Synthesis of 1H-1,2,3-triazole linked β-lactam-isatin bi-functional hybrids and preliminary analysis of in vitro activity against the protozoal parasite Trichomonas vaginalis

Article abstract of DOI:10.1016/j.ejmech.2013.03.019

Twenty-two different triazoles were prepared to examine the anti-Trichomonas vaginalis structure-activity relationships (SAR) within the β-lactam-isatin-triazole conjugate family. The compounds were synthesized by copper-catalyzed 'click chemistry.' In vi

Full text of DOI:10.1016/j.ejmech.2013.03.019

European Journal of Medicinal Chemistry 63 (2013) 897e906
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis of 1H-1,2,3-triazole linked b-lactameisatin bi-functional
hybrids and preliminary analysis of in vitro activity against the
protozoal parasite Trichomonas vaginalis
a
a
b
b
b
Raghu Raj , Pardeep Singh , Nathan T. Haberkern , Ryan M. Faucher , Neal Patel ,
b
a,
*
Kirkwood M. Land , Vipan Kumar
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
a
b
Department of Biological Sciences, University of the Pacific, Stockton, CA 95211, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 November 2012
Received in revised form
Twenty-two different triazoles were prepared to examine the anti-Trichomonas vaginalis structureeactivity
relationships (SAR) within the
sized by copper-catalyzed ‘click chemistry.’ In vitro activity against T. vaginalis was determined at 10 and
00 M for each compound, with eighteen of the synthesized hybrids showing 100% growth inhibition at
00 M. The compound 5i, with no cytotoxicity on cultured CHO-K1 cells, is considered a good compound
for further analysis.
b-lactameisatinetriazole conjugate family. The compounds were synthe-
28 February 2013
1
m
Accepted 9 March 2013
Available online 16 March 2013
1
m
Ó 2013 Elsevier Masson SAS. All rights reserved.
Keywords:
Click chemistry
b
1
-Lactameisatin conjugates
H-1,2,3-Triazole
Trichomonas vaginalis
Cytotoxicity
1
. Introduction
of parasitic infections [8], the recent revelations of its toxic effects,
including genotoxicity, gastric mucus irritation [9,10], and the
development of clinical resistance [11] demonstrate the need for the
development of new and efficient scaffolds against trichomoniasis.
The isatin (1H-indole-2,3-dione) moiety is a versatile scaffold
with wide possibilities for chemical modification, and is respon-
sible for a broad spectrum of biological properties in many syn-
thetically versatile molecules [12]. In recent years, Schiff and
Mannich bases of 1H-indole-2,3-diones were reported to exhibit
chemotherapeutic properties including antiviral [13], antituber-
cular [14], antifungal, and antibacterial activities [15]. Investigation
of the SARs in 1H-indole-2,3-dione derivatives revealed that 5-
halogenation [14,15], N-alkylation [16], N-Mannich base [15], and
3-thiosemicarbazone formation were effective in triggering a
marked rise in activity against various bacteria, fungi, and viruses.
Moreover, cyclization of 1H-indole-2,3-diones to 4-thiazoline [14],
4-thiazolidinone [17], and pyridazinoindole [16] was efficient in
increasing anti-microbial activity. Previous studies have also re-
Parasitic infections represent a major health threat in under-
developed countries, and have a deep impact on public health.
Malaria has been a major source of parasitic infections since an-
tiquity, yet today it remains responsible for the deaths of more than
one million people every year [1]. Similarly, infections such as Try-
panosoma cruzi, Leishmania mexicana, Giardia lamblia, Entamoeba
histolytica and Trichomonas vaginalis have worldwide distribution,
especially in under-developed countries where tropical climates
prevail in combination with poor sanitation and hygiene [2e4].
T. vaginalis, the causative organism of trichomoniasis is a mucosal
pathogen which affects the human urogenital tract, producing
malodorous vaginal discharge, vulval irritation and inflammation,
and punctate cervical microhemorrhages [5]. It is now well estab-
lished that trichomoniasis, significantly increase the host’s vulnera-
bility to contract HIV [6,7] and controlling it could significantly
reduce the transmission of new HIV infections. Although the
introduction of metronidazole heralded a new era for the treatment
ported the inhibitory activity of isatineb-thiosemicarbazones and
isatin derivatives on HIV replication [18], which has been extended
towards the synthesis of diverse N-Mannich base derivatives of 5-
substituted isatins with potential non-nucleoside reverse tran-
scriptase inhibitor (NNRTI) activity.
*
Corresponding author. Tel.: þ91 183 2258802 09x3320; fax: þ91 183 2258819 20.
E-mail address: vipan_org@yahoo.com (V. Kumar).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.03.019

898
R. Raj et al. / European Journal of Medicinal Chemistry 63 (2013) 897e906
b
-Lactam nucleus is an important heterocyclic core with pro-
R1
N
R1
O
nounced biological activities and present in most widely used an-
tibiotics such as penicillins [19], cephalosporins [20], carbapenems
and monobactams [21,22]. In recent years, synthesis and modifi-
(i)
N
OH
+
N3
O
N
3
cation of the
b-lactam ring to obtain compounds with diverse
Ph 3
Ph
4
pharmacological activities such as cholesterol absorption in-
hibitors, human cytomegalovirus protease inhibitors, thrombin
inhibitors, anti-hyperglycaemic, anti-tumour, anti-HIV, anti-
inflammatory, analgesic activities and serine-dependent enzyme
inhibitors has generated a renewed interest for this class of anti-
microbial agents [23].
Reagents and conditions: (i) p-toluene sulphonyl chloride, Et N, Dry Dichloromethane, rt.
3
Scheme 2. Synthesis of 3-azido-2-azetidinones.
(7:3) mixture in the presence of CuSO $5H O and sodium ascorbate
4
2
In continuation of our pursuit of the synthesis of biologically
potent novel functional entities [24], we present herein the synthesis
of 1H-1,2,3-triazole tethered bi-functional hybrids of C-5 substituted
for 7 h. After completion of reaction, as evidenced by TLC, the
products were purified after usual work up and re-crystallization.
The structures to desired hybrids were assigned on the basis of
spectral and analytical evidences. The cis-stereochemistry assigned
isatins with N-1 substituted
b-lactams (Fig. 1) and their in vitro
1
2
evaluation against T. vaginalis. The introduction of 1H-1,2,3-triazole
as linker is based on its ability to confer favourable properties viz.
moderate dipole character, hydrogen bonding capability, rigidity and
stability under in vivo conditions on the synthesized hybrids [25].
was on the basis of coupling constant J ¼ 5.7 Hz between H and H .
2.2. In vitro protozoal parasite susceptibility assay and mammalian
cell cytotoxic studies
2
. Results and discussion
To perform the initial susceptibility screens on T. vaginalis,
compounds were suspended in DMSO to obtain concentrations of
2.1. Synthetic chemistry
100
mM; 5
mL aliquots of these suspensions were diluted in 5 mL of
TYM Diamond’s media to obtain a final concentration of 100
m
M.
