Synthesis and antiplasmodial activity of glyco-conjugate hybrids of phenylhydrazono-indolinones and glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-diones

Article abstract of DOI:10.1016/j.ejmech.2018.06.042

A small library of 36 new glycohybrids of phenylhydrazono-indolinones was synthesized employing glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-diones and different phenylhydrazines via acid catalyzed reaction. All the compounds were screened for their antiplasmodial activity in vitro. Compounds 6c, 7c, and 7b showed significant activity with the IC₅₀ values 1.27, 1.64 and 1.96 μM, respectively against CQ sensitive Pf3D7 strain while compounds 7b and 6f showed good activity with IC₅₀ 1.61 and 1.93 μM, respectively against CQ resistant PfK1 strain.

Full text of DOI:10.1016/j.ejmech.2018.06.042

European Journal of Medicinal Chemistry 155 (2018) 764e771
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Synthesis and antiplasmodial activity of glyco-conjugate hybrids of
phenylhydrazono-indolinones and glycosylated 1,2,3-triazolyl-
methyl-indoline-2,3-diones
,
,
Ravi Kumar Thakur a 1, Prince Joshi b 1, Pragati Baranwal a, Gaurav Sharma d,
,
d,
,
c
,
, c, *, 2
Sanjeev K. Shukla c ***, Renu Tripathi b **, Rama Pati Tripathi a
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
b Parasitology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
c Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India
d Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow 226031, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A small library of 36 new glycohybrids of phenylhydrazono-indolinones was synthesized employing
glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-diones and different phenylhydrazines via acid cata-
lyzed reaction. All the compounds were screened for their antiplasmodial activity in vitro. Compounds 6c,
Received 15 October 2017
Received in revised form
15 June 2018
Accepted 16 June 2018
Available online 19 June 2018
7c, and 7b showed significant activity with the IC50 values 1.27, 1.64 and 1.96 mM, respectively against CQ
sensitive Pf3D7 strain while compounds 7b and 6f showed good activity with IC50 1.61 and 1.93
respectively against CQ resistant PfK1 strain.
mM,
© 2018 Elsevier Masson SAS. All rights reserved.
Keywords:
Isatin
Triazole
Glycosylation
Hydrazones
Antiplasmodial activity
1. Introduction
drugs including the artemisinins limits their utility [4e6]. The
problems associated with the existing drugs and the absence of any
viable vaccine, have triggered a massive effort to identify new
antimalarial leads acting through a novel mechanism.
Malaria, a parasitic disease mainly caused by Plasmodium fal-
ciparum claims millions of lives annually despite the availability of
various drugs belonging to aminoquinolines, arylaminoalcohols,
artemisinins, antifolates, antibiotics and inhibitors of the respira-
tory chain [1e3]. The arsenal of both prophylactic and curative
antimalarial drugs are scarce in number and development of
resistance to chloroquine and many other frontline antimalarial
Several molecules possessing isatin pharmacophore are known
to have a wide range of biological activities including antimalarial
activity [7]. Further, the possibility of chemical modifications at C-3,
C-5 and at N-1 position in the skeleton [8,9] has led to generation of
library of compounds for optimization of hits to potent leads in
drug design & development. Certain Schiff bases of isatin have
shown different pharmaceutical properties [10] and various spi-
rooxindoles have exhibited significant biological activities such as
antimalarial [11], antiviral [12], antifungal [13,14], anti-tumour
[15e17], anti-HIV [18], anticonvulsant [19], and anti-Parkinson's
[20] activity. Kumar et al. have established antimalarial activity in
triazole tethered isatin-ferrocene conjugates against 3D7 and W2
strains of Plasmodium falciparum [21]. Similarly, isatin-thiolactone
conjugates have been explored as potent antimalarial agents both
against chloroquine resistant (CQ-R) W2 strain of P. falciparum [22].
Raval et al. have also synthesized tetrahydropyrimidine-isatin hy-
brids as potent antiplasmodial agents against both 3D7 strain of
* Corresponding author. Medicinal and Process Chemistry Division, CSIR-Central
Drug Research Institute, Lucknow 226031, India.
** Corresponding author. Parasitology Division, CSIR-Central Drug Research
Institute, Lucknow 226031, India.
*** Corresponding author. Academy of Scientific and Innovative Research (AcSIR),
New Delhi 110001, India.
E-mail addresses: skshukla@cdri.res.in, sanshukla@rediffmail.com (S.K. Shukla),
renu1113@rediffmail.com, renu_tripathi@cdri.res.in (R. Tripathi), rpt.cdri@gmail.
com (R.P. Tripathi).
1
These authors contributed equally to this work.
Current Address: National Institute of Pharmaceutical Education and Research,
2
Raibarely 229010, India
https://doi.org/10.1016/j.ejmech.2018.06.042
0223-5234/© 2018 Elsevier Masson SAS. All rights reserved.

