiety of compound 6a has been functionalized to 4-
methoxyphenylmethyliden derivative (7) with the aim to
increase the lipophilicity of the molecule with antimi-
crobial activity.
ongoing efforts endowed with the discovery of nitrogen-
ated heterocycles with potential chemotherapeutic activi-
ties, we would like to report here the synthesis and
investigation of antimicrobial activities of new 1H-indole
derivatives incorporating such pharmacophore heterocycles
in a single structure as 1,2,4-triazole, 1,3-oxazole and/or
1,3-thiazole moieties.
Chemistry, results and discussion
The main aim of the present study is to synthesize and inves-
tigate the antimicrobial activity of new hybrid molecules
incorporating two or more heterocyclic pharmacophores.
The synthesis pathway leading to the title compounds was
shown in Fig. 1.
The reactions of compounds 2a, 2b with benzylisothi-
ocyanate in ethanol under reflux temperature has yielded
different type of products (8 and 9a); compound 2a has
produced 3-chlorobenzyl-2-({4-[2-(1H-indol-3-yl)ethyl]-5-
oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)-N-benzylhy-
drazinecarboxamide 9a by the treatment with benzylis-
othiocyanate in boiling ethanol, whereas the reaction of
compound 2b has resulted in further ring cyclization in the
same reaction conditions, thus, compound 8 has formed
(Fig. 2). On the other hand, the synthesis of compound 10
has been performed by intramolecular cyclization of car-
boxamide side chain of 9a in the presence of alcoholic
KOH under reflux conditions.
2-{3-(4-substitutedbenzyl)-4-[2-(1H-indol-3-yl)ethyl]-5-
oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazides (2a,
b) have been prepared by the way reported by us, recently,
starting from tryptamine [2-(1H-indol-3-yl)ethylamine] by
three steps (Bektas et al. 2010a, b). The condensation of
compounds 2a and 2b with two different aromatic sulfonyl
chlorides in boiling ethanol has afforded the corresponding
N0-(4-substitutedphenylsulfonyl)-2-{4-[2-(1H-indol-3-yl)
ethyl]-3-(4-substitutedbenzyl)-5-oxo-4,5-dihydro-1H-1,2,
4-triazol-1-yl}acetohydrazides (3a, b), while the reflux-
ing of the same intermediates (2a, b) with several alde-
hydes in ethanol has resulted in the formation of the
X
Fig. 1 Preparation of
compounds 1–4
O
R
O
NHN
R
SO2
NHNH2
N
N
NH2
N
N
H
O
N
O
N
X
SO2CI
N
H
N
1
N
H
H
3a-c
2a,b
X
2, 3
a
R
Br
Cl
CI
CI
b
c
R'CHO
CH3
Br
CI
CH3
d
O
R
H
NHN
C
N
N
R'
R
R'
-C6H4OCH3(4-)
4
a
O
N
CI
b
c
CI -CH2C6H5
CI
-C4H4N(2-)
-C6H4OCH3(4-)
-C4H4N(2-)
d
e
f
CH3
CH3
N
H
CH3
-C5H4N(2-)
4a-f
123

Med Chem Res (2012) 21:212–223
215
O
N
N
N
N
R
R
R
NHNH2
SH
N
N
SH
N
O
N
N
N
N
NH2
O
N
O
O
N
N
H2NNH2
CS2 / KOH
N
H
N
N
H
H
6a, b
5a, b
2a,b
CH3OC6H4CHO
ArNCX
N
N
NH
N
H3C
SH
CH3
N
N
N
O
N
N
N
C
N
O
N
O
N
H
O
NHNH
R
OCH3
X
N
N
C
NHAr
N
O
N
N
H
H
7
8
N
H
9a,b
KOH
N
(4-)CIC6H4COCH2Br
NH
N
CI
Cl
Ar
O
O
N
N
R
N
NHN
N
O
N
N
X
O
N
R
N
2, 5, 6
H
a
CI
N
CH3
b
10
H
11a, b
9a, 11a: R= CI, Ar= -CH2C6H5, X= O
9b, 11b: R= CH3, Ar= -C6H5, X=S
Fig. 2 Synthetic pathway for the preparation of compounds 5–11
With the aim of introducing of an 1,3-oxazole or
1,3-thiazole nucleus to molecule, compounds 9a and 9b were
condensed with 4-chlorophenacyl bromide in ethanol in the
presence of dried sodium acetate under reflux conditions;
thus, the synthesis of 11a and 11b has been achieved.
The structures of all newly synthesized compounds were
confirmed based on FT-IR, LC-MS, 1H NMR and 13C
NMR spectral data and elemental analysis.
cerevis (Sc) and Candida tropicalis (Ct) (data not shown).
Compounds 3a–d were found to be active against Gram neg-
ative bacillus, Pseudomonas aeruginosa (Pa), Gram positive
cocci Staphylococcus aureus (Sa), Gram positive spore bacillus
Bacillus cereus (Bc) and M. smegmatis (Ms). Nonpigmented
rapidly growing mycobacteria (M. smegmatis is one of them)
constitute a group of species of the genus Mycobacterium that
share some characteristics. On the contrary of expected, com-
pounds 4a, 4b, 4d–f) which contains an imine functionality in
their structures, exhibited no antimicrobial activity towards the
None of the synthesized compounds displayed anti-
fungal activity against Candida albicans (Ca), Saccharomyces
123

216
Med Chem Res (2012) 21:212–223
test microorganisms (data not shown). Only marginal activity
was observed for compound 4c on M. smegmatis. The com-
pounds having 1,3,4-oxadiazole nucleus, 5a and 5b, demon-
strated marginal activities on Sa, moderate activities on Bc
and good activities on Ef. The conversion of 1,3,4-oxadiazole
ring into 4-amino 1,2,4-triazole nucleus caused to loss of
antimicrobial activity against Sa and Ef for compounds 6a
and 6b, whereas these compounds found to posses moderate
activity against Bc and marginal activity against Ms. The
introduction of more lipophylic 4-methoxyphenylmethylene
moiety into position 4 of 5-sulfanyl-1,2,4-triazole scaffold in
compound 6a increased the antimicrobial activity on the test
microorganisms except Ef. Compounds 8 and 10, which have
the same chemical skeletons with the difference of a methyl
or chlor substituent at the position 4 of phenyl group, dis-
played similar activities on Pa, Bc and Ms. As an comparison
in the antimicrobial activities of compounds 8 and 10, the
substitution of methyl group by more polar chlor atom caused
an increase. The incorporation of 1,3-thiazole nucleus into
structure (for compound 11b) resulted in no antimicrobial
activity, whereas 1,3-oxadiazole moiety caused slight activity
on Sa and Ms for compound 11a.
Ms, while 11b displayed no activity against the test
microorganisms.
Experimental
All the chemicals were purchased from Fluka Chemie AG
Buchs (Switzerland), and they were used without further
purification. Melting points of the synthesized compounds
are determined in open capillaries on a Bu¨chi B-540
melting point apparatus and are uncorrected. Reactions are
monitored by thin-layer chromatography (TLC) on silica
gel 60 F254 aluminium sheets. The mobile phase was
ethanol and ethyl acetate (1:1) and detection was made
using UV light. IR spectra are recorded as potassium bro-
mide pellets using a PerkineElmer 1600 series FTIR
1
spectrometer. H NMR and 13C NMR spectra were recor-
ded on BRUKER AVENE II 400 MHz NMR Spectrometer
(Chemical shift in ppm down field from TMS as an internal
reference). Splitting patterns were designated as follows: s:
singlet; d: doublet; t: triplet; m: multiplet. The elemental
analysis was performed on a Costech Elemental Combus-
tion System CHNS-O elemental analyzer. All the com-
pounds gave C, H and N analysis within 0.4% of the
theoretical values. The mass spectra were obtained for
compounds 3, 6a–c and 11a at a Quattro LC-MS (70 eV)
Instrument. Compounds 2a, b were prepared by the way
reported previously (Bektas et al. 2010a, b).
Conclusion
This study reports the synthesis of some new 1H-indole
derivatives incorporating several other pharmacophore
heterocycles in a single structure. Hence, herein we com-
bined all these potential chemotherapeutic units, namely
1,2,4-triazole, 1,3-oxazole and/or 1,3-thiazole moieties.