ꢀ
The desired bi-functional hybrids were synthesized using click
The protozoal parasites were cultured for 24 h at 37 C. Cell counts
were normalized to the DMSO controls, in order to allow direct
comparison and averaging of the various trials. These data sets
were then transformed using Prism Software by Graphpad, by
taking the log of the drug concentrations for the trials, and input-
ting this transform into a log(inhibitor) vs. responseevariable slope
regression option. Within this nonlinear regression, constraints
were set to force the maximum value (top) to 1 and the minimum
value (bottom) to 0. The slope was left variable and then deter-
mined through which regression was performed. The sample size
consists of 4 independent trials carried out on 4 different days (to
account for possible variation in parasite culture). The assays were
performed in 15 mL culture tubes, with both WT and DMSO control
tubes to normalize for the effects of the solvent and in vitro con-
ditions. After 24 h, cells were counted using a hemacytometer. The
IC50 value for compound 5i was determined by running assays of
chemistry approach between N-substituted
b-lactams and 5-
substituted isatins containing the azide and terminal alkyne
respectively, in the presence of Cu(I) catalyst. The 5-substituted
isatins were prepared according to reported procedures and
N-propargylation was done using propargyl bromide in the pres-
ence of NaH as a base, and DMF as solvent (Schemes 1e3). The
desired N-substituted 3-azido-b-lactams 4 were prepared by
Staudinger reaction of appropriately functionalized 1-azadienes 3
with azido-ketene generated in situ from azido-acetic acid in the
presence of p-toluene sulphonylchloride and triethylamine [26].
The targeted diastereoselective, bi-functional hybrids were
synthesized by room temperature stirring of variedly substituted
3
2
-azido-2-azetidinones and propargylated isatins in EtOH:H O
R1
O
O
increasing drug concentrations, 5
regression analysis using Prism software, from GraphPad. To
screen compounds on mammalian cells, 100 M concentrations
mMe40 mM, and performing a
R
N
O
m
N
N3
were added to cultures of CHO-K1 cells. After 24 h, cells were
visualized under light microscopy to detect observable changes in
morphology.
Ph
R1
O
N
O
O
N
R
O
R
O
N
N
N
N
O
H1
N3
N
Ph
O
R1
N
(i)
R
N
H1
Fig. 1. General structure of lead compound and target hybrid compounds.
+
H3
N
O
H3
H2
H4
N
O
Ph
Ph
H2
N
O
O
H4
1
R
R
R
(i)
2
a-d
4a-f
5a-v
O
O
N
N
H
Reagent and conditions: (i) CuSO
EtOH/H O, rt, 7h.
4 2
.5H O (0.05 mmol), Sodium ascorbate (0.13 mmol),
1
2
2
Reagents and conditions: (i) Propargyl bromide, NaH, DMF, rt, 3 h.
Scheme 3. Diastereoselective synthesis of 1H-1,2,3-triazole-tethered b-lactameisatin
Scheme 1. Synthesis of N-propargylated isatins.
conjugates.

R. Raj et al. / European Journal of Medicinal Chemistry 63 (2013) 897e906
899
2.3. In vitro activity against T. vaginalis
3. Experimental section
The synthesized 1H-1,2,3-triazole-tethered
b
-lactameisatin
Melting points were determined by open capillary using Veego
Precision Digital Melting Point apparatus (MP-D) and are uncor-
rected. H NMR spectra were recorded in deuterochloroform and
conjugates were evaluated for their inhibitory influence on the
axenic in vitro growth of T. vaginalis strain G3 cultured in TYM
1
ꢀ
Diamond’s media for 24 h at 37 C. Table 1 lists the data obtained
6
DMSO-d with Jeol 300 (300 MHz) spectrometers using TMS as
from the initial percent inhibition screens at 10 and 100
m
M. As
internal standard. Chemical shift values are expressed as parts per
million downfield from TMS and J values are in hertz. Splitting
patterns are indicated as s: singlet, d: doublet, t: triplet, m:
multiplet, dd: double doublet, ddd: doublet of a doublet of a
doublet, and br: broad peak. C NMR spectra were recorded on
Jeol 300 (75 MHz) spectrometers in deuterochloroform and
evident from Table 1, the synthesized compounds show a con-
centration dependent inhibition of the parasite with average %age
inhibition increasing with the increase in concentration from 10
13
to 100
m
M. On comparing the effect of substituents at N-1 of the
M, the compounds
b
-lactam on the %age growth inhibition at 10
m
with N-aryl substituents (5iev) in general showed better activity
profiles than with N-alkyl substituents (5aeh). The presence of
6
DMSO-d using TMS as internal standard. High resolution mass
spectra were recorded on Bruker-micrOTOF-Q II spectrometer.
Column chromatography was performed on a silica gel (60e
120 mesh).
substituent at C-4 position of N-aryl ring of
influenced the activity profile with the compound 5m (R ¼ H)
showing 100% growth inhibition at 10 M while the introduction
of both electron donating (eCH ) and electron withdrawing
b-lactam further
m
3
3.1. Procedure for the preparation of b-lactameisatin hybrids
substituent (F, Cl) decreased the %age growth inhibition. A similar
preference for hydrogen substituent at C-5 position of isatin has
been observed in most of the conjugates. However, the %age
To a stirred solution of appropriate acetylenic isatins 2ae
d (1 mmol) in ethanol:water (7:3) mixture and azide 4aef
(1 mmol) were added copper sulphate (0.05 mmol) and sodium
ascorbate (0.13 mmol). The reaction mixture was allowed to stir at
room temperature for 8 h and the progress was monitored using
TLC. After the completion of reaction, water (25 mL) was added and
the reaction mixture was extracted twice with dichloromethane
(2 ꢁ 30 mL). The combined organic layers were dried over anhy-
drous sodium sulphate, and concentrated under reduced pressure
to yield a crude product which was purified via re-crystallization
using 8:2 (chloroform:methanol) mixture.
growth inhibition at 10
mM seem to depend profoundly on the
presence of phenyl ring at N-1 position as evident by better ac-
tivity profile shown by series 5mep among the test compound;
5
q being an exception. The compound 5h, with an optimum
combination of substituent (H) at N-aryl of -lactam as well as C-5
of isatin proved to be the most potent among the synthesized
conjugates exhibiting 100% growth inhibition at 10 M. The in-
crease in concentration from 10 M to 100 M greatly improved
b
m
m
m
the activity with 18 of the 22 test compounds exhibiting 100%
growth inhibition irrespective of the substituent present at N-1 of
b
-lactam or at C-5 position of isatin as depicted in Table 1 and
3.1.1. 1-[1-(1-Cyclohexyl-2-oxo-4-styryl-azetidin-3-yl)-1H-[1,2,3]
graphically represented in Fig. 2. The active compounds from the
preliminary inhibition data were chosen in order to determine
their IC50 which is the minimum concentration required for 50%
growth inhibition and the results are tabulated in Table 2. As
evident from Table 2, although the synthesized scaffolds are not
as active as that of standard drug metronidazole, most of the
compounds showed potent activity against the G3 strain of
T. vaginalis. The compound 5n having phenyl-substituent on N-1
triazol-4-ylmethyl]-1H-indole-2,3-dione (5a)
ꢀ
1
Brick red crystalline solid, mp 200e202 C, H NMR: d 1.08e2.04
(m,10H, cyclohexyl), 3.45e3.60 (m,1H, cyclohexyl), 4.72 (dd, J ¼ 5.1,
2
3
8.7 Hz, 1H, H ), 4.98 (s, 2H, eCH
2
), 5.66 (dd, J ¼ 8.7, 15.6 Hz, 1H, H ),
1
4
5.90 (d, J ¼ 5.1 Hz, 1H ), 6.60 (d, J ¼ 15.6 Hz, 1H, H ), 7.03e7.26 (m,
7H, ArH), 7.39e7.44 (m, 1H, ArH), 7.53 (d, J ¼ 7.2 Hz, 1H, ArH), 7.76
13
(s, 1H, triazole ring), C NMR: d 25.0, 30.5, 31.6, 35.3, 53.1, 59.2, 67.1,
111.2, 117.4, 121.5, 123.4, 123.9, 125.2, 126.5, 128.7, 135.0, 137.1, 138.5,
of
ring proved to be the most active scaffold among the library of
compounds with an IC50 of 7.06 M. All the compounds except 5i
exerted cytotoxic effects on CHO-k1 cells as observed by direct
visualization of cellular morphology. 5i with an IC50 of 7.69
and no visual morphological effect on cultured CHO-K1 cells is
considered as a good candidate for further evaluations. The dosee
response curve for the potent scaffolds 5i and 5n are elucidated in
Fig. 3 while the doseeresponse curves for the scaffolds 5e, 5f, 5i,
b
-lactam ring and flouro-substituent at C-5 position of isatin
27 5 3
141.8, 150.0, 157.8, 160.4, 182.8, HRMS Calculated for C28H N O
[M þ H]þ 482.2114 found 482.2112.