R.K. Thakur et al. / European Journal of Medicinal Chemistry 155 (2018) 764e771
765
P. falciparum [23]. Carbodithioate 2,3-dioxoindoline and many
other derivatives of isatin have also been shown to possess good
antimalarial activity against Plasmodium falciparum [24]. The isatin
hydrazones on the other hand are endowed with diverse range of
biological activities such as antimalarial [25], antimicrobial [26],
anticonvulsant [27], anti-inflammatory [28], antiplatelet [29], and
antitumoral [30]. Some of the reported molecules having isatin core
or hydrazones with significant antiplasmodial activities are depic-
ted in Fig. 1 [31,32].
Recently, we have explored the antitubercular and antimalarial
activities in triazole derivatives [33,34]. The antimalarial activity of
triazole derivatives has been shown to be due to interference with
p53 protein and killing the malaria parasite [34a]. The triazole with
high dipole moment, rigidity, stability and hydrogen bonding
capability under in vivo conditions, has imparted significance of
this pharmacophore in drug development [35].
Hybridization of active pharmacophore with sugar offers good
pharmacokinetic properties and improves their solubility [36], in
cases of poor solubility in DMSO. Keeping in view the above points
and in continuation of our effort to develop new antimalarials
[34,37], we thought to prepare molecules with two different
pharmacophores exhibiting antimalarial activities and conjugate
them with sugars to improve the solubility of the molecules (Fig. 1).
To the best of our knowledge glycohybrids of this nature containing
isatin hydrazones have not been reported previously.
methyl-indoline-2,3-diones (3) by N-alkylation of isatin (1) with
propargyl bromide in presence of K2CO3 in DMF at an ambient
temperature [38]. The resulting N-propargylated isatin (2) was then
subjected to Cu (I) catalyzed azide-alkyne cycloaddition with
different sugar azides (I - IV) prepared by the methods earlier re-
ported [36b,39], in THF-H2O (1:1) using equimolar quantities of the
reactants, CuSO4.5H2O (10 mol%) and sodium ascorbate (20 mol%)
at room temperature. The reaction conditions were optimum and
were monitored (by TLC) until the reaction was complete (Scheme
1). The respective cycloaddition products (3a-3d) were obtained in
higher yields (90e95%). The structure elucidation of the cyclo-
adducts was made on the basis of their spectroscopic data.
The glycohybrids of phenylhydrazono indolinones were pre-
pared by reaction of substituted phenyl hydrazine hydrochlorides
(4a-4f) with the glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-
diones (3a-3d), in ethanol in presence of acetic acid as catalyst at
reflux temperature [40], to give the desired products (5e8) in good
to excellent yield (85e95%) (Scheme 2, Table 1). The structure of all
the synthesized compounds was established on the basis of their
spectroscopic data (1H, 13C and mass).
The complete assignment of 1H and 13C NMR signals were done
by utilizing various 1D (1H, 13C and DEPT) and 2D (COSY, TOCSY,
NOESY, HSQC, HMBC) NMR experiments of one of the prototypes
5b. HMBC correlation of H-2000 with C-3 and C-3000 showed their
connectivity. As reported in the literature, isatin hydrazones exist
predominately as the Z conformation in solution, presumably due
to the intramolecular hydrogen bonding between the NH of the
hydrazone linkage and the carbonyl group of the indolinone [41].
Confirmation of this stereochemistry was achieved by observing
nOe effect (Suppl., S88), for this compound we did not observe any
nOe correlations between H-4 of the isatin core and the hydrazone
2. Results and discussion
2.1. Chemistry
To start with, we have prepared glycosylated 1,2,3-triazolyl-
Fig. 1. Design of glycohybrids of phenylhydrazono indolinones based on reported potent antimalarials having an isatin/indole core or hydrazones.

766
R.K. Thakur et al. / European Journal of Medicinal Chemistry 155 (2018) 764e771
Scheme 1. Synthesis of glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-diones. Reagent and Conditions: a) Propargyl bromide, K2CO3, DMF, rt, 6 h, 72% b) respective Sugar Azide
(I-IV), CuSO4.5H2O, Na-Ascorbate, THF:H2O (1:1 v/v), rt, 4 h, 90e95%.
Scheme 2. Synthesis of glycohybrids of phenylhydrazono indolinones from glycosylated-1,2,3-triazolyl-methyl-indoline-2,3-diones. Reagent and Conditions: a) Glacial acetic acid
(0.5 mL), Ethanol, 80 ꢀC, 1 h, 85e95%.