The antimicrobial screening studies were also performed in
the study. 1,2,4-Triazole nucleus is one of the active
components present in many standard drugs and it is
known to increase the pharmacological activity of the
molecules. The presence of 1H-indole, 1,3-oxazole or 1,3-
thiazole nucleus is also instrumental in contributing to the
net biological activity of a system.
General method for the synthesis of compounds 3a–c
To a solution of the corresponding compound 2 in tetra-
hydrofurane (10 mmol) 4-chlorobenzensulfonylchloride
(10 mmol) was added and the reaction mixture was
refluxed in the presence of triethylamine (20 mmol) for
4 h. Then, the reaction content was allowed to reach to
room temperature and water was added into it. The formed
solid was filtered off, recrystallized from ethanol–water
(1:2) to obtain the pure product.
The antimicrobial screening suggests that among the
newly synthesized compounds, compounds, 3a–d exhibited
activity against P. aeruginosa (Pa), S. aureus (Sa),
B. cereus (Bc) and M. smegmatis (Ms). On the other hand,
among compounds 4, only compound 4c displayed activity
on M. smegmatis. The compounds having 1,3,4-oxadiazole
nucleus, 5a and 5b, were found to be active on Sa, Bc and
Ef. Compounds 6a and 6b, which contain 4-amino-1,2,4-
triazole moiety instead of 1,3,4-oxadiazole nucleus, dem-
onstrated moderate activity against Bc and marginal
activity against Ms. Compounds 8 and 10, which have the
same chemical skeletons with the difference of a methyl or
chlor substituent at the position 4 of phenyl group, dis-
played similar activities on Pa, Bc and Ms. On the other
hand, compound 11a exhibited slight activity on Sa and
N0-(4-Bromophenylsulfonyl)-2-{4-[2-(1H-indol-3-yl)ethyl]-
3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-
yl}acetohydrazide (3a)
Yield 78%, mp. 185–186°C; Anal. Calcd. (%) for:
C27H24BrClN6O4S: C, 50.36, H, 3.76, N, 13.05, S, 4.98,
Found; C, 50.42, H, 3.82, N, 13.14, S, 4.87; IR (KBr, m,
cm-1): 3256, 3134 (NH), 2978, 2832 (CH2), 1702, 1695
(–C=O); 1H NMR (DMSO-d6) d (ppm): 2.81 (2H, bs, tryp-
CH2), 3.47 (2H, s, benzyl-CH2), 3.66 (2H, bs, tryp-CH2),
4.27 (2H, s, CH2), 7.00–7.10 (6H, m, ar–H), 7.32–7.36 (4H,
m, ar–H), 7.75 (3H, s, ar–H), 10.16 (1H, s, NH), 10.38 (1H,
123

Med Chem Res (2012) 21:212–223
217
s, NH), 10.93 (1H, s, NH); 13C NMR (DMSOd6) d (ppm):
23.89 (tryp-CH2), 30.18 (benzyl-CH2), 42.09 (tryp-CH2),
45.69 (CH2), ar–C: [110.14 (C), 111.49 (C), 117.99 (C),
118.56 (C), 121.17 (C), 123.31 (C), 126.81 (C), 127.76 (C),
128.42 (2C), 129.57 (C), 129.91 (2C), 130.47 (C), 131.62
(C), 132.46 (C), 133.74 (C), 136.12 (C), 138.08 (C), 145.20
(C)], 153.72 (triazole C-3), 165.80 (triazole C-5), 170.85
(C=O).
N0-(4-Chlorophenylsulfonyl)-2-{4-[2-(1H-indol-3-
yl)ethyl]-3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-
triazol-1-yl}acetohydrazide (3d)
Yield 83%, mp. 203–205°C; Anal. Calcd. (%) for:
C28H27ClN6O4S: C, 58.08, H, 4.70, N, 14.51, S, 5.54,
Found; C, 58.15, H, 4.75, N, 14.83, S, 5.63; IR (KBr, m,
cm-1): 3225, 3180 (NH), 2932, 2856 (CH2), 1706, 1692
1
(C=O); H NMR (DMSO-d6) d (ppm): 2.26 (3H, s, CH3),
2.80 (2H, t, tryp-CH2, J = 5.8 Hz), 3.40 (2H, s, DMSO-d6-
benzyl-CH2), 3.62 (2H, bs, tryp-CH2), 4.29 (2H, s, CH2),
6.85-6.89 (2H, m, ar–H), 6.95–7.07 (5H, m, ar–H),
7.35–7.39 (2H, m, ar–H), 7.48–7.64 (2H, m, ar–H),
7.73–7.85 (2H, m, ar–H), 10.17 (1H, s, NH), 10.41 (1H, s,
NH), 10.92 (1H, s, NH); 13C NMR (DMSO-d6) d (ppm):
20.56 (CH3), 23.87 (tryp-CH2), 30.56 (benzyl-CH2), 42.03
(tryp-CH2), 45.67 (CH2), ar–C: [110.17 (C), 111.46 (C),
118.02 (C), 118.49 (C), 121.14 (C), 123.26 (C), 126.82 (C),
128.36 (2C), 129.10 (2C), 129.51 (2C), 131.67 (2C),
136.00 (C), 136.15 (C), 137.65 (C), 137.96 (C), 145.58
(C)], 153.78 (triazole C-3), 165.83 (triazole C-5), 170.14
(C=O).
N0-(4-Chlorophenylsulfonyl)-2-{4-[2-(1H-indol-3-
yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-
triazol-1-yl}acetohydrazide (3b)
Yield 75%, mp. 192–193°C; Anal. Calcd. (%) for:
C27H24Cl2N6O4S: C, 54.10, H, 4.04, N, 14.02, S, 5.35,
Found; C, 54.17, H, 4.12, N, 14.14, S, 5.32; IR (KBr, m,
cm-1): 3252, 3145 (NH), 2973, 2856 (CH2), 1700, 1695
1
(–C=O); H NMR (DMSO-d6) d (ppm): 2.78 (2H, bs, trp-
CH2), 3.44 (2H, s, benzyl-CH2), 3.62 (2H, bs, tryp-CH2),
4.32 (2H, s, CH2), 7.12–7.18 (6H, m, ar–H), 7.36–7.45 (4H,
m, ar–H), 7.79 (3H, s, ar–H), 10.08 (1H, s, NH), 10.43 (1H,
s, NH), 10.92 (1H, s, NH); 13C NMR (DMSOd6) d (ppm):
23.94 (tryp-CH2), 29.18 (benzyl-CH2), 43.09 (tryp-CH2),
46.34 (CH2), ar–C: [110.43 (C), 111.28 (C), 117.96 (C),
118.58 (C), 121.17 (C), 123.36 (C), 126.89 (C), 127.74 (C),
128.49 (2C), 129.57 (C), 129.87 (2C), 130.43 (C), 131.62
(C), 132.56 (C), 133.78 (C), 136.12 (C), 138.18 (C), 146.68
(C)], 154.39 (triazole C-3), 165.82 (triazole C-5), 170.88
(C=O).
General method for the synthesis of compounds
4a–f and 7
A mixture of the corresponding compound 2 (for 4a–f) or
6b (for 7) (10 mmol) and appropriate aldehyde (10 mmol)
in absolute ethanol was refluxed for 3 h. After cooling the
mixture to room temperature, a white solid appeared. This
crude product recrystallized from dimethyl sulfoxide/water
(1:2). The obtained solid was washed several times with
water and dried in vacuum to yield the target product.