m
3.1.2. 1-[1-(1-Cyclohexyl-2-oxo-4-styryl-azetidin-3-yl)-1H-[1,2,3]
m
M
triazol-4-ylmethyl]-5-fluoro-1H-indole-2,3-dione (5b)
ꢀ
1
Brick red crystalline solid, mp 210e212 C, H NMR: d 1.23e2.01
(m,10H, cyclohexyl), 3.46e3.61 (m,1H, cyclohexyl), 4.72 (dd, J ¼ 5.1,
2
3
8.4 Hz, 1H, H ), 4.97 (s, 2H, eCH
2
), 5.66 (dd, J ¼ 8.4, 15.6 Hz, 1H, H ),
1
4
5.91 (d, J ¼ 5.1 Hz,1H, H ), 6.58 (d, J ¼ 15.6 Hz,1H, H ), 7.05e7.26 (m,
13
5
n, 5o, 5p, 5r, 5s, 5t, 5u and 5v are provided in the Supplementary
material.
In conclusion, the present manuscript describes the synthesis
of novel 1H-1,2,3-triazole-tethered -lactameisatin conjugates
utilizing Cu(I)-mediated azideealkyne cycloaddition reactions,
and their in vitro activity against T. vaginalis at 10 and 100 M.
M showed the
-lactam and C-5
M revealed 18
8H, ArH), 7.76 (s, 1H, triazole ring), C NMR: d 23.7, 29.3, 30.3, 34.2,
51.6, 58.0, 65.8, 111.2, 111.3, 117.0, 121.3, 123.1, 125.3, 127.3, 127.5,
134.1, 135.5, 140.2, 144.9, 151.2, 155.0, 157.1, 159.6, 182.2, HRMS
b
Calculated for C28
H26FN
5
O
3
[M þ H]þ 500.2020 found 500.2017.
m
3.1.3. 5-Chloro-1-[1-(1-cyclohexyl-2-oxo-4-styryl-azetidin-3-yl)-
The preliminary growth inhibition data at 10
m
1H-[1,2,3]triazol-4-ylmethyl]-1H-indole-2,3-dione (5c)
ꢀ
1
dependence of activity on substituents at N-1 of
b
Brick red crystalline solid, mp 219e220 C, H NMR: d 1.23e2.31
of isatin ring. The increase in concentration to 100
m
(m,10H, cyclohexyl), 3.45e3.60 (m,1H, cyclohexyl), 4.71 (dd, J ¼ 5.1,
2
3
of the test compounds exhibiting 100% growth inhibition irre-
spective of the substituents present with most potent compound
8.7 Hz, 1H, H ), 4.96 (s, 2H, eCH
2
), 5.65 (dd, J ¼ 8.7, 15.6 Hz, 1H, H ),
1
4
5.89 (d, J ¼ 5.1 Hz, 1H, H ), 6.59 (d, J ¼ 15.6 Hz, 1H, H ), 7.00e7.34
13
5
n having an IC50 of 7.06
the synthesized chimeras on CHO-K1 cells showed 5i to be non-
cytotoxic with an IC50 value of 7.69 M making it an ideal starting
m
M. The cytotoxic evaluation studies of
(m, 8H, ArH), 7.72 (s, 1H, triazole ring), C NMR: d 25.5, 30.8,
31.5, 35.2, 53.3, 59.5, 67.8, 111.3, 117.5, 121.7, 123.2, 123.8, 125.5,
126.4, 128.4, 135.6, 137.2, 138.6, 141.4, 150.9, 156.6, 157.3, 160.2,
m
point for the synthesis of new pharmacological templates against
T. vaginalis.
182.6, HRMS Calculated for C28
516.1727.
H26ClN
5
O
3
[M þ H]þ 516.1724 found

900
R. Raj et al. / European Journal of Medicinal Chemistry 63 (2013) 897e906
Table 1
Inhibitory activity of compound library against G3 strain of T. vaginalis tested at 10
m
M and 100 mM.
Code Structure Average % inhibition 10
m
M
Average % inhibition at at 100
m
M
C log P [27] a
O
O
N
O
N
N
N
N
5a
26.80
100.00
4.02
O
O
N
O
N
N
N
N
5b
0.00
100.00
4.17
F
O
O
N
O
N
N
N
N
5c
7.30
100.00
4.74
Cl
O
O
N
O
N
N
N
N
5d
4.90
100.00
4.89
Br
O
O
N
O
N
N
N
N
5e
9.80
95.65
4.34
CH
3
O
N
O
O
N
5
5
5
f
7.80
0.00
7.30
100.00
19.57
67.39
3.58
3.90
4.47
N
N
N
O
O
F
N
O
N
g
N
N
N
O
O
Cl
O
N
N
h
N
N
N

R. Raj et al. / European Journal of Medicinal Chemistry 63 (2013) 897e906
901
Table 1 (continued )
Code
Structure
Average % inhibition 10
m
M
Average % inhibition at at 100
m
M
C log P [27] a
O
O
N
O
F
N
N
N
N
5i
38.50
100.00
4.17
O
O
N
O
F
N
N
N
N
5j
19.50
100.00
4.50
F
O
O
N
O
F
N
N
N
N
5k
14.60
100.00
5.07
Cl
O
O
N
O
F
N
N
N
N
5l
0.00
100.00
5.22
Br
O
O
N
O
N
N
N
N
5m
100.00
100.00
3.89
O
O
N
O
N
N
N
N
5n
58.50
100.00
4.21
F
O
O
N
O
N
N
N
N
5o
61.00
100.00
4.78
Cl
(
continued on next page)

902
R. Raj et al. / European Journal of Medicinal Chemistry 63 (2013) 897e906
Table 1 (continued )
Code
Structure
Average % inhibition 10
m
M
Average % inhibition at at 100
m
M
C log P [27] a
O
O
N
O
N
N
N
N
5p
83.00
100.00
4.93
Br
O
O
N
O
N
N
N
N
5q
0.00
82.61
4.39
CH3
O
O
N
O
Cl
Cl
N
N
N
N
5r
80.50
100.00
4.74
O
O
N
O
N
N
N
N
5s
53.70
100.00
5.64
Cl
O
O
N
O
H C
N
N
3
N
N
5t
4.90
100.00
4.39
O
O
N
O
H C
N
N
3
N
N
5u
58.50
100.00
4.71
F
O
O
N
O
H C
N
N
3
N
N
5v
48.80
100.00
5.28
Cl
a
Calculated using Chem Draw Ultra 10.0.