NH, which suggests that it exists as Z conformation in solution.
good activity against the sensitive strain 3D7 with IC50 1.27 and
1.64 M respectively, while 7b with 4-bromo and 6f with 3-chloro
substitution on the phenyl ring of hydrazone showed good activity
against the resistant strain K1 with IC50 1.61 and 1.93 M, respec-
Moreover, the chemichal shift value of hydrazone NH (NH-2000) at
m
d
12.71 ppm is in good agreement with previous reported value for
hydrazone NH in case of Z conformation, which further supported
that it exists as Z conformation.
m
tively. The above compound 7b and another compound 6b with 4-
Further, we have synthesized deacetylated glycohybrids of
phenylhydrazono indolinones from respective acetylated ana-
logues. The deacetylation was performed by treating the corre-
sponding acetylated compound (5 or 6) in MeOH with methanolic
NaOMe at room temperature, to give the desired deacetylated an-
alogues (9 or 10) in good yields (75e85%) (Scheme 3, Table 2). All
the synthesized deacetylated analogues were characterized by
their spectroscopic data 1H, 13C and mass.
bromo substitution, showed good to moderate activity against the
sensitive strain 3D7 with IC50 1.96 and 2.09 mM, respectively. It is
also evident from the results that antiplasmodial activity enhanced
in different phenylhydrazono indolinones as compared to in-
termediates 3a-3d. The effect of substituents in the sugar moiety
and nature of sugar in the targeted compounds was also studied in
displaying the antiplasmodial activity. Compounds 5a-f with an
acetylated glucose unit showed moderate to less antiplasmodial
activities with IC50 values in 2.25e4.13
and K1 strains, except compounds 5a, 5d and 5f which were found
inactive at higher concentration with IC50 values in 5.72e8.67
mM range against both 3D7
2.2. Biology
m
M
range against K1 strain. On the other hand, compounds 6a-f with an
acetylated galactose unit and compounds 7a-f having a diacetonide
protected galactose unit, displayed comparatively very good results
The glycohybrids of phenylhydrazono indolinones (5, 6, 7, 8, 9
and 10) were screened in vitro against Chloroquine-susceptible
(3D7) and Chloroquine-resistant (K1) strains of P. falciparum for
their antiplasmodial activity. The cytotoxic concentrations 50%
with IC50 values in good to moderate range of 1.2e2.5 mM against
3D7 and K1 strains. Compounds 8a-f with acetonide protected
(CC50 in mM) and selectivity indices (SI) against both Pf strains are
xylose sugar unit showed moderate to less activity against both the
enlisted in Table 3.
strains with IC50 values in 3.08e4.79 mM range. Based on the
As evident from the activity results, on in vitro screening of the
intermediates glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-
diones 3a-3d against P. falciparum 3D7 strain, compounds 3a and
observation of antiplasmodial activities of the acetylated analogues
6, compounds 5 and 6 were deacetylated to give the respective
deacetylated analogues 9 and 10 (Scheme 3, Table 3). These
deacetylated analogues also showed moderate to less activity
against both strains, but displayed poor results as compared to
acetylated analogues. Most of the compounds among 9a-f, with a
glucose unit were found inactive at higher concentration with IC50
3d showed moderate to less activity with IC50 values of 3.54
4.33 M, respectively. Compounds 3b and 3c were found inactive at
higher concentration with IC50 values in 7.51e8.41 M range
mM and
m
m
against both 3D7 and K1 strains. Compounds 6c and 7c having 4-
methoxy group in the phenyl ring of hydrazone moiety, exhibited

R.K. Thakur et al. / European Journal of Medicinal Chemistry 155 (2018) 764e771
767
Table 1
Synthesis of glycohybrids of phenylhydrazono indolinones (5e8) by the reaction of glycosylated 1,2,3-triazolyl-methyl-indoline-2,3-diones (3a-3d) and different phenyl
hydrazine hydrochlorides (4a-4f).

768
R.K. Thakur et al. / European Journal of Medicinal Chemistry 155 (2018) 764e771
Scheme 3. Deacetylation of the synthesized acetylated analogues (5 and 6). Reagent and Conditions: a) NaOMe, Methanol, rt, 0.5 h, 75e85%.
values in 6.73e9.34
pound 9c which showed moderate activity with IC50 of 3.27
against 3D7 strain. The deacetylated analogues 10a-f, with a
galactose unit showed comparatively better results with some
m
M range against both strains, except com-
values and their safety is also reflected by their high SI values 49.22,
60.69 and 64.17 M, respectively for Pf3D7 strain. The compounds
6f and 7b with good activity against PfK1 resistant strain have also
exhibited high SI values as 45.51 and 73.88 M, respectively.
mM
m
m
moderate to less activities having IC50 values in 2.62e5.20
range against both strains and few of them were found inactive at
higher concentration with IC50 values in 6.64e8.68 M range. Thus,
m
M
Therefore, our active compounds have no cytotoxicity and can be
persuaded for further development.
m
the acetylated analogues 5e6 exhibited better activity than their
respective deacetylated analogues 9e10, similar to our previous
3. Conclusion
report [37]. The compounds with IC50 < 5 mM in either of the Pf
In conclusion,
a
small library of glycohybrids of
strains, were also evaluated for their cytotoxicity against a monkey
kidney cell line (VERO) and these compounds have SI values greater
than the desired one. The most active compounds 6c, 7b and 7c
phenylhydrazono-indolinones (5e8, 9 and 10) were prepared as
possible antiplasmodial agents with a view to develop them as
antimalarials. Out of all the compounds screened againt both
Chloroquine-sensitive 3D7 and Chloroquine-resistant K1 strains of
P. falciparum, 6c, 6f, 7b and 7c have displayed considerably good
with IC50 values < 2
values as 62.52, 118.96 and 105.25
clearly indicate that our active compounds have very good CC50
mM against Pf3D7 strain, have shown high CC50
mM, respectively. These values
activity with IC50 values < 2 mM against either of the strains. The

R.K. Thakur et al. / European Journal of Medicinal Chemistry 155 (2018) 764e771
769
Table 2
Synthesis of deacetylated glycohybrids of phenylhydrazono indolinones (9 and 10) from the respective acetylated analogues (5 and 6).