N0-(4-Bromophenylsulfonyl)-2-{4-[2-(1H-indol-3-yl)ethyl]-
3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-
yl}acetohydrazide (3c)
2-{4-[2-(1H-Indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-
4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-(4-
methoxyphenylmethyliden)acetohidrazide (4a)
Yield 80%, mp. 175–177°C; Anal. Calcd. (%) for: C28H27
BrN6O4S: C, 53.94, H, 4.36, N, 13.48, S, 5.14, Found; C,
53.84, H, 4.31, N, 13.52, S, 5.22; IR (KBr, m, cm-1): 3217,
3125 (NH), 2924, 2852 (CH2), 1710, 1690 (C=O); 1H
NMR (DMSO-d6) d (ppm): 2.25 (3H, s, CH3), 2.77 (2H, t,
tryp-CH2, J = 6.2 Hz), 3.42 (2H, s, benzyl-CH2), 3.61
(2H, t, tryp-CH2, J = 6.2 Hz), 4.28 (2H, s, CH2),
6.85–6.89 (3H, d, ar–H, J = 7.6), 6.94–7.12 (5H, m, ar–H),
7.34–7.39 (2H, m, ar–H), 7.59 (3H, s, ar–H), 10.15 (1H, s,
NH), 10.38 (1H, s, NH), 10.90 (1H, s, NH); 13C NMR
(DMSOd6) d (ppm): 20.55 (CH3), 23.83 (tryp-CH2), 30.55
(benzyl-CH2), 42.01 (tryp-CH2), 45.60 (CH2), ar–C:
[110.11 (C), 111.43 (C), 117.99 (C), 118.43 (C), 121.01
(C), 124.13 (C), 126.63 (C), 128.18 (2C), 129.07 (2C),
129.53 (2C), 131.65 (2C), 132.44 (C), 135.96 (C), 138.09
(C), 145.03 (C), 147.85 (C)], 153.72 (triazole C-3), 165.78
(triazole C-5), 170.18 (C=O).
Yield 78%, mp. 238–239°C; Anal. Calcd. (%) for:
C29H27N6O3Cl; IR (KBr, m, cm-1): 3339 (NH), 1707 (tri-
azole C=O), 1688 (hydrazide-C=O), 1607 (C=N); 1H NMR
(DMSO-d6) d (ppm): 2.84 (bs, 2H, tryp-CH2), 3.45 (s, 2H,
benzyl-CH2), 3.70 (bs, 2H, tryp-CH2), 3.79 (s, 3H, OCH3),
4.46, 4.85 (s, 2H, CH2), 6.96–7.14 (m, 7H, ar–H),
7.30–7.45 (m, 4H, ar–H), 7.65–7.68 (d, 2H, arH,
J = 7.0 Hz), 7.96 and 8.14 (s, 1H, cis–trans amid con-
formers), 10.95 (s, 1H, tryp-NH), 11.55 (d, 1H, NH). MS
(ESI): m/z (%) 543 (M, 82), 545 (M ? 2, 40), 565 (100),
357 (40), 229 (84). 13C NMR (DMSO-d6) d (ppm): 23.61
(trp-CH2), 32.46 (benzil-CH2), 42.34 (trp-CH2), 47.84 (N-
CH2), 55.42 (OCH3), ar–C: [111.90 (C), 112.56 (C), 115.94
(2C), 117.58 (C), 119.59 (C), 121.28 (C), 124.38 (C),
127.39 (C), 127.53 (C), 129.30 (2C), 129.67 (2C), 132.43
123

218
Med Chem Res (2012) 21:212–223
1
1687 (hydrazide-C=O), 1606(C=N); H NMR (DMSO-d6)
(2C), 135.71 (C), 136.90 (C), 161.56 (C), 163.98 (C)],
142.62 (–N=CH), 145.02 (triazol C-5), 155.39 (triazol
C-3), 168.28 (C=O).
d (ppm): 2.25 (s, 3H, CH3), 2.81 (t, 2H, tryp-CH2), 3.41 (s,
2H, benzyl-CH2), 3.66 (t, 2H, tryp-CH2), 3.79 (s, 3H,
OCH3), 4.87 (s, 2H, CH2), 6.86–7.15 (m, 9H, ar–H),
7.36–7.45 (m, 2H, ar–H), 7.84 (d, 2H, arH), 7.98, 8.16
(s, 1H, cis–trans amid conformers), 10.95 (s, 1H, tryp-NH),
11.56 (d, 1H, NH). 13C NMR (DMSO-d6) d (ppm): 21.28
(CH3), 24.61 (tryp-CH2), 31.27 (benzyl-CH2), 42.73 (tryp-
CH2), 46.94 (NCH2), 55.96 (OCH3), ar–C: [110.90 (C),
112.20 (C), 114.97 (2C), 118.79 (C), 119.23 (C), 121.88
(C), 124.08 (C), 127.21 (C), 127.53 (C), 129.11 (2C),
129.65 (2C), 132.48 (2C), 136.71 (C), 136.86 (C), 144.66
(C), 161.50 (C)], 146.30 (N=CH), 154.84 (triazole C-3),
163.70 (triazole C-5), 168.56 (C=O). MS (ESI): m/z (%)
523 ([M?]?1, 88), 545 ([M?]?Na, 100), 380 (24), 144
(28).
2-{4-[2-(1H-Indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-
4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-(2-
phenylethyliden)acetohydrazide (4b)
Yield 75%, mp. 242–243°C; Anal. Calcd. (%) for:
C29H28N7O3Cl : C, 62.42, H, 5.06, N, 17.57, Found; C,
62.32, H, 5.15, N, 17.43; IR (KBr, m, cm-1): 3305 (NH),
1
1697, 1710 (C=O), 1569 (C=N); H NMR (DMSO-d6) d
(ppm): 2.82 (bs, 2H, tryp-CH2), 3.42 (s, 2H, benzyl-CH2),
3.68 (bs, 2H, tryp-CH2), 4.27 (s, 2H, CH2), 4.42 (s, 2H,
CH2), 6.96–7.29 (m, 7H, ar–H), 7.31–7.42 (m, 7H, ar–H),
8.05 (s, 1H, NH), 9.26 (s, 1H, NH), 9.89 (s, 1H, NH), 10.95
(s, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 23.85 (tryp-
CH2), 31.07 (benzyl-CH2), 41.12 (trp-CH2), 42.14 (N–
CH2), 46.24 (CH2), ar–C: [110.05 (C), 111.76 (C), 115.19
(C), 116.89 (C), 117.55 (C), 118.38 (C), 120.56 (C), 121.13
(C), 123.36 (2C), 124.84 (2C), 125.72 (2C), 128.06 (2C),
129.18 (C), 131.56 (C), 136.08 (C), 137.89 (C)], 144.56
(triazole C-3), 145.02 (triazol C-5), 154.01 (triazol C-3),
167.98 (C=O). MS (ESI): m/z (%) 513 ([M?], 38), 535
(M ? Na, 100), 357 (20), 144 (34).
2-{4-[2-(1H-Indol-3-yl)ethyl]-3-(4-methylbenzyl)-5-oxo-
4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-(pyrrol-2-
ylmethyliden)acetohydrazide (4e)
Yield 88%, mp. 238–239°C; Anal. Calcd. (%) for:
C27H27N7O2; IR (KBr, m, cm-1): 3221, 3146 (NH), 1692
(triazole C=O), 1671 (hydrazide-C=O), 1577 (C=N); H
1
NMR (DMSO-d6) d (ppm): 2.28 (s, 3H, CH3), 2.83 (t, 2H,
tryp-CH2, 7.4 Hz), 3.44 (s, 2H, benzyl-CH2), 3.67 (t, 2H,
tryp-CH2, J = 7.4 Hz), 4.88 (s, 2H, CH2), 6.15 (t, 1H, ar–
H), 6.48 (bs, 1H, ar–H), 6.89–7.14 (m, 8H, ar–H),
7.38–7.47 (m, 2H, ar–H), 7.87, 8.08 (s, 1H, cis–trans amid
conformers), 10.97 (s, 1H, tryp-NH), 11.40, 11.52 (s, 2H,
2NH). 13C NMR (DMSO-d6) d (ppm): 20.52 (CH3), 23.81
(tryp-CH2), 30.48 (benzyl-CH2), 41.97 (tryp-CH2), 46.17
(NCH2), ar–C: [104.21 (C), 109.11 (C), 110.117 (C),
111.39 (C), 112.59 (C), 117.98 (C), 118.42 (C), 121.07 (C),
123.28 (C), 126.60 (C), 126.76 (C), 127.03 (C), 128.28
(2C), 129.06 (2C), 131.73 (C), 136.06 (C)], 145.50
(N=CH), 154.17 (triazole C-3), 162.40 (triazole C-5),
167.54 (C=O). MS (ESI): m/z (%) 482 (M ? 1, 46), 504
(M ? Na, 64), 345 (22), 229 (100), 108 (40).