R. Raj et al. / European Journal of Medicinal Chemistry 63 (2013) 897e906
903
Fig. 2. Graphical representation of inhibitory activities of test compounds at 100 mM.
3
3
1
.1.4. 5-Bromo-1-[1-(1-cyclohexyl-2-oxo-4-styryl-azetidin-3-yl)-
2H, eCH
2
), 5.55 (dd, J ¼ 8.4, 15.9 Hz, 1H, H ), 5.95 (d, J ¼ 5.1 Hz, 1H,
4
1
H-[1,2,3]triazol-4-ylmethyl]-1H-indole-2,3-dione (5d)
H ), 6.47 (d, J ¼ 15.9 Hz, 1H, H ), 7.01e7.45 (m, 13H, ArH), 7.53 (d,
ꢀ
1
13
Brick red crystalline solid, mp 201e203 C, H NMR:
d
1.27e1.98
J ¼ 6.9 Hz, 1H, ArH), 7.74 (s, 1H, triazole H), C NMR:
d 35.2, 45.3,
(
8
m,10H, cyclohexyl), 3.47e3.62 (m,1H, cyclohexyl), 4.72 (dd, J ¼ 5.1,
59.6, 67.9, 111.1, 117.4, 119.6, 123.5, 123.9, 125.2, 126.5, 128.2, 128.6,
128.7, 129.0, 134.3, 134.8, 137.9, 138.4, 141.8, 149.9, 157.8, 160.9,
2
.4 Hz, 1H, H ), 4.94 (q, J ¼ 15.6 Hz, 2H, eCH ), 5.65 (dd, J ¼ 8.4,
2
3
1
[M þ H]þ 490.1811 found
1
5.9 Hz, 1H, H ), 5.89 (d, J ¼ 5.1 Hz, 1H, H ), 6.57 (d, J ¼ 15.9 Hz, 1H,
182.7, HRMS Calculated for C29
490.1815.
23 5 3
H N O
4
H ), 7.04e7.26 (m, 6H, ArH), 7.46 (t, J ¼ 1.8, 9.6 Hz, 1H, ArH), 7.60 (d,
13
J ¼ 2.4 Hz, 1H, ArH), 7.75 (s, 1H, triazole ring), C NMR:
d 25.5, 30.8,
31.2, 35.4, 53.4, 59.8, 67.2, 111.1, 117.9, 121.6, 123.3, 123.6, 125.6,
3.1.7. 1-[1-(1-Benzyl-2-oxo-4-styryl-azetidin-3-yl)-1H-[1,2,3]
1
26.2, 128.8, 135.2, 137.4, 138.1, 141.9, 150.2, 156.9, 157.9, 160.5,
triazol-4-ylmethyl]-5-fluoro-1H-indole-2,3-dione (5g)
[M þ H]þ 560.1219 found
Brick red crystalline solid, mp 215e217 C, H NMR:
J ¼ 14.9 Hz, 1H, eCH benzyl), 4.53 (dd, J ¼ 5.1, 8.4 Hz, 1H, H ), 4.77
),
ꢀ
1
d 4.17 (d,
182.9, HRMS Calculated for C28
H26BrN
5
O
3
2
5
60.1217.
2
(
d, J ¼ 14.9 Hz, 1H, eCH
2
benzyl), 4.95 (q, J ¼ 15.6 Hz, 2H, eCH
2
3
1
3.1.5. 1-[1-(1-Cyclohexyl-2-oxo-4-styryl-azetidin-3-yl)-1H-[1,2,3]
5.53 (dd, J ¼ 8.4, 15.9 Hz, 1H, H ), 5.93 (d, J ¼ 5.1 Hz, 1H, H ), 6.43
4
triazol-4-ylmethyl]-5-methyl-1H-indole-2,3-dione (5e)
(d, J ¼ 15.9 Hz, 1H, H ), 6.95e7.35 (m, 13H, ArH), 7.71 (s, 1H, triazole
ꢀ
1
13
Brick red crystalline solid, mp 207e208 C, H NMR:
d
1.27e1.97
ring), C NMR:
d
19.1, 37.7, 58.9, 67.7, 109.3, 114.4, 114.7, 117.4, 117.5,
(
m, 10H, cyclohexyl), 2.35 (s, 3H, eCH ), 3.46e3.61 (m, 1H, cyclo-
3
119.3, 123.0, 123.6, 125.1, 127.1, 127.2, 133.4, 133.6, 136.4, 137.1, 140.5,
2
hexyl), 4.72 (dd, J ¼ 5.1, 8.4 Hz, 1H, H ), 4.97 (q, J ¼ 15.6 Hz, 2H, e
5 3
146.4, 156.2, 158.5, 160.0, 182.4, HRMS Calculated for C29H22FN O
3
[M þ H]þ 508.1707 found 508.1705.
CH
2
), 5.65 (dd, J ¼ 8.4, 15.9 Hz, 1H, H ), 5.90 (d, J ¼ 5.1 Hz, 1H,
1
4
H ), 6.57 (d, J ¼ 15.9 Hz, 1H, H ), 7.03e7.26 (m, 6H, ArH), 7.31e7.34
(
m, 1H, ArH), 7.46 (d, J ¼ 2.1 Hz, 1H, ArH), 7.74 (s, 1H, triazole ring),
3.1.8. 1-[1-(1-Benzyl-2-oxo-4-styryl-azetidin-3-yl)-1H-[1,2,3]
triazol-4-ylmethyl]-5-chloro-1H-indole-2,3-dione (5h)
1
3
C NMR:
d
19.4, 23.7, 29.3, 30.3, 34.1, 51.6, 58.1, 65.8, 109.7, 116.3,
ꢀ
1
1
1
21.3, 122.9, 124.0, 125.4, 127.3, 127.4, 134.1, 135.6, 137.5, 140.5,
Brick red crystalline solid, mp 210e211 C, H NMR:
J ¼ 15.0 Hz, 1H, eCH benzyl), 4.53 (dd, J ¼ 5.1, 8.4 Hz, 1H, H ), 4.78
(d, J ¼ 15.0 Hz, 1H, eCH benzyl), 4.97 (q, J ¼ 15.6 Hz, 2H, eCH ),
.53 (dd, J ¼ 8.4, 15.9 Hz, 1H, H ), 5.92 (d, J ¼ 5.1 Hz, 1H, H ), 6.46
d 4.17 (d,
2
50.2, 156.6, 157.2, 159.6, 182.3, HRMS Calculated for C29
H
29BrN
5
O
3
2
þ
[M þ H] 496.2270 found 496.2266.
