Novel arylidene derivatives of quinoline based thiazolidinones: Synthesis, in vitro, in vivo and in silico study as antimalarials

Full text of DOI:10.1016/j.exppara.2018.01.015

Experimental Parasitology 185 (2018) 107e114
Contents lists available at ScienceDirect
Experimental Parasitology
journal homepage: www.elsevier.com/locate/yexpr
Novel arylidene derivatives of quinoline based thiazolidinones:
Synthesis, in vitro, in vivo and in silico study as antimalarials
,
*
Sandeep Jain a, Ajay Kumar b, Deepika Saini a
a Drug Discovery and Research Laboratory, Department of Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, 125001,
India
b Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, 136119, India
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ Synthesis and characterization of
arylidene derivatives of quinoline
based thiazolidinones.
ꢀ Evaluation for in vitro antimalarial
potential against CQ-sensitive and
CQ-resistant strains of P. falciparum.
ꢀ Top five potent compounds were
further evaluated in vivo against
P. berghei.
ꢀ Docking studies have been per-
formed in the active site of
P. falciparum lactate dehydrogenase.
ꢀ 5g was found to be most promising
candidate
with
73.38%
of
suppression.
a r t i c l e i n f o
and the most lethal parasite is former one. The parasitic multipli-
Article history:
cation begins in the liver, infecting erythrocytes where a cyclic
asexual replication begins with the cycles of fever and chills as
symptoms of malaria. This infected person with severe illness can
result to death within hours to days; if untreated (Warhurst et al.,
2003; Mishra et al., 2017). According to the World Health Organi-
sation (WHO) report, 212 million new cases of malaria worldwide
in 2015 were reported (range 148e304 million). The WHO African
Region accounted for most global cases of malaria (90%), followed
by the South-East Asia Region (7%) and the Eastern Mediterranean
Region (2%) (WHO, World Malaria Report, 2016). The surge in
resistance of malaria parasites particularly in P. falciparum is an
important factor in the persistence of this disease as a major
worldwide public health threat (Sinha et al., 2014). The existing
chemotherapy lacks satisfaction and effectiveness due to the side
effects associated to long-term treatments. The existing drugs come
across shortcomings like drug resistance and strain sensitivity for
the clinically accessible chemotherapy (Sahu et al., 2016; Manohar
et al., 2014; Teixeira et al., 2014).
Received 19 April 2017
Received in revised form
3 January 2018
Accepted 14 January 2018
1. Introduction
Malaria is a common and life-threatening disease transmitted
via the bites of infected female Anopheles mosquitoes and caused by
protozoan parasites of the genus Plasmodium. The prevalent species
responsible for it are Plasmodium falciparum and Plasmodium vivax
* Corresponding author. Drug Discovery and Research Laboratory, Department of
Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology,
Hisar, 125001, Haryana, India.
Quinoline derived drugs like chloroquine, amodiaquine, qui-
nine, quinidine, mefloquine, primaquine, lumefantrine, and hal-
ofantrine have long been used against malaria and all these shows
E-mail address: deepika.saini.666@gmail.com (D. Saini).
https://doi.org/10.1016/j.exppara.2018.01.015
0014-4894/© 2018 Elsevier Inc. All rights reserved.

108
S. Jain et al. / Experimental Parasitology 185 (2018) 107e114
potent activity against the erythrocytic stage of infection (Olson
et al., 1999). Primaquine also kills intrahepatic forms and gameto-
cytes. The drugs act by accumulating in the parasite food vacuole
and forming a complex with heme that prevents crystallization in
the Plasmodium food vacuole. Heme polymerase activity is re-
straint, resulting in accumulation of cytotoxic-free heme (Foley and
Tilley, 1998; Bekhit et al., 2012). The appearance of drug-resistant
strains of the malaria parasite was the distressing outcome of ef-
forts for the development of insecticide-resistant mosquitos
(Kumar et al., 2015).
hydrazino-4-methylquinoline, compound 2 in EtOH (20 ml) was
added in an equimolar amount of various aromatic aldehyde and
refluxed in the presence of 1e2 drop of glacial acetic acid for 6 h.