2-{4-[2-(1H-Indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-
4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-(pyrrol-2-
ylmethyliden)acetohydrazide (4c)
IR (KBr, m, cm-1): 3280, 3110 (NH), 1693 (triazole C=O),
1668 (hydrazide-C=O), 1574 (C=N); 1H NMR (DMSO-d6)
d (ppm): 2.84 (t, 2H, tryp-CH2, 6.8 Hz), 3.47 (s, 2H, ben-
zyl-CH2), 3.74 (t, 2H, tryp-CH2, 6.8 Hz), 4.42, 4.84 (s, 2H,
CH2), 6.11 (s, 1H, ar–H), 6.44 (bs, 1H, ar–H), 6.90–7.14
(m, 6H, ar–H), 7.32–7.44 (m, 4H, ar–H), 7.83, 8.04 (s, 1H,
cis–trans amid conformers), 10.98 (s, 1H, trp-NH), 11.38,
11.42 (s, 2H, 2NH). 13C NMR (DMSO-d6) d (ppm): 24.66
(trp-CH2), 30.90 (benzil-CH2), 42.84 (tryp-CH2), 47.05
(N–CH2), ar–C: [109.93 (C), 110.91 (C), 112.23 (C),
113.42 (C), 118.76 (C), 119.31 (C), 121.92 (C), 122.66 (C),
124.14 (C), 127.41 (C), 127.58 (C), 129.16 (2C), 131.20
(2C), 132.33 (C), 134.61 (C), 136.87 (C)], 146.00 (N=CH),
154.93 (triazole C-3), 163.21 (triazole C-5), 168.32 (C=O).
MS (ESI): m/z (%) 502 ([M?]?1, 48), 524 (M ? Na, 100),
345 (22), 144 (28).
2-{4-[2-(1H-Indol-3-yl)ethyl]-3-(4-methylbenzyl)-5-oxo-
4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-(pyridin-2-
ylmethyliden)acetohydrazide (4f)
Yield 90%, mp. 244–245°C; Anal. Calcd. (%) for:
C28H27N7O2; IR (KBr, m, cm-1): 3327 (NH), 1704 (triazole
C=O), 1691 (hydrazide-C=O), 1581 (C=N); 1H NMR
(DMSO-d6) d (ppm): 2.25 (s, 3H, CH3), 2.80 (t, 2H, tryp-
CH2), 3.41 (s, 2H, benzyl-CH2), 3.66 (t, 2H, tryp-CH2),
4.53, 4.93 (s, 2H, CH2), 6.87 (d, 2H, ar–H), 6.97–7.14 (m,
5H, ar–H), 7.35–7.44 (t, 3H, ar–H, J = 8.2 Hz), 7.83–7.86
(t, 1H, ar–H), 7.92–8.01 (d, 2H, ar–H), 8.24 and 8.62 (s,
1H, cis–trans amid conformers), 10.95 (s, 1H, tryp-NH),
2-{4-[2-(1H-Indol-3-yl)ethyl]-3-(4-methylbenzyl)-
5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-
(4-methoxyphenylmethyliden)acetohydrazide (4d)
Yield 80%, mp. 256–257°C; Anal. Calcd. (%) for: C30H30
N6O3; IR (KBr, m, cm-1): 3323(NH), 1707 (triazole C=O),
123

Med Chem Res (2012) 21:212–223
219
11.92 (s, 1H, NH). 13C NMR (DMSO-d6) d (ppm): 21.30
(CH3), 24.64 (tryp-CH2), 31.27 (benzyl-CH2), 42.72 (tryp-
CH2), 46.93 (NCH2), ar–C: [110.88 (C), 112.19 (C), 118.78
(C), 119.20 (C), 120.60 (C), 121.87 (C), 124.06 (C), 125.07
(C), 127.55 (C), 129.07 (2C), 129.85 (2C), 132.51 (C),
136.70 (C), 136.86 (C), 137.58 (C), 150.18 (C), 153.25
(C)], 145.74 (N=CH), 154.78 (triazole C-3), 164.27 (tria-
zole C-5), 169.07 (C=O). MS (ESI): m/z (%) 494 ([M?]?1,
96), 516 ([M?]?Na, 98), 351 (32), 144 (38).
tryp-CH2, J = 6.4 Hz), 5.06 (2H, s, NCH2), 6.91–7.02 (5H,
m, ar–H), 7.28–7.36 (4H, m, ar–H), 10.91 (1H, s, NH),
13.49 (1H, s, SH). 13C NMR (DMSO-d6) d (ppm): 24.52
(tryp-CH2), 30.85 (benzyl-CH2), 41.37 (tryp-CH2), 43.18
(NCH2), ar–C: [110.87 (C), 112.22 (C), 118.54 (C), 119.32
(C), 121.88 (C), 124.05 (C), 127.59 (C), 129.17 (2C),
131.25 (2C), 132.35 (C), 134.22 (C), 136.82 (C)], 147.09
(triazole C-3), 153.96 (triazole C-5), 159.83 (oxadiazole C-
2), 178.71 (oxadiazole C-5); MS (ESI): m/z (%) 467
([M?]?1, 14), 203 (42), 143 (100).
4-[2-(1H-Indol-3-yl)ethyl]-5-(4-methylbenzyl)-2-{[4-(4-
methoxyphenylmethylidenamino) -5-sulfanyl-4H-1,2,4-
triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (7)
4-[2-(1H-Indol-3-yl)ethyl]-5-(4-methylbenzyl)-2-[(5-
sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dihydro-3H-
1,2,4-triazol-3-one (5b)
Yield 72%, mp. 211–212°C; Anal. Calcd. (%) for:
C31H30N8O2S: C, 64.32, H, 5.23, N, 19.36, S, 5.54, Found;
C, 64.42, H, 5.43, N, 19.38, S, 5.59; IR (KBr, m, cm-1):
3181 (NH), 2923, 2846 (CH2), 1689 (C=O); 1H NMR
(DMSO-d6) d (ppm): 2.17 (3H, s, CH3), 2.47 (3H, s, CH3),
2.82 (2H, s, tryp-CH2), 3.36 (2H, s, benzyl-CH2), 3.65 (2H,
s, tryp-CH2), 4.86 (2H, s, CH2), 6.92–7.24 (7H, m, ar–H),
7.27–7.79 (6H, m, ar–H), 9.82 (1H, s, CH), 10.53 (1H, s,
NH), 13.67 (1H, s, SH). 13C NMR (DMSO-d6) d (ppm):
21.37 (CH3), 23.46 (tryp-CH2), 32.25 (benzyl-CH2),
38.87–41.38 (DMSO-d6 ? tryp-CH2), 43.87 (NCH2),
55.52 (OCH3), ar–C: [110.66 (C), 111.18 (C), 112.21 (C),
112.34 (C), 115.52 (C), 118.78 (C), 119.24 (C), 120.94
(2C), 121.84 (C), 123.02 (C), 125.56(2C), 127.52 (C),
129.14 (2C), 129.86 (2C), 132.32 (C), 136.46 (C)], 142.18
(CH), 145.76 (triazole C-3), 148.58 (triazole C-5), 155.68
(oxadiazole C-2), 167.54 (oxadiazole C-5); MS (ESI): m/z
(%) 579 ([M?]?1, 25), 302 (10), 152 (100).