2
2
3
1
5
4
3
.1.6. 1-[1-(1-Benzyl-2-oxo-4-styryl-azetidin-3-yl)-1H-[1,2,3]
(d, J ¼ 15.9 Hz, 1H, H ), 7.00e7.53 (m, 13H, ArH), 7.73 (s, 1H, triazole
13
triazol-4-ylmethyl]-1H-indole-2,3-dione (5f)
ring), C NMR: d 35.1, 45.2, 59.4, 67.8,111.4,117.3, 119.6,123.8,123.7,
ꢀ
1
Brick red crystalline solid, mp 214e215 C, H NMR:
J ¼ 15.0 Hz, 1H, eCH benzyl), 4.54 (dd, J ¼ 5.1, 8.4 Hz, 1H, H ), 4.79
d, J ¼ 15.0 Hz, 1H, eCH benzyl), 4.98 (a pair of doublet, J ¼ 15.9 Hz,
d
4.19 (d,
125.6, 126.2, 128.5, 128.8, 128.9, 129.1, 134.2, 134.9, 137.8, 138.5,
141.9, 149.5, 156.4, 157.3, 160.2, 182.5, HRMS Calculated for
2
2
(
2
C
29
H22ClN
5
O
3
[M þ H]þ 524.1411 found 524.1414.
3
.1.9. 1-{1-[1-(4-Fluoro-phenyl)-2-oxo-4-styryl-azetidin-3-yl]-1H-
Table 2
[1,2,3]triazol-4-ylmethyl}-1H-indole-2,3-dione (5i)
IC50 determination of active compounds.
ꢀ
1
Brick red crystalline solid, mp 230e231 C, H NMR:
d 5.01 (a
Compound
IC50 (mM) (G3)
pair of doublet, J ¼ 15.6 Hz, 2H, eCH ), 5.15 (dd, J ¼ 5.4, 7.2 Hz, 1H,
2
5
5
5
5
5
5
5
5
5
5
5
e
f
i
n
o
p
r
s
t
u
v
44.51
8.68
7.69
7.06
9.82
9.34
8.27
9.94
27.46
22.09
10.05
0.72
2
3
1
H ), 5.82 (dd, J ¼ 7.2,15.9 Hz,1H, H ), 6.16 (d, J ¼ 5.4 Hz,1H, H ), 6.37
4
(
d, J ¼ 15.9 Hz, 1H, H ), 7.00e7.51 (m, 13H, ArH), 7.80 (s, 1H, triazole
13
ring), C NMR:
d 34.2, 46.1, 67.4, 111.8, 116.9, 117.7, 120.6, 123.3,
123.6, 125.9, 126.5, 128.1, 128.8, 129.7, 134.3, 134.8, 137.2, 138.7,
1
[
41.0, 149.6, 157.3, 160.8, 182.5, HRMS Calculated for C28
H20FN
5
O
3
M þ H]þ 494.1550 found 494.1552.
3.1.10. 5-Fluoro-1-{1-[1-(4-fluoro-phenyl)-2-oxo-4-styryl-azetidin-
3-yl]-1H-[1,2,3]triazol-4-ylmethyl}-1H-indole-2,3-dione (5j)
a
Metronidazole
ꢀ
1
Brick red crystalline solid, mp 218e219 C, H NMR:
d
5.03
a
2
Current FDA approved treatment for T. vaginalis infections.
(q, J ¼ 15.6 Hz, 2H, eCH ), 5.17 (t, J ¼ 5.4, 7.2 Hz, 1H, H ), 5.81
2

904
R. Raj et al. / European Journal of Medicinal Chemistry 63 (2013) 897e906
Fig. 3. Doseeresponse curve for 5i and 5n.
3
1
4
(
dd, J ¼ 7.2, 15.9 Hz, 1H, H ), 6.18 (d, J ¼ 5.4 Hz, 1H, H ), 6.39 (d,
J ¼ 15.9 Hz, 1H, H ), 7.00e7.55 (m, 13H, ArH), 7.80 (s, 1H, triazole
4
13
J ¼ 15.9 Hz, 1H, H ), 6.98e7.26 (m, 10H, ArH), 7.45e7.49 (m, 2H,
ring), C NMR:
d
35.0, 45.2, 67.7, 111.5, 117.6, 119.8, 123.4, 123.8,
13
ArH), 7.81 (s, 1H, triazole ring), C NMR:
d
34.5, 46.3, 67.1, 111.6,
125.8, 126.3, 128.1, 128.6, 128.7, 129.4, 134.6, 134.9, 137.6, 138.5,
141.5, 149.2, 156.4, 157.9, 160.0, 182.4, HRMS Calculated for
1
1
16.1, 117.6, 120.2, 123.5, 123.8, 125.3, 126.7, 128.2, 128.6, 129.4,
34.6, 134.9, 137.1, 138.6, 141.4, 149.8, 157.0, 158.2, 160.7, 182.9,
C
28
H20FN
5
O
3
[M þ H]þ 494.1550 found 494.1557.
HRMS Calculated for C28
5
H
19
F
2
N
5
O
3
[M þ H]þ 512.1456 found
12.1459.
3.1.15. 5-Chloro-1-[1-(2-oxo-1-phenyl-4-styryl-azetidin-3-yl)-1H-
1,2,3]triazol-4-ylmethyl]-1H-indole-2,3-dione (5o)
[
ꢀ
1
3
3
.1.11. 5-Chloro-1-{1-[1-(4-fluoro-phenyl)-2-oxo-4-styryl-azetidin-
-yl]-1H-[1,2,3]triazol-4-ylmethyl}-1H-indole-2,3-dione (5k)
Brick red crystalline solid, mp 203e205 C, H NMR:
Brick red crystalline solid, mp 216e217 C, H NMR: d 4.95 (q,
2
J ¼ 15.6 Hz, 2H, eCH ), 5.20 (dd, J ¼ 5.1, 7.2 Hz, 1H, H ), 5.80 (dd,
2
ꢀ
1
3
1
d
5.01 (q,
J ¼ 7.2, 15.9 Hz, 1H, H ), 6.15 (d, J ¼ 5.1 Hz, 1H, H ), 6.68 (d,
2
4
J ¼ 15.9 Hz, 2H, eCH
2
), 5.18 (t, J ¼ 5.4, 7.2 Hz, 1H, H ), 5.80 (dd,
J ¼ 15.9 Hz, 1H, H ), 7.01e7.56 (m, 13H, ArH), 7.81 (s, 1H, triazole
3
1
13
J ¼ 7.2, 15.9 Hz, 1H, H ), 6.19 (d, J ¼ 5.4 Hz, 1H, H ), 6.37 (d,
ring), C NMR:
d
35.0, 45.8, 67.4, 111.2, 117.9, 119.5, 123.8, 123.9,
4
J ¼ 15.9 Hz, 1H, H ), 6.99e7.26 (m, 10H, ArH), 7.30e7.48 (m, 2H,
125.1, 126.6, 128.4, 128.7, 128.8, 129.2, 134.4, 134.7, 137.9, 138.5,
141.2, 149.1, 156.1, 157.2, 160.3, 182.0, HRMS Calculated for
13
ArH), 7.82 (s, 1H, triazole ring), C NMR:
d 34.2, 46.1, 67.6, 111.5,
1
1
16.0, 117.5, 120.1, 123.6, 123.4, 125.8, 126.9, 128.3, 128.9, 129.1,
34.2,134.6,137.7,138.5,141.1,149.4,156.2,157.5,160.3,182.1, HRMS
C
28
H20ClN
5
O
3
[M þ H]þ 510.1255 found 510.1251.