SAR study revealed that compounds with acetylated or diacetonide
galactose units showed better activity against both strains than
those with acetylated glucose or acetonide xylose units. Also, the
acetylated compounds are more active than their respective
deacetylated compounds.
erythrocytes at 5% hematocrit in complete medium. RPMI-1640
(HEPES modified) medium (Sigma) supplemented with 0.5%
AlbuMaxII, 0.2% glucose, sodium bicarbonate and 15 mM hypoxan-
thine and incubated at 37 ꢀC in CO2 incubator. Parasite growth rate
and stage was determined by the test of Giemsa's stained thin
smears of the RBCs. All the above mentioned final compounds were
tested over a concentration range of 150 nM to 10 mM. P. falciparum
4. Materials & methods
drug susceptibility test was carried out by determining fifty percent
inhibitory concentration (IC50) according to the method of Johnson
et al. (2007) with some modifications [43]. Briefly, two fold serial
dilutions of compounds and chloroquine were prepared in 96 well
4.1. In vitro cultivation of P. falciparum
The CQ sensitive (3D7) and resistant (K1) strains of P. falciparum
were cultured in vitro as per Trager and Jensen (1976) method with
some modifications [42]. Cultures were maintained in fresh human
plates and then 50
mL asynchronous cultures of infected erythro-
cytes with 0.8e1% parasitaemia and 1% hematocrit was added to

770
R.K. Thakur et al. / European Journal of Medicinal Chemistry 155 (2018) 764e771
Table 3
In vitro antiplasmodial activity and cytotoxicity of compounds (3, 5e10).
Com. Code
IC50
(
m
M)a,b
CC50
(
m
M)b,d
SI(
m
M)c
Com.
Code
IC50
(
m
M)a,b
CC50
(
m
M)b,d
SI(m
M)c
Pf3D7
PfK1
Pf3D7
PfK1
Pf3D7
PfK1
Pf3D7
PfK1
3a
3b
3c
3d
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
3.54
8.40
8.41
4.33
3.73
3.79
3.05
3.33
2.25
3.96
3.50
2.09
1.27
3.67
2.44
2.47
3.87
1.96
1.64
3.59
>10
8.07
7.51
3.40
7.11
3.84
4.13
5.72
3.80
8.67
4.13
2.91
3.12
4.28
3.00
1.93
2.62
1.61
2.29
2.77
136.60
ND
ND
38.58
NA
NA
13.66
NA
NA
7e
7f
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
9e
9f
10a
10b
10c
10d
10e
10f
3.07
3.23
4.67
4.05
3.80
4.79
3.08
4.47
4.70
9.34
3.27
7.78
8.00
6.73
4.8
2.64
2.49
4.66
3.52
3.28
3.40
3.99
3.42
8.11
7.95
4.89
7.01
8.53
7.62
8.68
4.68
5.20
3.30
3.23
2.62
0.5
122.41
117.05
82.14
72.92
74.46
104.62
83.78
70.00
88.45
ND
39.87
36.23
17.58
18.00
19.59
21.84
21.20
15.65
18.81
NA
46.36
47.00
17.62
20.71
22.70
30.77
20.99
20.46
10.91
NA
16.28
NA
NA
NA
9.60
>200
46.18
28.85
30.66
31.23
22.63
30.54
29.43
18.62
39.89
49.22
20.57
32.22
35.56
27.20
60.69
64.17
34.94
Chloroquine
58.82
15.13
30.26
23.06
13.17
18.08
13.44
15.77
28.65
20.03
17.64
26.20
45.51
40.17
73.88
45.96
147.80
107.62
116.21
95.27
75.37
68.73
116.55
65.17
83.39
62.52
75.52
78.62
87.85
105.27
118.96
105.25
125.63
79.64
ND
ND
24.35
NA
NA
ND
NA
83.37
91.48
76.21
93.70
92.08
84.49
>500
17.36
25.84
22.02
12.24
13.86
12.53
>71428.6
3.59
3.46
7.65
6.64
6.74
0.007
19.54
14.65
28.39
28.50
32.24
>1000
7a
7b
7c
7d
a
50% Inhibitory concentration against chloroquine sensitive (3D7) and resistant (K1) strains of P. falciparum.