Yield 90%, mp. 158–159°C; Anal. Calcd. (%) for:
C23H22N6O2S: C, 61.87, H, 4.97, N, 18.82, S, 7.18, Found;
C, 61.82, H, 4.92, N, 18.88, S, 7.25; IR (KBr, m, cm-1):
3321 (NH), 2921, 2857 (CH2), 1694 (C=O); 1H NMR
(DMSO-d6) d (ppm): 2.24 (3H, s, CH3), 2.83 (2H, t, tryp-
CH2, 7.0 Hz), 3.46 (2H, bs, DMSO-d6 ? benzyl CH2),
3.71 (2H, t, tryp-CH2, J = -7.0 Hz), 5.09 (2H, s, NCH2),
6.83–6.87 (2H, m, ar–H), 6.96–6.99 (1H, m, ar–H),
7.03–7.10 (4H, m, ar–H), 7.33–7.38 (2H, m, ar–H), 10.92
(1H, s, NH), 13.85 (1H, s, SH). 13C NMR (DMSO-d6) d
(ppm): 21.24 (CH3), 24.35 (tryp-CH2), 31.14 (benzyl-
CH2), 41.04 (tryp-CH2), 43.21(NCH2), ar–C: [110.85 (C),
112.17 (C), 118.51 (C), 119.35 (C), 121.92 (C), 123.81 (C),
127.49 (C), 129.08 (2C), 129.87 (2C), 131.92 (C), 136.62
(C), 136.89 (C)], 147.61 (triazole C-3), 154.08 (triazole
C-5), 159.80 (oxadiazole C-2), 178.56 (oxadiazole C-5);
MS (ESI): m/z (%) 447 ([M?]?1, 10), 405 (35), 143 (100).
General method for the synthesis of compounds 5a, b
General method for the synthesis of compounds 6a, b
The corresponding compound 2 (10 mmol) and CS2
(0.60 ml, 10 mmol) were added to a solution of KOH
(0.56 g, 10 mol) in 50 ml H2O and 50 ml ethanol. The
reaction mixture was allowed to reflux for 3 h. Then, the
reaction content was acidified with conc. HCl. The pre-
cipitate formed was filtered off, washed with H2O and
recrystallized from ethanol to afford the desired compound.
The mixture of corresponding compound 5 (10 mmol) and
hydrazine hydrate (25 mmol) in ethanol was heated under
reflux with stirring for 2 h, then reaction was maintained at
room temperature for an additional 3 h. Water added to the
reaction mixture and was left to cool overnight. The pre-
cipitate formed was filtered off and recrystallized from
ethanol: water (1:4) to obtain the target compound.
4-[2-(1H-Indol-3-yl)ethyl]-5-(4-chlorobenzyl)-2-[(5-
sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dihydro-3H-
1,2,4-triazol-3-one (5a)
4-[2-(1H-Indol-3-yl)ethyl]-5-(4-chlorobenzyl)-2-[(4-
amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-2,4-
dihydro-3H-1,2,4-triazol-3-one (6a)
Yield 92%, mp. 165–166°C; Anal. Calcd. (%) for:
C22H19ClN6O2S: C, 56.59, H, 4.10, N, 18.00, S, 6.87,
Found; C, 56.55, H, 4.17, N, 18.12, S, 6.84; IR (KBr, m,
Yield 78%, mp. 189–190°C; Anal. Calcd. (%) for: C22H21
ClN8OS: C, 54.94, H, 4.40, N, 23.30, S, 6.67, Found; C,
54.90, H, 4.43, N, 23.28, S, 6.62; IR (KBr, m, cm-1): 3277,
1
1
cm-1): 3330 (NH), 2950, 2776 (CH2), 1682 (C=O); H
3079 (NH), 2924 (CH2), 1685 (C=O); H NMR (DMSO-
NMR (DMSO-d6) d (ppm): 2.82 (2H, s, tryp-CH2),
3.42 (2H, bs, DMSO-d6 ? benzyl CH2), 3.66–3.70 (2H, d,
d6) d (ppm): 2.78 (2H, s, tryp-CH2), 3.46 (2H, s, benzyl-
CH2), 3.65 (2H, d, tryp-CH2), 4.95 (2H, s, NCH2), 5.57
123

220
Med Chem Res (2012) 21:212–223
(2H, s, NH2), 6.65–7.06 (5H, m, ar–H), 7.28–7.33 (4H, m,
ar–H), 10.90 (1H, s, NH), 13.71 (1H, s, SH). 13C NMR
(DMSO-d6) d (ppm): 23.83 (tryp-CH2), 30.13 (benzyl-
CH2), 38.07–40.58 (DMSO-d6 ? tryp-CH2), 42.14
(NCH2), ar–C: [110.05 (C), 111.42 (C), 117.90 (C), 118.48
(C), 121.10 (C), 123.30 (C), 126.75 (C), 128.41 (2C),
130.38 (2C), 131.53 (C), 133.72 (C), 136.04 (C)], 145.61
(triazole C-3), 147.57 (triazole C-5), 153.42 (oxadiazole C-
2), 166.35 (oxadiazole C-5); MS (ESI): m/z (%) 483
(M ? 2, 100), 503 (M ? Na, 18), 156 (30).
(ppm): 2.25 (3H, s, CH3), 2.58 (2H, t, tryp-CH2,
J = 6.8 Hz), 3.63 (2H, t, tryp-CH2, J = 7.0 Hz), 4.23 (2H,
s, CH2), 4.43 (2H, s, CH2), 6.85–6.99 (2H, m, ar–H),
7.03–7.27 (5H, m, ar–H), 7.30–7.41 (6H, m, ar–H), 8.05
(1H, s, ar–H), 9.90 (1H, s, NH), 10.93 (1H, s, NH). 13C
NMR (DMSO-d6) d (ppm): 21.58 (CH3), 22.74 (tryp-CH2),
31.52 (benzyl-CH2), 38.49–40.24 (DMSO-d6 ? CH2),
41.46 (tryp-CH2), 42.48 (CH2), ar–C: [110.10 (C), 111.38
(C), 117.64 (2C), 118.44 (2C), 121.13 (C), 123.06 (2C),
126.34 (C), 127.28 (C), 128.76 (2C), 129.13 (C), 129.38
(2C), 131.34 (C), 132.74 (C), 136.17 (C), 136.18 (C)],
146.44 (triazole C-3), 147.26 (triazole C-3), 152.56 (tria-
zole C-5), 168.42 (triazole C-5); MS (ESI): m/z (%) 520
([M?]?1, 62), 405 (56), 229 (40), 143 (100).
4-[2-(1H-Indol-3-yl)ethyl]-5-(4-methylbenzyl)-2-[(4-
amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-2,4-
dihydro-3H-1,2,4-triazol-3-one (6b)
Yield 69%, mp. 180–185°C; Anal. Calcd. (%) for:
C23H24N8OS: C, 59.98, H, 5.25, N, 24.33, S, 6.96, Found;
C, 59.92, H, 5.21, N, 24.38, S, 6.98; IR (KBr, m, cm-1):
3373, 3269, 3170 (NH ? NH2), 2923 (CH2), 1686 (C=O);
1H NMR (DMSO-d6) d (ppm): 2.21 (3H, s, CH3), 2.74 (2H,
s, tryp-CH2), 3.52 (2H, s, benzyl-CH2), 3.60 (2H, s, tryp-
CH2), 4.95 (2H, s, CH2), 5.78 (2H, s, NH2), 6.87–7.04 (7H,
m, ar–H), 7.31–7.42 (2H, m, ar–H), 10.88 (1H, s, NH),
13.70 (1H, s, SH). 13C NMR (DMSO-d6) d (ppm): 21.30
(CH3), 24.56 (tryp-CH2), 31.28 (benzyl-CH2), 38.82–41.33
(DMSO-d6? tryp-CH2), 42.87 (NCH2), ar–C: [110.85 (C),
113.21 (C), 112.17 (C), 118.70 (C), 119.18 (C), 121.85 (C),
124.02 (C), 127.52 (C), 129.04 (2C), 129.87 (2C), 132.38
(C), 136.74 (C)], 146.77 (triazole C-3), 148.37 (triazole C-
5), 154.21 (oxadiazole C-2), 167.10 (oxadiazole C-5); MS
(ESI): m/z (%) 460 (M, 35), 461 ([M?]?1, 58), 148 (100).