The resulting solution was poured on crushed ice to yield hydra-
zones in high yield (Unsal-Tan et al., 2012; Kumar et al., 2007).
2.1.1.1. 1-Benzylidene-2-(4-methylquinolin-2-yl)hydrazine
(3a).
Yield 73%, mp 153e154 ꢁC IR (
y
, cmꢂ1): 3354.20 (N-H), 2919.50 (C-
H), 1612.10 (C¼N); 1H NMR (400 MHz, CDCl3,
d): 8.59 (s, br, 1H, NH),
8.23 (s, 1H, quinoline ring), 7.43e7.89 (m, 9H, aromatic), 7.28 (s, 1H,
-N¼CH), 2.74 (s, 3H, CH3 of Qu-ring).
Several biological activities are associated with
a five-
membered ring thiazolidine which is an important pharmaco-
phore. 4-Thiazolidinones having wide range of biological activities
are evolved from thiazolidine with a carbonyl group at the position
4. Substitution of group to the carbon atom present at position 2
shows marked difference in structure and physicochemical prop-
erties of 4-thiazolidones (Singh et al., 2010; Dorn et al., 1995). Rigid
molecules present in the nitrogen containing heterocyclic skeleton
(thiazolidine-4-one) show biologically active scaffold for the design
of new antimalarial drugs active against Plasmodium malaria
parasite (Rojas Ruiz et al., 2011; Kumar et al., 2014; Rosenthal et al.,
2002). In the current study, novel thiazolidinone-quinoline hybrids
and their corresponding arylidene derivatives were prepared in
good yield. Structure-Activity relationship has also been estab-
lished to get a deep insight into the effect of different substitutions
on antimalarial potential of the series. This work also includes the
docking simulation of the active agents among the series to get an
idea about the ligand receptor interaction. We, herein present
study, reported the synthesis, in vitro, in vivo and in silico screening
of synthesized series for antimalarial potential.
2.1.1.2. 1-(4-chlorobenzylidene)-2-(4-methylquinolin-2-yl)hydrazine
(3b). Yield 71%, mp 166e168 ꢁC IR ( , cmꢂ1): 3361.12 (N-H), 2921.17
y
(C-H), 1613.24 (C¼N), 653.27 (C-Cl); 1H NMR (400 MHz, CDCl3,
d):
8.61 (s, br, 1H, NH), 8.26 (s, 1H, quinoline ring), 7.83 (d, 2H),
7.65e7.89 (m, 4H), 7.29 (s, 1H, -N¼CH), 6.98 (d, 2H), 2.78 (s, 3H,
CH3).
2.1.1.3. 1-(4-methylbenzylidene)-2-(4-methylquinolin-2-yl)hydrazine
(3c). Yield 79%, mp 172e174 ꢁC IR ( , cmꢂ1): 3349.11 (N-H), 2929.41
y
(C-H), 1609.81 (C¼N); 1H NMR (400 MHz, CDCl3,
d): 8.61(s, br, 1H,
NH), 8.23 (s, 1H, quinoline ring), 7.86 (d, 2H), 7.55e7.78 (m, 4H),
7.26 (s,1H, -N¼CH), 6.99 (d, 2H), 2.73 (s, 3H, CH3 of Qu-ring), 2.31 (s,
3H, CH3).
2.1.1.4. 1-(4-methoxybenzylidene)-2-(4-methylquinolin-2-yl)hydra-
zine (3d). Yield 81%, mp 151e153 ꢁC IR ( , cmꢂ1): 3327.33 (N-H),
y
2932.45 (C-H), 1615.11 (C¼N); 1H NMR (400 MHz, CDCl3,
d): 8.64 (s,
2. Experimental
br, 1H, NH), 8.23 (s, 1H, quinoline ring), 7.81 (d, 2H), 7.68e7.90 (m,
4H), 7.28 (s, 1H, -N¼CH), 6.98 (d, 2H), 3.89 (s, 3H, OCH3), 2.79 (s, 3H,
CH3).
2.1. Synthetic strategy adopted
The synthetic protocol followed for the synthesis of compounds
under study has been outlined in Scheme 1.