Values are represented as average of at least duplicate determinations.
b
c
Selectivity index (SI) ¼ CC50/IC50
.
d
50% Cytotoxic concentrations. NA ¼ Not applicable. ND ¼ Not done.
each well (100
mL-final volume). Eight wells were treated as posi-
Acknowledgements
tive control (without drug) and 4 wells as negative control (without
parasite and drug). These plates were incubated in CO2 incubator
RKT and PJ are thankful to UGC, New Delhi and DBT for
providing fellowships. Financial support from Indo-France project
(CEFIPRA-5303-2) is also greatly acknowledged. We thank SAIF-
CDRI for the analytical facilities and Mrs. Shashi Rastogi for tech-
nical assistance. This is a CDRI communicaation No 9701.
maintained at 37 ꢀC for 72 h. Then 100
mL lytic buffer containing
SYBR Green 1x final concentration was added to each well and
incubated for 2 h at room temperature in a dark place. Plates were
read under fluorescence reader at Ex. 485 nm, Em. 535 nm. Fifty
percent inhibitory concentration (IC50) was determined by quan-
tifying DNA in treated and control cultures of parasites in human
erythrocytes according to the SYBR Green I (Sigma Aldrich) fluo-
rescence based method.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.ejmech.2018.06.042.
4.2. Cytotoxicity assay
References
Cytotoxic level of compounds was determined according to
O'Brien et al. (2000) method with few modifications [44]. The
monkey kidney cell line (VERO) was maintained in vitro in MEM
medium (Sigma) supplied with 15% fetal bovine serum (FBS) and 5%
CO2 at 37 ꢀC. An appropriate serial drug dilution was prepared in
culture plates and the cells were exposed to the concentrations of
particular compounds for three days, 10% resazurin, a cell viability
marker, was added and read under fluorescent reader at excitation
of 530 25 nm and emission of 590 25 nm wavelength for
calculation of the median cytotoxic concentration (CC50).
[1] World Malaria Report, World Health Organization, Geneva, 2013, 2013.
[2] N.J. White, S. Pukrittayakamee, T.T. Hien, M.A. Faiz, O.A. Mokuolu,
A.M. Dondorp, Malaria, Lancet 383 (2014) 723e735.
[3] M. Schlitzer, Malaria chemotherapeutics part I: history of antimalarial drug
development, currently used therapeutics and drugs in clinical development,
ChemMedChem 2 (2007) 944e986.
[4] M.L. Gazarini, C.A. Sigolo, R.P. Markus, A.P. Thomas, C.R.S. Garcia, Antimalarial
drugs disruption homeostasis in malarial parasites, Mem. Inst. Oswaldo Cruz
102 (2007) 329e334.
[5] C.R.S. Garcia, M.F. de Azevedo, G. Wunderlich, A. Budu, J.A. Young, L. Bannister,
Plasmodium in the postgenomic era: new insights into the molecular cell
biology of malaria parasites, Int. Rev. Cell Mol. Biol. 266 (2008) 85e156.
[6] N.J. White, Artemisinin resistance-the clock is ticking, Lancet 376 (2010)
2051e2052.
[7] (a) N. Khan, Z. Khan, W. Ahmed, N. Khan, Z. Hameed, Recent pharmacological
advancements in isatin chemistry, Int. J. Chem. Sci. 12 (2014) 1596e1606;
(b) F.A. Khan, A. Maalik, Advances in pharmacology of isatin and its de-
rivatives: a Review, Trop, J. Pharm. Res. 14 (2015) 1937e1942;
(c) Y.Q. Hu, C. Gao, S. Zhang, L. Xu, Z. Xu, L.S. Feng, X. Wu, F. Zhao, Quinoline
hybrids and their antiplasmodial and antimalarial activities, Eur. J. Med. Chem.
139 (2017) 22e47.
Author contributions
The manuscript was written through contributions from all
authors. All authors have given approval to the final version of the
manuscript. R.K.T. and P.J. contributed equally to this work.
[8] (a) S.N. Pandeya, S. Smitha, M. Jyoti, S.K. Sridhar, Biological activities of isatin
and its derivatives, Acta Pharm. 55 (2005) 27;
(b) 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, Synthesis and structure-activity relationships of novel indirubin
derivatives as potent anti-proliferative agents with CDK2 inhibitory activities,
Bioorg. Med. Chem. 14 (2006) 237;
(c) A.H. Abadi, S.M. Abou-Seri, D.E. Abdel-Rahman, C. Klein, O. Lozach,
L. Meijer, Synthesis of 3-substituted-2-oxoindole analogues and their
Conflicts of interest
The authors declare that they have no conflicts of interest with
the contents of this article.

R.K. Thakur et al. / European Journal of Medicinal Chemistry 155 (2018) 764e771
evaluation as kinase inhibitors, anticancer and antiangiogenic agents, Eur. J. J. Med. Chem. 52 (2009) 407;
771
Med. Chem. 41 (2006) 296;
(b) M. Whitnall, J. Howard, P. Ponka, D.R. Richardson, A class of iron chelators
with a wide spectrum of potent antitumor activity that overcomes resistance
to chemotherapeutics, Proc. Natl. Acad. Sci. U. S. A 103 (2006) 14901.