3-Chlorobenzyl-2-({4-[2-(1H-indol-3-yl)ethyl]-5-oxo-4,5-
dihydro-1H-1,2,4-triazol-1-yl}acetyl)-N-
benzylhydrazinecarboxamide (9a)
Yield 75%, mp. 242–243°C; Anal. Calcd. (%) for:
C29H28N7O3Cl : C, 62.42, H, 5.06, N, 17.57, Found; C,
62.32, H, 5.15, N, 17.43; IR (KBr, m, cm-1): 3305 (NH),
1
1697, 1710 (C=O), 1569 (C=N); H NMR (DMSO-d6) d
(ppm): 2.82 (bs, 2H, tryp-CH2), 3.42 (s, 2H, benzyl-CH2),
3.68 (bs, 2H, tryp-CH2), 4.27 (s, 2H, CH2), 4.42 (s, 2H,
CH2), 6.96–7.29 (m, 7H, ar–H), 7.31–7.42 (m, 7H, ar–H),
8.05 (s, 1H, NH), 9.26 (s, 1H, NH), 9.89 (s, 1H, NH), 10.95
(s, 1H, NH). 13C NMR (DMSO-d6) d (ppm): 23.85 (tryp-
CH2), 31.07 (benzyl-CH2), 41.12 (tryp-CH2), 42.14
(NCH2), 46.24 (CH2), ar–C: [110.05 (C), 111.76 (C),
115.19 (C), 116.89 (C), 117.55 (C), 118.38 (C), 120.56 (C),
121.13 (C), 123.36 (2C), 124.84 (2C), 125.72 (2C), 128.06
(2C), 129.18 (C), 131.56 (C), 136.08 (C), 137.89 (C)],
144.56 (triazole C-3), 153.82 (triazole C-5), 165.74 (C=O),
175.61 (C=O); MS (ESI): m/z (%) 558.10 (M, 15), 425
(20), 168 (40), 156 (100).
General method for the synthesis of compounds 8, 9a
and 9b
A mixture of the corresponding compound 2 (10 mmol)
and phenyl isothiocyanate (for compound 9b) or benzy-
lisothiocyanate (for compounds 8 and 9a) (15 mmol) was
refluxed in ethanol for 4 h. On cooling the resulting solu-
tion to room temperature, a white solid was obtained. This
crude product was filtered and recrystallized from ethanol
(9a, b) or dimethyl sulfoxide/water (8) (1:2) to afford the
desired product.
Synthesis of 5-(4-methylbenzyl)-4-[2-(1H-indol-3-yl)ethyl]-
2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-
yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (10)
A solution of compound 9a (10 mmol) in 2 N NaOH was
heated under reflux for 3 h. The resulting solution was
allowed to reach to room temperature and acidified to pH
3–4 with 37% HCl. The precipitate formed was filtered off,
washed with water and recrystallized from ethanol/water
(1:1) to afford the desired compound. Yield 85%, mp.
206–208°C; Anal. Calcd. (%) for: C29H26ClN7O2: C,
64.50, H, 4.85, N, 18.16, Found; C, 64.73, H, 4.80, N,
18.22; IR (KBr, m, cm-1): 3232 (NH), 2950, 2845 (CH2),
5-(4-Chlorobenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-
benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-
2,4-dihydro-3H-1,2,4-triazol-3-one (8)
Yield 88%, mp. 204–205°C; Anal. Calcd. (%) for:
C30H29N7O2: C, 69.35, H, 5.63, N, 18.87, Found; C, 68.72,
H, 5.58, N, 18.72; IR (KBr, m, cm-1): 3241 (NH), 2952,
1
1712, 1690 (C=O); H NMR (DMSO-d6) d (ppm): 2.56
(2H, t, tryp-CH2, J = 6.8 Hz), 3.60 (2H, t, trp-CH2,
1
2851 (CH2), 1709, 1684 (C=O); H NMR (DMSO-d6) d
123

Med Chem Res (2012) 21:212–223
221
2-{4-[2-(1H-Indol-3-yl)ethyl]-3-(4-methylbenzyl)-5-oxo-
J = 7.0 Hz), 4.14 (2H, s, CH2), 4.48 (2H, s, CH2),
6.80–6.92 (2H, m, ar–H), 7.13–7.32 (5H, m, ar–H),
7.35–7.55 (6H, m, ar–H), 8.02 (1H, s, ar–H), 9.87 (1H, s,
NH), 10.95 (1H, s, NH). 13C NMR (DMSO-d6) d (ppm):
22.45 (tryp-CH2), 30.52 (benzyl-CH2), 38.49–40.24 (DMSO-
d6? CH2), 41.32 (tryp-CH2), 43.57 (CH2), ar–C: [110.17 (C),
111.35 (C), 117.56 (2C), 118.44 (2C), 121.13 (C), 123.12
(2C), 126.65 (C), 127.28 (C), 128.76 (2C), 129.13 (C), 129.38
(2C), 131.34 (C), 132.74 (C), 135.68 (C), 136.22(C)],
145.45 (triazole C-3), 147.84 (triazole C-3), 153.36 (tria-
zole C-5), 165.3642 (triazole C-5); MS (ESI): m/z (%) 542
(M?2, 15), 464 (24), 176 (25), 148 (100).
4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-[3-phenyl-4-(4-
chlorophenyl)-1,3-thiazol-2(3H)-ylidene]acetohydrazide
(11b)
Yield 75%, mp. 170–171°C; Anal. Calcd. (%) for:
C37H32N7O2SCl: C, 65.91, H, 4.78, N, 14.54, S, 4.76,
Found; C, 65.88, H, 4.75, N, 14.56, S, 4.72; IR (KBr, m,
cm-1): 3255, 3241 (NH), 2978, 2838 (CH2), 1719, 1685
1
(C=O); H NMR (DMSO-d6) d (ppm): 2.25 (3H, s, CH3),
2.43 (2H, t, tryp-CH2, J = 6.8 Hz), 3.60 (2H, t, tryp-CH2,
J = 7.0 Hz), 3.92 (2H, s, CH2), 4.33 (2H, s, CH2), 4.92
(1H, s, thiazole), 6.92 (1H, bs, ar–H), 7.10–7.55 (10H, m,
ar–H), 7.66–7.82 (5H, m, ar–H), 8.05 (2H, s, ar–H), 9.86
(1H, s, NH), 10.22 (1H, s, NH). 13C NMR (DMSO-d6) d
(ppm): 20.51 (CH3), 22.64 (tryp-CH2), 30.65 (benzyl-
CH2), 38.49–40.24 (DMSO-d6? CH2), 40.46 (tryp-CH2),
40.58 (thiazole C5), 42.48 (CH2), ar–C:[110.12 (C), 111.38
(C), 116.96 (2C), 118.65 (2C), 122.34 (2C), 123.45 (2C),
125.94 (CH ? thiazole C5), 126.34 (C), 127.28 (C),
128.76 (2C), 129.13 (C), 129.38 (2C), 131.34 (C), 132.74
(C), 136.17 (2C), 136.18 (2C), 135.12 (C)], 150.12 (tria-
zole C-3), 151.84 (triazole C-3), 152.48 (thiazole C-4),
153.94 (thiazole C-2), 191.14 (C=O); MS (ESI): m/z (%)
675 ([M?]?1, 45), 415 (85), 229 (34), 143 (100).
General method for the synthesis of compounds 11a
and 11b
The mixture of corresponding compound 9 (10 mmol),
4-chlorophenacyl bromide (10 mmol) and in ethanol was
refluxed in the presence of dried sodium acetate
(200 mmol) for 8 h. Then, the reaction content was cooled
to room temperature, poured into ice-cold water while
stirring and left overnight in cold. The formed solid was
filtered, washed with water three times and recrystallized
from dimethyl sulfoxide-water (1:1) to afford pure
compounds.
Antimicrobial activity assessment
All bacterial and yeast strains were obtained from the
Hifzissihha Institute of Refik Saydam (Ankara, Turkey)
and were as follows: Pseudomonas aeruginosa ATCC
27853, Enterococcus faecalis ATCC 29212, S. aureus
ATCC 25923, B. cereus 709 ROMA, Ms: Mycobacterium
smegmatis ATCC607, C. albicans ATCC 60193, Sc: Sac-
charomyces cerevisiae RSKK 251. All the newly synthe-
sized compounds were dissolved in dimethyl sulfoxide
(DMSO) and ethanol to prepare chemicals of stock solution
of 10 mg/1 ml.