Calculated for C28
H19ClFN
5
O
3
[M þ H]þ 528.1160 found 528.1158.
3.1.16. 5-Bromo-1-[1-(2-oxo-1-phenyl-4-styryl-azetidin-3-yl)-1H-
1,2,3]triazol-4-ylmethyl]-1H-indole-2,3-dione (5p)
[
ꢀ
1
3
3
.1.12. 5-Bromo-1-{1-[1-(4-fluoro-phenyl)-2-oxo-4-styryl-azetidin-
-yl]-1H-[1,2,3]triazol-4-ylmethyl}-1H-indole-2,3-dione (5l)
Brick red crystalline solid, mp 227e228 C, H NMR:
Brick red crystalline solid, mp 234e235 C, H NMR: d 4.98 (s,
2
2H, eCH
2
), 5.25 (dd, J ¼ 5.4, 8.1 Hz, 1H, H ), 5.93 (dd, J ¼ 8.1, 15.9 Hz,
1 4
ꢀ
1
3
d
4.94 (q,
1H, H ), 6.36 (d, J ¼ 5.4 Hz, 1H, H ), 6.78 (d, J ¼ 15.9 Hz, 1H, H ), 6.85
2
J ¼ 15.6 Hz, 2H, eCH
2
), 5.17 (t, J ¼ 5.1, 7.2 Hz, 1H, H ), 5.79 (dd,
(d, J ¼ 8.4 Hz, 1H, ArH), 7.06e7.70 (m, 12H, ArH), 8.17 (s, 1H, triazole
3
1
13
J ¼ 7.2, 15.9 Hz, 1H, H ), 6.18 (d, J ¼ 5.1 Hz, 1H, H ), 6.62 (d,
ring), C NMR:
d
35.2, 45.2, 67.5, 111.3, 117.6, 119.4, 123.3, 123.5,
4
J ¼ 15.9 Hz, 1H, H ), 7.00e7.26 (m, 10H, ArH), 7.33e7.51 (m, 2H,
125.8, 126.3, 128.1, 128.5, 128.7, 129.4, 134.4, 134.6, 137.3, 138.6,
141.5, 149.4, 156.8, 157.5, 160.7, 182.1, HRMS Calculated for
13
ArH), 7.80 (s, 1H, triazole ring), C NMR:
d 34.5, 46.5, 67.6, 111.9,
1
1
16.3, 117.4, 120.3, 123.3, 123.8, 125.8, 126.7, 128.2, 128.7, 129.5,
34.5, 134.6, 137.8, 138.3, 141.3, 149.8, 155.4, 157.8, 160.8, 182.9,
C
28
H20BrN
5
O
3
[M þ H]þ 554.0750 found 554.0753.
HRMS Calculated for C28
5
H19BrFN
5
O
3
[M þ H]þ 572.0655 found
3.1.17. 5-Methyl-1-[1-(2-oxo-1-phenyl-4-styryl-azetidin-3-yl)-1H-
[1,2,3]triazol-4-ylmethyl]-1H-indole-2,3-dione (5q)
72.0651.
ꢀ
1
Brick red crystalline solid, mp 223e224 C, H NMR:
3H, eCH
d 2.34(s,
3
.1.13. 1-[1-(2-Oxo-1-phenyl-4-styryl-azetidin-3-yl)-1H-[1,2,3]
triazol-4-ylmethyl]-1H-indole-2,3-dione (5m)
3
), 4.97 (q, J ¼ 15.6 Hz, 2H, eCH ), 5.20 (dd, J ¼ 5.1, 7.2 Hz,
2
2
3
1
1H, H ), 5.82 (dd, J ¼ 7.2, 15.9 Hz, 1H, H ), 6.18 (d, J ¼ 5.1 Hz, 1H, H ),
ꢀ
1
4
Brick red crystalline solid, mp 210e211 C, H NMR:
d
4.96 (a pair
6.68 (d, J ¼ 15.9 Hz, 1H, H ), 7.00e7.55 (m, 13H, ArH), 7.80 (s, 1H,
2
13
of doublet, J ¼ 15.6 Hz, 2H, eCH
2
), 5.19 (dd, J ¼ 5.1, 7.2 Hz, 1H, H ),
triazole ring), C NMR:
d
22.4, 35.0, 45.3, 67.5, 111.1, 117.8, 119.7,
3
1
5
.81 (dd, J ¼ 7.2, 15.9 Hz, 1H, H ), 6.17 (d, J ¼ 5.1 Hz, 1H, H ), 6.67 (d,
123.1, 123.6, 125.3, 126.8, 128.5, 128.7, 128.8, 129.9, 134.3, 134.6,
137.5, 138.8, 141.7, 149.2, 156.2, 157.4, 160.1, 182.2, HRMS Calculated
4
J ¼ 15.9 Hz, 1H, H ), 7.02e7.57 (m, 14H, ArH), 7.82 (s, 1H, triazole
13
[M þ H]þ 490.1801 found 490.1804.
ring), C NMR:
1
d
35.1, 45.4, 67.6, 111.0, 117.3, 119.4, 123.6, 123.8,
23 5 3
for C29H N O
25.2, 126.3, 128.2, 128.6, 128.8, 129.2, 134.5, 134.8, 137.4, 138.8,
1
[
41.9, 149.3, 157.7, 160.2, 181.8, HRMS Calculated for C28
H
21
N
5
O
3
3.1.18. 1-{1-[1-(4-Chloro-phenyl)-2-oxo-4-styryl-azetidin-3-yl]-
M þ H]þ 476.1644 found 476.1642.
1H-[1,2,3]triazol-4-ylmethyl}-1H-indole-2,3-dione (5r)
ꢀ
1
Brick red crystalline solid, mp 203e205 C, H NMR:
d 4.95 (a
2
3.1.14. 5-Fluoro-1-[1-(2-oxo-1-phenyl-4-styryl-azetidin-3-yl)-1H-
pair of doublet, J ¼ 15.9 Hz, 2H, eCH ), 5.17 (t, J ¼ 5.4, 7.2 Hz,1H, H ),
2
3
1
[1,2,3]triazol-4-ylmethyl]-1H-indole-2,3-dione (5n)
5.79 (dd, J ¼ 7.2, 16.2 Hz, 1H, H ), 6.17 (d, J ¼ 5.4 Hz, 1H, H ), 6.67 (d,
ꢀ
1
4
Brick red crystalline solid, mp 209e210 C, H NMR:
d
4.97 (q,
J ¼ 16.2 Hz, 1H, H ), 7.02e7.56 (m, 13H, ArH), 7.80 (s, 1H, triazole
2
13
J ¼ 15.6 Hz, 2H, eCH
2
), 5.20 (dd, J ¼ 5.1, 7.2 Hz, 1H, H ), 5.82 (dd,
ring), C NMR:
d
34.4, 46.3, 67.2, 111.4, 116.6, 117.0, 121.1, 122.9,
3
1
J ¼ 7.2, 15.9 Hz, 1H, H ), 6.18 (d, J ¼ 5.1 Hz, 1H, H ), 6.66 (d,
123.7, 125.4, 126.5, 128.2, 128.5, 129.6, 134.5, 134.8, 137.4, 138.6,

R. Raj et al. / European Journal of Medicinal Chemistry 63 (2013) 897e906
905
1
41.2, 149.9, 157.2, 160.8, 182.4, HRMS Calculated for C28
H
20ClN
5
O
3
[3] E. Pozio, World distribution of Trichinella spiralis. Infections in animals and
þ
humans, Vet. Parasitol. 149 (2007) 3e21.