[31] (a) R. Raj, J. Gut, P.J. Rosenthal, V. Kumar, 1H-1,2,3-Triazole-tethered isatin-7-
chloroquinoline and 3-hydroxy-indole-7-chloroquinoline conjugates: syn-
thesis and antimalarial evaluation, Bioorg. Med. Chem. Lett 24 (2014)
756e759;
(b) M. Rottman, C. McNamara, B.K.S. Yeung, M.C.S. Lee, B. Zou, B. Russell,
P. Seitz, D.M. Plouffe, N.V. Dharia, J. Tan, S.B. Cohen, K.R. Spencer,
G.E. Gonzalez-paez, S.B. Lakshminarayana, A. Goh, R. Suwanarusk, T. Jegla,
E.K. Schmitt, H.P. Beck, R. Brun, F. Nosten, L. Renia, V. Dartois, T.H. Keller,
D.A. Fidock, E.A. Winzeler, T.T. Diagana, Spiroindolones, a potent compound
class for the treatment of malaria, Science 329 (2010) 1175e1180;
(c) A.B. Oliveira, M.F. Dolabela, F.C. Braga, R.L.R.P. Jacome, F.P. Varotti,
M.M. Povoa, Plant-derived antimalarial agents: new leads and efficient phy-
thomedicines. Part I. Alkaloids, An. Acad. Bras. Cienc. 81 (2009) 4.
[32] (a) B.N. Acharya, D. Saraswat, M.P. Kaushik, Pharmacophore based discovery
of potential antimalarial agent targeting haem detoxification pathway, Eur. J.
Med. Chem. 43 (2008) 2840e2852;
(d) A. Gursoy, N. Karali, Synthesis and primary cytotoxicity evaluation of 3-
[[(3-phenyl-4(3H)-quinazolinone-2-yl)-mercaptoacetyl]hydrazono]-1H-2-
indolinones, Eur. J. Med. Chem. 38 (2003) 633.
[9] G.R. Newkome, W.W. Pandler, Contemporary Heterocyclic Chemistry, Wiley,
New York, 1982;
[10] A.A. Jarrahpour, D. Khalili, Synthesis of 3,3'-[methylenebis(3,1-
phenylenenitrilo)]bis[1,3-dihydro]-2H-indol-2-one as a novel bis-Schiff base,
Molbank 4 (2005). M437.
[11] C.L. Woodard, Z. Li, A.K. Kathcart, J. Terrell, L. Gerena, M. Lopez-Sanchez,
D.E. Kyle, A.K. Bhattacharjee, D.A. Nichols, W. Ellis, S.T. Prigge, J.A. Geyer,
N.C. Waters, Oxindole-based compounds are selective inhibitors of Plasmo-
dium falciparum cyclin dependent protein kinases, J. Med. Chem. 46 (2003)
3877e3882.
[12] T. Jiang, K.L. Kuhen, K. Wolff, H. Yin, K. Bieza, J. Caldwell, B. Bursulaya,
T. Tuntland, K. Zhang, D. Karanewsky, Y. He, Design, synthesis and biological
evaluations of novel oxindoles as HIV-1 non-nucleoside reverse transcriptase
inhibitors. Part I, Bioorg. Med. Chem. Lett 16 (2006) 2109e2112.
[13] R.A. Amal, R. Raghunathan, M.R. Sridevikumaria, N. Raman, Synthesis, anti-
microbial and antifungal activity of a new class of spiro pyrrolidines, Bioorg.
Med. Chem. 11 (2003) 407e419.
[14] M.C. Rodriguez-Arguelles, S. Mosquera-Vazaquez, P. Touron-Touceda,
J. Sanmartin-Matalobos, A.M. Garcia-Deibe, M. Belicchi-Ferraris, G. Pelosi,
C. Pelizzi, F. Zani, Complexes of 2-thiophenecarbonyl and isonicotinoyl
hydrazones of 3-(N-methyl)isatin: a study of their antimicrobial activity,
J. Inorg. Biochem. 101 (2007) 138e147.
[15] R. Tripathy, A. Reiboldt, P.A. Messina, M. Iqbal, J. Singh, E.R. Bacon,
T.S. Angeles, S.X. Yang, M.S. Albom, C. Robinson, H. Chang, B.A. Ruggeri,
J.P. Mallamo, Structure-guided identification of novel VEGFR-2 kinase in-
hibitors via solution phase parallel synthesis, Bioorg. Med. Chem. Lett 16
(2006) 2158.
(b) C. Fattorusso, G. Campiani, G. Kukreja, M. Persico, S. Butini, M.P. Romano,
M. Altarelli, S. Ros, M. Brindisi, L. Savini, E. Novellino, V. Nacci, E. Fattorusso,
S. Parapini, N. Basilico, D. Taramelli, V. Yardley, S. Croft, M. Borriello,
S. Gemma, Design, synthesis, and structure-activity relationship studies of 4-
quinolinyl-and 9-acrydinylhydrazones as potent antimalarial agents, J. Med.