3-(4-Chlorobenzyl)-2-{4-[2-(1H-indol-3-yl)ethyl]-5-oxo-
4,5-dihydro-1H-1,2,4-triazol-1-yl}-N0-[3-benzyl-4-(4-
chlorophenyl)-1,3-oxazol-2(3H)-ylidene]acetohydrazide
(11a)
Yield 82%, mp. 167–168°C; Anal. Calcd. (%) for:
C35H31N7O3Cl2: C, 64.16, H, 4.51, N, 14.16, Found; C,
64.22, H, 4.61, N, 14.20; IR (KBr, m, cm-1): 3240, 3233
(NH), 2975, 2842 (CH2), 1715, 1688 (C=O); 1H NMR
(DMSO-d6) d (ppm): 2.82 (2H, bs, tryp-CH2), 3.44 (2H, s,
CH2), 3.67 (2H, bs, tryp-CH2), 4.22 (2H, s, CH2), 4.41 (2H,
s, CH2), 5.47 (1H, s, thiazole), 6.96–7.38 (15H, m, ar–H),
7.61–7.65 (1H, d, ar–H, J = 7.4 Hz), 7.95–8.03 (2H, t, ar–
H, J = 7.4 Hz), 9.87 (1H, s, NH), 10.93 (1H, s, NH). 13C
NMR (DMSO-d6) d (ppm): 23.45 (tryp-CH2), 31.46 (ben-
zyl-CH2), 38.42–40.24 (DMSO-d6 ? CH2), 41.46 (tryp-
CH2), 41.84 (thiazole C5), 45.70 (CH2), ar–C: [110.124(C),
111.42 (C), 116.96 (2C), 118.60 (2C), 121.34 (2C), 122.49
(2C), 124.82 (CH ? thiazole C5), 126.62 (C), 127.58 (C),
128.73 (2C), 129.39 (C), 129.69 (2C), 131.50 (C), 132.72
(C), 135.29 (2C), 136.91 (2C), 136.98 (C)], 150.15 (tria-
zole C-3), 151.3 (triazole C-3), 152.68 (thiazole C-4),
153.92 (thiazole C-2), 190.44 (C=O); MS (ESI): m/z (%)
693 ([M?]?1, 32), 715 (M ? Na, 58).
Agar-well diffusion method
Simple susceptibility screening test using agar-well diffu-
sion method as adapted earlier (Ahmad et al., 1998) was
used. Each microorganism was suspended in Mueller–
Hinton (MH) (Difco, Detroit, MI) broth and diluted
approximately to 106 colony forming unit (cfu)/ml. They
were ‘flood-inoculated’ onto the surface of MH agar and
Sabouraud Dextrose Agar (SDA) (Difco, Detriot, MI) and
then dried. For C. albicans and C. tropicalis, SDA were
used. Five-millimetre diameter wells were cut from the
agar using a sterile cork-borer, and 50 ml of the extract
substances was delivered into the wells. The plates were
incubated for 18 h at 35°C. Antimicrobial activity was
123

222
Med Chem Res (2012) 21:212–223
Bektas H, Karaali N, Sahin D, Demirbas¸ A, Alpay-Karaoglu S,
Demirbas N (2010a) Synthesis of some new 1,2,4-triazoles
starting from isonicotinic acid hydrazide and evaluation of their
antimicrobial activities. Molecules 15:2427–2438
Table 1 Screening for antimicrobial activity of the compounds
(50 ll)
Compound
no.
Microorganisms and inhibition zone (mm)
Bektas H, Demirbas N, Demirbas A, Alpay-Karaoglu S (2010b)
Synthesis of some new biheterocyclic triazole derivatives and
evaluation of their antimicrobial activity. Turk J Chem 34:165–180
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
Cai S, Li QS, Borchardt RT, Kuczera K, Schowen RL (2007) The
antiviral drug ribavirin is a selective inhibitor of S-adenosyl-l-
homocysteine hydrolase from Trypanosoma cruzi. Bioorg Med
Chem 15:7281–7287
Cui Y, Dang Y, Yang Y, Zhang S, Ji R (2005) Syntheses and
antibacterial activity of a series of 3-(pyridine-3-yl)-2-oxazolid-
inone. Eur J Med Chem 40:209–214
Das B, Rudra S, Yadav A, Raj A, Rao AVSR, Srinivas ASSV, Soni A,
Saini S, Shukla S, Pandya M, Bhateja P, Malhotra S, Mathur T,
Arora SK, Rattan A, Mehta A (2005) Synthesis and SAR of
novel oxazolidinones: discovery of ranbezolid. Bioorg Med
Chem Lett 15:4261–4267
Pa
Sa
Ef
–
Bc
Ms
3a
12
12
10
10
–
8
11
–
12
12
8
9
14
7
3b
3c
–
–
3d
4c
7
10
–
9
–
–
6
5a
–
8
10
12
–
6
–
5b
6a
–
12
–
8
8
–
7
7
6b
7
–
–
–
7
6
12
6
11
–
–
12
7
6
8
–
10
–
9a
–
–
–
–
9b
10
–
–
–
–
–
Demirbas A, Johansson CB, Duman N, Ikizler AA (1996) Synthesis
and biological activities of some 4,5-dihydro-1H-1,2,4-triazol-5-
one derivatives. Acta Pol Pharm 53:117–123
10
–
–
–
12
6
10
–
11a
11b
Amp.
Strep.
5
–
Demirbas N, Ugurluoglu R, Demirbas A (2002) Synthesis of
3-alkyl(aryl)-4-alkylidenamino-4,5-dihydro-1H–1,2,4-triazol-5-
ones and 3-alkyl-4-alkylamino-4,5-dihydro-1H–1,2,4-triazol-5-
ones as antitumor agents. Bioorg Med Chem 10:3717–3723
Demirbas N, Demirbas A, Alpay-Karaoglu S, C¸ elik E (2005) Synthesis
and antimicrobial activities of some new [1,2,4] triazolo[3,4-b]
[1,3,4]thiadiazoles and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines.
Arkivoc i:75–91
Demirbas A, Ceylan S, Demirbas N (2007) Synthesis of some new
five membered heterocycles, a facile synthesis of oxazolidinon-
es. J Heterocycl Chem 44:1271–1280
Demirbas A, Sahin D, Demirbas N, Alpay-Karaoglu S (2009)
Synthesis of some new 1,3,4-thiadiazol-2-ylmethyl-1,2,4-tria-
zole derivatives and investigation of their antimicrobial activi-
ties. Eur J Med Chem 44:2896–2903
–
–
–
–
–
18
35
10
15
35
Ms, Mycobacterium smegmatis ATCC607; Pa, Pseudomonas aeru-
ginosa ATCC 43288; Sa, Staphylococcus aureus ATCC 25923; Ef,
Enterococcus faecalis ATCC 29212; Bc, Bacillus cereus 702 Roma;
Amp., ampicillin; Strep., streptomycin; –, no activity
evaluated by measuring the zone of inhibition against the
test organism. Ampicillin (10 mg) and Fluconazole (5 mg)
were used as standard drugs. Dimethyl sulfoxide and eth-
anol were used as solvent controls. The antimicrobial
activity results are summarized in Table 1.
Dixit PP, Patil VJ, Nair PS, Jain S, Sinha N, Arora SK (2006) Synthesis
of 1-[3-(4-benzotriazol-1/2-yl-3-fluoro-phenyl)-2-oxo-oxazoli-
din-5-ylmethyl]-3-substituted-thiourea derivatives as antituber-
culosis agents. Eur J Med Chem 41:423–428
Acknowledgments This project was supported by Scientific and
Technological Research Council of Turkey (TUBITAK, Project no:
107T333) and Karadeniz Technical University, BAP, Turkey (Ref.
No. 2007.111.002.6) and is gratefully acknowledged.
´
Ezabadi IR, Camoutsis C, Zoumpoulakis P, Geronikaki A, Sokovic
ˇ
´
M, Glamocilija J, Ciric A (2008) Sulfonamide-1,2,4-triazole
derivatives as antifungal and antibacterial agents: synthesis,
biological evaluation, lipophilicity, and conformational studies.
Bioorg Med Chem 16:1150–1161
References
´
Giraud F, Guillon R, Loge C, Pagniez F, Picot C, Le Borgne M, Le Pape P
(2008) Design, synthesis, and evaluation of 1-(N-benzylamino)-2-
phenyl-3(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents.