[M þ H] 510.1255 found 510.1258.
[
[
4] H.H. García, A.E. Gonzalez, R.H. Gilman, Curr. Opin. Infect. Dis. 16 (2003) 411e419.
5] World Health Organization, Department of Reproductive Health and Research,
Prevalence and Incidence of Selected Sexually Transmitted Infections, Chla-
mydia trachomatis, Neisseria gonorrhoeae, Syphilis and Trichomonas vaginalis:
Methods and Results Used by WHO to Generate 2005 Estimates, WHO, 2011.
www.who.int/reproductivehealth/publications/rtis/9789241502450/en/
index.html.
3
3
.1.19. 5-Chloro-1-{1-[1-(4-chloro-phenyl)-2-oxo-4-styryl-azetidin-
-yl]-1H-[1,2,3]triazol-4-ylmethyl}-1H-indole-2,3-dione (5s)
ꢀ
1
Brick red crystalline solid, mp 218e219 C, H NMR:
d
4.96 (q,
2
J ¼ 15.6 Hz, 2H, eCH ), 5.16 (t, J ¼ 5.4, 7.2 Hz, 1H, H ), 5.81 (dd,
2
3
1
[6] T.V. Nguyen, N.V. Khuu, P.H. Truong, A.P. Nguyen, L.X. Truong, R. Detels, AIDS
J ¼ 7.2, 16.2 Hz, 1H, H ), 6.17 (d, J ¼ 5.4 Hz, 1H, H ), 6.69 (d,
Behav. 13 (2009) 873e880.
4
J ¼ 16.2 Hz, 1H, H ), 7.00e7.54 (m, 12H, ArH), 7.81 (s, 1H, triazole
[
[
7] S. Aboud, G. Msamanga, J.S. Read, A. Mwatha, Y.Q. Chen, D. Potter,
M. Valentine, U. Sharma, I. Hoffmann, T.E. Taha, R.L. Goldenberg, W.W. Fawzi,
Int. J. STD AIDS 19 (2008) 824e832.
8] J.A. Upcroft, R.W. Campbell, K. Banekli, P. Upcroft, P. Vanelle, Antimicrob.
Agents Chemother. 43 (1999) 73e76.
ring), 13C NMR:
d 34.1, 46.3, 67.8, 111.6, 117.2, 117.8, 121.0, 123.7,
123.9, 125.2, 126.4, 128.0, 128.4, 129.5, 134.6, 134.8, 137.7, 138.8,
141.1, 149.7, 155.8, 157.6, 160.8, 182.0, HRMS Calculated for
C
H19Cl
28 2
N
5
O
3
[M þ H]þ 544.0865 found 544.0867.
[9] D.W. Kim, J.M. Park, B.W. Yoon, M.J. Baek, J.E. Kim, S. Kim, J. Neurol. Sci. 224
2004) 107e111.
(
[
[
10] A.F. el-Nahas, I.M. el-Ashmawy, Basic Clin. Pharmacol. Toxicol. 94 (2004) 226e231.
11] (a) J.M. Wright, R.I. Webb, P. O’donoghue, P. upcroft, J.A. Upcroft, J. Eukaryot.
Microbiol. 57 (2010) 171e176;
(b) J.A. upcroft, L.A. Dunn, T. Wal, S. Tabrizi, M.G. Delgadillo-Correa,
P.J. Johnson, S. Garland, P. Siba, P. Upcroft, Sex Health 6 (2009) 334e338.
12] (a) A. Medvedev, O. Buneeva, V.Glover, Biologics: Targets Ther. 1 (2007) 151e162;
3
.1.20. 1-[1-(2-Oxo-4-styryl-1-p-tolyl-azetidin-3-yl)-1H-[1,2,3]
triazol-4-ylmethyl]-1H-indole-2,3-dione (5t)
ꢀ
1
Brick red crystalline solid, mp 230e231 C, H NMR:
H, eCH ), 5.16 (dd,
), 4.97 (a pair of doublet, J ¼ 15.9 Hz, 2H, eCH
J ¼ 5.4, 7.2 Hz, 1H, H ), 5.79 (dd, J ¼ 7.2, 16.2 Hz, 1H, H ), 6.16 (d,
d
2.31 (s,
3
3
2
[
2
3
(b) K.L. Vine, L. Matesic, J.M. Locke, M. Ranson, D. Skropeta, AnticancerAgents Med.
1
4
J ¼ 5.4 Hz, 1H, H ), 6.64 (d, J ¼ 16.2 Hz, 1H, H ), 7.01e7.42 (m, 12H,
Chem. 9 (2009) 397e414;
(c) G. Krishnegowda, A.S.P. Gowda, H.R.S. Tagaram, K.F.S. O’ Carroll, R.B. Irby,
A.K. Sharma, S. Amin, Bioorg. Med. Chem. 19 (2011) 6006e6014;
13
ArH), 7.51 (dd, J ¼ 7.5 Hz, 1H, ArH), 7.80 (s, 1H, triazole ring),
C
NMR: 23.2, 34.1, 45.8, 67.5, 111.0, 117.2, 117.4, 121.8, 123.3, 123.7,
d
(d) S.N. Pandeya, S. Smitha, M. Jyoti, S.K. Sridhar, Acta Pharm. 55 (2005) 27e46;
1
25.3, 126.6, 128.3, 128.5, 129.6, 134.4, 134.6, 137.6, 138.5, 141.3,
(e) M.J. Moon, S.K. Lee, J.W. Lee, W.K. Song, S.W. Kim, J.I. Kim, C. Cho, S.J. Choi,
Y.C. Kim, Bioorg. Med. Chem. 14 (2006) 237e246;
149.4,157.5,160.2,182.4, HRMS Calculated for C29
H
23
N
5
O
3
[M þ H]þ
(f)A.H. Abadi, S.M. Abou-Seri, D.E. Abdel-Rahman, C. Klein, O.Lozach, L.Meijer, Eur.
4
90.1801 found 490.1802.
J. Med. Chem. 41 (2006) 296e305.
[13] (a) D. Sriram, Y. Perumal, Curr. Med. Chem. 10 (2003) 1689e1695;
(
4
(
b) M.C. Pirrung, S.V. Pansare, K. Das Sarma, K.A. Keith, E.R. Kern, J. Med. Chem.
8 (2005) 3045e3050;
c) T.R. Bal, B. Anand, P. Yogeeswari, D. Sriram, Bioorg. Med. Chem. Lett. 15
3
.1.21. 5-Fluoro-1-[1-(2-oxo-4-styryl-1-p-tolyl-azetidin-3-yl)-1H-
[1,2,3]triazol-4-ylmethyl]-1H-indole-2,3-dione (5u)
ꢀ
1
Brick red crystalline solid, mp 224e225 C, H NMR:
H, eCH
d
2.35 (s,
(2005) 4451e4455.