Chem. 51 (2008) 1333e1343.
[33] (a) R.P. Tripathi, A.K. Yadav, A. Ajay, S.S. Bisht, V. Chaturvedi, S.K. Sinha,
Application of Huisgen (3þ2) cycloaddition reaction: synthesis of 1-(2,3-
dihydrobenzofuran-2-yl-methyl [1,2,3]-triazoles and their antitubercular
evaluations, Eur. J. Med. Chem. 45 (2010) 142e148;
(b) B.K. Singh, A.K. Yadav, B. Kumar, A. Gaikwad, S.K. Sinha, V. Chaturvedi,
R.P. Tripathi, Preparation and reactions of sugar azides with alkynes: synthesis
of sugar triazoles as antitubercular agents, Carbohydr. Res. 343 (2008)
1153e1162.
[16] A. Cane, M.C. Tournaire, D. Barritault, M. Crumeyrolle-Arias, The endogenous
oxindoles 5-hydroxyoxindole and isatin are antiproliferative and proapopto-
tic, Biochem. Biophys. Res. Commun 276 (2000) 379.
[17] V.C. da Silveira, J.S. Luz, C.C. Oliveira, I. Graziani, M.R. Ciriolo, A.M. Costa-
Ferreira, Double-strand DNA cleavage induced by oxindole-Schiff base cop-
per(II) complexes with potential antitumor activity, J. Inorg. Biochem. 102
(2008) 1090.
[34] (a) N. Devender, S. Gunjan, S. Chhabra, K. Singh, V.R. Pasam, S.K. Shukla,
A. Sharma, S. Jaiswal, S.K. Singh, Y. Kumar, J. Lal, A.K. Trivedi, R. Tripathi,
R.P. Tripathi, Identification of
b-Amino alcohol grafted 1,4,5 trisubstituted
1,2,3-triazoles as potent antimalarial agents, Eur. J. Med. Chem. 109 (2016)
187e198;
[18] T.R. Bal, B. Anand, P. Yogeeswari, D. Sriram, Synthesis and evaluation of anti-
(b) N. Devender, S. Gunjan, R. Tripathi, R.P. Tripathi, Synthesis and anti-
plasmodial activity of novel indoleamide derivatives bearing sulfonamide and
triazole pharmacophores, Eur. J. Med. Chem. 131 (2017) 171e184.
[35] H.C. Kolb, K.B. Sharpless, Drug discov. Today Off. 8 (2003) 1128e1137.
[36] (a) K. Song, I.S. Yoon, N.A. Kim, D.H. Kim, J. Lee, H.J. Lee, S. Lee, S. Choi,
M.K. Choi, H.H. Kim, S.H. Jeong, W.S. Son, D.D. Kim, Y.K. Shin, Glycoengin-
HIV activity of isatin
Lett 15 (2005) 4451.
b-thiosemicarbazone derivatives, Bioorg. Med. Chem.
[19] M. Verma, S.N. Pandeya, K.N. Singh, J.P. Stables, Anticonvulsant activity of
Schiff bases of isatin derivatives, Acta Pharm. 54 (2004) 49e56.
[20] N. Igosheva, C. Lorz, E. O'Conner, V. Glover, H. Mehmet, Isatin, an endogenous
monoamine oxidase inhibitor, triggers a dose- and time-dependent switch
from apoptosis to necrosis in human neuroblastoma cells, Neurochem. Int. 47
(2005) 216e224.
[21] K. Kumar, B. Pradines, M. Madamet, R. Amalvict, N. Benoit, V. Kumar, 1H-1,2,3-
triazole tethered isatin-ferrocene conjugates: synthesis and in vitro antima-
larial evaluation, Eur. J. Med. Chem. 87 (2014) 801e804.
eering of interferon-b 1a improves its biophysical and pharmacokinetic
properties, PLoS One 9 (2014) 96967;
(b) K.K.G. Ramakrishna, R.K. Thakur, V.R. Pasam, J. Pandey, R. Mahar,
S.K. Shukla, A.K. Tamrakar, R.P. Tripathi, Synthesis of novel glycosyl-1,2,3-1H-
triazolyl methyl quinazolin-4(3H)-ones and their effect on GLUT4 trans-
location, Tetrahedron 73 (2017) 187e203.
[22] R.H. Hans, I.J.F. Wiid, P.D. van Helden, B. Wan, S.G. Franzblau, J. Gut,
P.J. Rosenthal, K. Chibale, Novel thiolactone-isatin hybrids as potential anti-
malarial and antitubercular agents, Bioorg. Med. Chem. Lett 21 (2011)
2055e2058.
[23] T.N. Akhaja, J.P. Raval, Design, synthesis and in vitro evaluation of
tetrahydropyrimidineeisatin hybrids as potential antitubercular and anti-
malarial agents, Chin. Chem. Lett. 23 (2012) 785.