Bioorg Med Chem Lett 18:1820–1824
Ahmad I, Mehmood Z, Mohammed F (1998) Screening of some
Indian medicinal plants for their antimicrobial properties.
J Ethnopharmacol 62:183–193
´
GiraudF, Guillon R, LogeC, Pagniez F, Picot C, LeBorgneM, LePapeP
(2009) Synthesis and structure-activity relationships of 2-phenyl-1-
[(pyridinyl- and piperidinylmethyl)amino]-3-(1H–1,2,4-triazol-1-
yl)propan-2-ols as antifungal agents. Bioorg Med Chem Lett 19:
301–304
Ashok M, Holla BS, Poojary B (2007) Convenient one pot synthesis
and antimicrobial evaluation of some new Mannich bases
carrying 4-methylthiobenzyl moiety. Eur J Med Chem 42:
1095–1101
Gupta A, Unadkat JD, Mao Q (2007) Interface interactions of azole
antifungal agents with the human breast cancer resistance
protein. J Pharm Sci 96:3226–3235
Hancu G, Gaspar A, Gyeresi A (2007) Separation of 1,4-benzodi-
azepines by micellar electrokinetic capillary chromatography.
J Biochem Biophys Methods 69:251–259
Bayrak H, Demirbas A, Demirbas N, Alpay-Karaoglu S (2009a)
Synthesis of some new 1,2,4-triazoles, their Mannich and Schiff
bases and evaluation of their antimicrobial activities. Eur J Med
Chem 44:1057–1066
Bayrak H, Demirbas A, Demirbas N, Alpay-Karaoglu S (2009b)
Synthesis of some new 1,2,4-triazoles starting from isonicotinic
acid hydrazide and evaluation of their antimicrobial activities.
Eur J Med Chem 44:4362–4366
Hester SD, Nesnow S (2008) Transcriptional responses in thyroid
tissues from rats treated with a tumorigenic and a non-
123

Med Chem Res (2012) 21:212–223
223
tumorigenic triazole conazole fungicide. Toxicol Appl Pharm
227:357–369
Holla BS, Poojary NK, Rao SB, Shivananda MK (2002) New bis-
aminomercaptotriazoles and bis-triazolothiadiazoles as possible
anticancer agents. Eur J Med Chem 37:511–517
Ikizler AA, Uzunali E, Demirbas¸ A (2000) Synthesis of some 1,2,4-
triazole derivatives as potential antitumor agents. Indian J Pharm
Sci 5:289–292
Isloor AM, Kalluraya B, Shetty P (2009) Regioselective reaction:
synthesis, characterization and pharmacological studies of some
new Mannich bases derived from 1,2,4-triazoles. Eur J Med
Chem 44:3784–3787
Rostom SAF, Ashour HMA, Abd El Razik HA (2009) Azole
antimicrobial pharmacophore-based tetrazoles: synthesis and
biological evaluation as potential antimicrobial and anticonvul-
sant agents. Bioorg Med Chem 17:2410–2422
Sahoo PK, Sharma ER, Pattanayak EP (2010) Synthesis and evaluation
of 4-amino-5-phenyl-4H-[1,2,4]-triazole-3-thiol derivatives as
antimicrobial agents. Med Chem Res 19:127–135
Sawa M, Mizuno K, Harada H, Tateishi H, Arai Y, Suzuki S, Oue M,
Tsujiuchi H, Furutanic Y, Kato S (2005) Tryptamine-based
human beta 3-adrenergic receptor agonists. Part 3: improved oral
bioavailability via modification of the sulfonamide moiety.
Bioorg Med Chem Lett 15:1061–1064
Jenkins PR, Wilson J, Emmerson D, Garcia MD, Smith MR, Gray SJ,
Britton RG, Mahale S, Chaudhuri B (2008) Design, synthesis
and biological evaluation of new tryptamine and tetrahydro-beta-
carboline-based selective inhibitors of CDK4. Bioorg Med Chem
16:7728–7739
Schiller SD, Fung HB (2007) Posaconazole: an extended-spectrum
triazole antifungal agent. Clin Ther 29:1862–1886
Solomon VR, Hua C, Lee H (2010) Design and synthesis of anti-breast
cancer agents from 4-piperazinylquinoline: a hybrid pharmaco-
phore approach. Bioorg Med Chem 18:1563–1572
¨
Kaplancikli ZA, Turan-Zitouni G, Ozdemir A, Revial G (2008) New
triazole and triazolothiadiazine derivatives as possible antimi-
crobial agents. Eur J Med Chem 43:155–159
Karthikeyan MK, Prasad DJ, Poojary B, Bhat KS, Holla BS, Kumari
NS (2006) Synthesis and biological activity of Schiff and
Mannich bases bearing 2,4-dichloro-5-fluorophenyl moiety.
Bioorg Med Chem 14:7482–7489
Kobeci GC, Slatford PA, Whittlesey MK, Williams JMJ (2005)
N-alkylation of phenethylamine and tryptamine. Bioorg Med
Chem Lett 15:535–537
Kuc¸ukguzel SG, Rollas S, Erdeniz H, Kiraz M (1999) Synthesis,
characterization and antimicrobial evaluation of ethyl 2-arylhy-
drazono-3-oxobutyrates. Eur J Med Chem 34:153–160
Ozdemir A, Zitouni GT, Kaplancikli ZA, Revial G, Guven K (2007)
Synthesis and antimicrobial activity of 1-(4-aryl-2-thiazolyl)-3-
(2-thienyl)-5-aryl-2-pyrazoline derivatives. Eur J Med Chem
42:403–409
Rao BM, Sangaraju S, Srinivasu MK, Madhavan P, Devi ML, Kumar
PR, Chandrasekhar KB, Arpitha C, Balaji TS (2006) Develop-
ment and validation of a specific stability indicating high
performance liquid chromatographic method for rizatriptan
benzoate. J Pharm Biomed Anal 41:1146–1151
Rawal RK, Phabhakar YS, Kati SB, De Clercq E (2005) 2-(Aryl)-3-
furan-2-ylmethyl-thiazolidin-4-ones as selective HIV-RT inhib-
itors. Bioorg Med Chem 13:6771–6776
Rawal RK, Tripathi R, Kati SB, Pannecouque C, De Clercq E (2007)
Design, synthesis, and evaluation of 2-aryl-3-heteroaryl-1,3-
thiazolidin-4-ones as anti-HIV agents. Bioorg Med Chem 15:
1725–1731
Tozkoparan B, Gokhan N, Aktay G, Yes¸ilada E, Ertan M (2000)
6-Benzylidenethiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substi-
tuted with ibuprofen: synthesis, characterization and evaluation
of anti-inflammatory activity. Eur J Med Chem 35:743–750
Tuncbilek M, Kiper T, Altanlar N (2009) Synthesis and in vitro
antimicrobial activity of some novel substituted benzimidazole
derivatives having potent activity against MRSA. Eur J Med
Chem 44:1024–1033
Turan-Zitouni G, Sıvacı M, Kılıc¸ FS, Erol K (2001) Synthesis of some
triazolyl-antipyrine derivatives and investigation of analgesic
activity. Eur J Med Chem 36:685–689
Weidinger-Wells MA, Boggs CM, Foleno BD, Melton J, Bush K,
Goldschmidt RM, Hlasta DJ (2002) Novel piperidinyloxy
oxazolidinone antibacterial agents. Diversification of the N-sub-
stituent. Bioorg Med Chem 10:2345–2351
Yamazaki Y, Kawano Y, Yamanaka A, Maruyama
S (2009)
N-[(Dihydroxyphenyl)acyl]serotonins as potent inhibitors of
tyrosinase from mouse and human melanoma cells. Bioorg
Med Chem Lett 19:4178–4182
Yu LT, Ho MT, Chang CY, Yang TK (2007) Asymmetric zinc-
Reformatsky reaction of Evans chiral imide with acetophenones
and its application to the stereoselective synthesis of triazole
antifungal agents. Tetrahedron 18:949–962
Yuksek H, Demirbas¸ A, Ikizler A, Johansson CB, C¸ elik C, Ikizler AA
(1997) Synthesis and antibacterial activities of some 4,5-
dihydro-1H-1,2,4-triazol-5-ones. Arzn-Forsh Drug Res 47:405–
409
123