[
14] D. Sriram, P. Yogeeswari, G. Gopal, Eur. J. Med. Chem. 40 (2005) 1373e1376.
3
1
6
3
), 4.95 (q, J ¼ 15.6 Hz, 2H, eCH ), 5.15 (dd, J ¼ 5.4, 7.2 Hz,
2
2
3
1
[15] S.N. Pandeya, D. Sriram, G. Nath, E. DeClercq, Arzneim. Forsch./Drug Res. 50
2000) 55e59.
H, H ), 5.79 (dd, J ¼ 7.2, 16.2 Hz, 1H, H ), 6.17 (d, J ¼ 5.4 Hz, 1H, H ),
(
4
.65 (d, J ¼ 16.2 Hz, 1H, H ), 7.00e7.41 (m, 11H, ArH), 7.50 (dd,
[16] V.S. Velezheva, P.J. Brennan, V.Y. Marshakov, D.V. Gusev, I.N. Lisichkina,
A.S. Peregudov, L.N. Tchernousova, T.G. Smirnova, S.N. Andreevskaya,
A.E. Medvedev, J. Med. Chem. 47 (2004) 3455e3461.
17] M.A. Badawy, S.A. Abdel-Hady, Arch. Pharm. (Weinheim) 324 (1991) 349e351.
18] (a) D. Sriram, T.R. Bal, P. Yogeeswari, Farmaco 60 (2005) 377e384;
(b) D. Sriram, T.R. Bal, P. Yogeeswari, Med. Chem. 1 (2005) 277e285.
19] J.M. Brynaert, C. Brulé, Compr. Heterocycl. Chem. 2 (2008) 173e237.
20] B. Alcaide, C. Aragoncillo, P. Almendros, in: Comprehensive Heterocyclic
Chemistry III, vol. 2, Elsevier Ltd, Oxford, 2008, pp. 112e164.
13
J ¼ 7.5 Hz, 1H, ArH), 7.77 (s, 1H, triazole ring), C NMR:
d 23.5, 34.7,
4
5.9, 67.1, 111.4, 117.5, 117.8, 121.5, 123.4, 123.7, 125.5, 126.7, 128.1,
[
[
128.7, 129.4, 134.5, 134.7, 137.8, 138.4, 141.6, 149.6, 157.2, 159.0,
þ
160.6, 182.0, HRMS Calculated for C29
H22FN
5
O
3
[M þ H] 508.1707
[
[
found 508.1721.
3
.1.22. 5-Chloro-1-[1-(2-oxo-4-styryl-1-p-tolyl-azetidin-3-yl)-1H-
[21] A.K. Halve, D. Bhadauria, R. Dubey, Bioorg. Med. Chem. Lett. 17 (2007) 341e345.
[22] (a) B. Alcaide, P. Almendros, C. Aragoncillo, Chem. Rev. 107 (2007) 4437e4492;
[1,2,3]triazol-4-ylmethyl]-1H-indole-2,3-dione (5v)
(
(
b) B. Alcaide, P. Almendros, Curr. Med. Chem. 11 (2004) 1921e1949;
c) A.R.A.S. Deshmukh, B.M. Bhawal, D. Krishnaswamy, V.V. Govande,
ꢀ
1
Brick red crystalline solid, mp 212e213 C, H NMR:
d 2.33 (s, 3H,
eCH ), 5.16 (dd, J ¼ 5.4, 7.2 Hz, 1H,
3
), 4.96 (q, J ¼ 15.6 Hz, 2H, eCH
2
B.A. Shinkre, A. Jayanthi, Curr. Med. Chem. 11 (2004) 1889e1920;
(d) B. Alcaide, P. Almendros, Synlett 3 (2002) 381e393;
(e) P. Claudio, A.M. Jesús, G. Iñaki, O. Mikel, Synlett 12 (2001) 1813e1826.
23] (a) S.B. Rosenblum, T. Huynh, A. Afonso, H.R. Davis Jr., N. Yumibe, J.W. Clader,
D.A. Burnett, J. Med. Chem. 41 (1998) 973e980;
2
3
1
H ), 5.80 (dd, J ¼ 7.2,15.9 Hz,1H, H ), 6.17 (d, J ¼ 5.4 Hz,1H, H ), 6.66
4
(
1
d, J ¼ 15.9 Hz, 1H, H ), 7.02e7.43 (m, 11H, ArH), 7.51 (dd, J ¼ 7.5 Hz,
[
13
H, ArH), 7.81 (s, 1H, triazole ring), C NMR: d 23.3, 34.5, 46.0, 67.3,
(
b) A.D. Borthwick, G. Weingarten, T.M. Haley, M. Tomaszewski, W. Wang, Z. Hu,
J. Bedard, H. Jin, L. Yuen, T.S. Mansour, Bioorg. Med. Chem. Lett. 8 (1998)365e370;
c) M.W. Jenny, Methods for testing the antimicrobial activity of extracts, in:
111.6, 117.4, 117.7, 121.6, 123.1, 123.7, 125.2, 126.7, 128.2, 128.6, 129.4,
1
34.2,134.7, 137.2,138.9,141.5,149.7, 155.8,157.6,160.4,182.1, HRMS
(
Calculated for C29
H22ClN O
5 3
[M þ H]þ 524.1411 found 524.1415.
I. Ahmad, F. qil, M. Owais (Eds.), Modern Phytomedicine, Turning Medicinal
Plants into Drugs, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2006, p.
157;
Acknowledgements
(d) G. Veinberg, I. Shestakova, M. Vorona, I. Kenepe, E. Lukevics, Bioorg.
Med. Chem. Lett. 14 (2004) 147e150;
(
(
e) T. Sperka, J. Pitlik, P. Bagossi, J. Tozser, Bioorg. Med. Chem. Lett. 15
2005) 3086e3090;
Financial assistance from Board of Research in Nuclear Sciences
under DAE Research Award for Young Scientist Scheme (VK) is
gratefully acknowledged.
(f) M.I. Konaklieva, Curr. Med. Chem. Anti-infect. Agents 1 (2002) 215e238;
g) A. Clemente, A. Domingos, A.P. Grancho, J. Iley, R. Moreira, J. Neres,
N. Palma, A.B. Santana, E. Valente, Bioorg. Med. Chem. Lett. 11 (2001)
065e1068.
(
1
[
24] (a) P. Singh, R. Raj, V. Kumar, M.P. Mahajan, P.M.S. Bedi, T. Kaur, A.K. Saxena,
Appendix A. Supplementary material
Eur. J. Med. Chem. 47 (2012) 594e600;
(
b) P. Singh, P. Singh, M. Kumar, J. Gut, P.J. Rosenthal, K. Kumar, V. Kumar,
M.P. Mahajan, K. Bisetty, Bioorg. Med. Chem. Lett. 22 (2012) 57e61;
c) K. Kumar, P. Singh, L. Kremer, Y. Guérardel, C. Biot, V. Kumar, Dalton Trans.
1 (2012) 5778e5781;
d) K. Kumar, S.C. Kremer, L. Kremer, Y. Guérardel, C. Biot, V. Kumar, Dalton
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.03.019.
(
4
(
Trans. 42 (2013) 1492e1500;
(e) K. Kumar, S. Sagar, L. Esau, M. Kaur, V. Kumar, Eur. J. Med. Chem. 58 (2012)
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