[24] W. Chu, J. Zhang, C. Zenq, J. Rothfuss, Z. Tu, Y. Chu, D.E. Reichert, M.J. Welch,
R.H. Mach, N-benzylisatin sulfonamide analogues as potent caspase-3 in-
hibitors: synthesis, in vitro activity, and molecular modeling studies, J. Med.
Chem. 48 (2005) 7637e7647.
[25] S.E. Harpstrite, S.D. Collins, A. Oksman, D.E. Goldberg, V. Sharma, Synthesis,
characterization, and antimalarial activity of novel schiff-base-phenol and
naphthalene-amine ligands, Med. Chem. 4 (2008) 392e395.
[26] A. Masunari, L.C. Tavares, A new class of nifuroxazide analogues: synthesis of
5-nitrothiophene derivatives with antimicrobial activity against multidrug-
resistant Staphylococcus aureus, Bioorg. Med. Chem. 15 (2007) 4229.
[27] J.V. Ragavendran, D. Sriram, S.K. Patel, I.V. Reddy, N. Bharathwajan, J. Stables,
P. Yogeeswari, Design and synthesis of anticonvulsants from a combined
phthalimideeGABAeanilide and hydrazone pharmacophore, Eur. J. Med.
Chem. 42 (2007) 146.
[28] U. Salgin-Goksen, N. Gokhan-Kelekci, O. Goktas, Y. Koysal, E. Kilic, S. Isik,
G. Aktay, M. Ozalp, 1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones,
1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones:
synthesis, analgesic-anti-inflammatory and antimicrobial activities, Bioorg.
Med. Chem. 15 (2007) 5738.
[29] G.A. Silva, L.M.M. Costa, F.C.F. Brito, A.L.P. Miranda, E.J. Barreiro, C.A.M. Fraga,
New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-
acylhydrazone derivatives, Bioorg. Med. Chem. 12 (2004) 3149.
[30] (a) P.V. Bernhardt, P.C. Sharpe, M. Islam, D.B. Lovejoy, D.S. Kalinowski,
D.R. Richardson, Iron chelators of the dipyridylketone thiosemicarbazone
class: precomplexation and transmetalation effects on anticancer activity,
[37] K.K.G. Ramakrishna, S. Gunjan, A.K. Shukla, V.R. Pasam, V.M. Balaramnavar,
A. Sharma, S. Jaiswal, J. Lal, R. Tripathi, A.R. Ramachandran, R.P. Tripathi,
Identification of novel phenyl butenonyl C-Glycosides with ureidyl and sul-
fonamidyl moieties as antimalarial agents, ACS Med. Chem. Lett. 5 (2014)
878e883.
[38] G. Smith, M. Glaser, M. Perumal, Q.D. Nguyen, B. Shan, E. Arstad, E.O. Aboagye,
Design, synthesis, and biological characterization of a caspase 3/7 selective
isatin labeled with 2-[18F]fluoroethylazide, J. Med. Chem. 51 (2008)
8057e8067.
[39] R.K. Thakur, A. Mishra, K.K.G. Ramakrishna, R. Mahar, S.K. Shukla,
A.K. Srivastava, R.P. Tripathi, Synthesis of novel pyrimidine nucleoside ana-
logues owning multiple bases/sugars and their glycosidase inhibitory activity,
Tetrahedron 70 (2014) 8462e8473.
[40] W.M. Eldehna, A. Altoukhy, H. Mahrous, H.A. Abdel-Aziz, Design, synthesis
and QSAR study of certain isatin-pyridine hybrids as potential anti-
proliferative agents, Eur. J. Med. Chem. 90 (2015) 684e694.
[41] H.N. Bramson, J. Corona, S.T. Davis, S.H. Dickerson, M. Edelstein, S.V. Frye,
R.T. Gampe Jr., P.A. Harris, A. Hassell, W.D. Holmes, R.N. Hunter, K.E. Lackey,
B. Lovejoy, M.J. Luzzio, V. Montana, W.J. Rocque, D. Rusnak, L. Shewchuk,
J.M. Veal, D.H. Walker, L.F. Kuyper, Oxindole-based inhibitors of cyclinde-
pendent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray
crystallographic analysis, J. Med. Chem. 44 (2001) 4339e4358.
[42] W. Trager, J.B. Jensen, Human malaria parasites in continuous culture, Science
193 (1976) 673e675.
[43] J.D. Johnson, A.D. Richard, G. Lucia, L. Miriam, E.R. Norma, C.W. Norman,
Assessment and continued validation of the malaria SYBR green I-based
fluorescence assay for use in malaria drug screening, Antimicrob. Agents
Chemother. 51 (2007) 1926e1933.
[44] J. O'Brien, I. Wilson, T. Orton, F. Pognan, Investigation of the alamar blue
(resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity,
Eur. J. Biochem. 267 (2000) 5421e5427.