2.1.1.5. 1-(4-methylquinolin-2-yl)-2-(thiophen-2-ylmethylene)hy-
drazine (3e). Yield 69%, mp 140e142 ꢁC IR ( , cmꢂ1): 3341.29 (N-H),
y
2.1.1. General experimental procedure for synthesis of hydrazone
(3a-e)
2922.17 (C-H), 1613.62 (C¼N); 1H NMR (400 MHz, CDCl3,
d): 8.59 (s,
br, 1H, NH), 8.17 (s, 1H, quinoline ring), 7.21 (s, 1H, -N¼CH),
The whole synthesis is outlined in Scheme 1. To a mixture of 2-
6.83e7.56 (m, 7H), 2.70 (s, 3H, CH3).
Scheme 1. Synthesis of arylidene derivatives (5 a-r): a) 1e2 drops Glacial acetic acid, Ethanol, reflux, 6 h. b) Thioglycolic acid, 1,4-Dioxane, ZnCl2, reflux, 8e10 h. c) Glacial acetic
acid, Sodium acetate, reflux, 12 h.

S. Jain et al. / Experimental Parasitology 185 (2018) 107e114
109
2.1.2. General experimental procedure for synthesis of
thiazolidinone (4a-e)
2.1.3.2. 5-(4-chlorobenzylidene)-3-(4-methylquinolin-2-ylamino)-2-
phenylthiazolidin-4-one (5b). Yield 56%, mp 219e221 ꢁC IR (v,
cmꢂ1): 1525 (¼C-H), 2975 (¼C-H), 1569 (C¼N); 1H NMR (400 MHz,
To a solution of compound (3) (0.01 mol) in 1,4 dioxane (50 ml)
was added mercapto acetic acid (0.015 mol) with stirring and a little
amount of anhydrous ZnCl2 was added. The mixture was refluxed
for 10e12 h, after the completion of reaction, it was cooled and the
excess solvent distilled and poured into sodium bicarbonate solu-
tion to neutralize it. The solid product was filtered and washed with
cold water. The resulting solid was recrystallized in ethanol (99%)
(Desai and Dodiya, 2014; Nagalakshmi et al., 2013).
DMSO-d6, d): 8.24 (s, 1H, NH), 8.13 (s, 1H, H3 of quinoline), 6.88 (s,
1H, thiazolidinone, 2nd position), 6.78e7.67 (m, 13H), 5.82 (s,
1H, ¼CH-Ar), 2.73 (s, 3H, CH3 of quinoline); MS: m/z ¼ 458.73
(Mþ1); Anal. Calcd for C26H20ClN3OS: C, 68.19; H, 4.40; N, 9.18.
Found: C, 68.21; H, 4.46; N, 9.25.
2.1.3.3. 5-(4-methylbenzylidene)-3-(4-methylquinolin-2-ylamino)-
2-phenylthiazolidin-4-one (5c). Yield 60%, mp 199e201 ꢁC IR (v,
cmꢂ1): 1526 (¼C-H), 2972 (¼C-H), 1571 (C¼N); 1H NMR (400 MHz,
2.1.2.1. 3-(4-methylquinolin-2-ylamino)-2-phenylthiazolidin-4-one
(4a). Yield 51%, mp 202e204 ꢁC IR ( , cmꢂ1): 3406.34 (N-H),
y
DMSO-d6, d):8.23 (s, 1H, NH), 8.11 (s, 1H, H3 of quinoline), 6.92e7.83
1656.17 (C¼O); 1H NMR (400 MHz, DMSO-d6,
d): 8.46 (s, 1H, NH),
(m, 13H), 6.86 (s, 1H, thiazolidinone, 2nd position), 5.80 (s,
1H, ¼CH-Ar), 2.69 (s, 3H, CH3 of quinoline), 2.45 (s, 3H, CH3 of
phenyl). MS: m/z ¼ 438.47 (Mþ1); Anal. Calcd for C27H23N3OS: C,
74.11; H, 5.30; N, 9.60. Found: C, 74.19; H, 5.37; N, 9.71.
8.16 (s, 1H, H3 of quinoline), 7.33e7.90 (m, 9H), 6.77 (s, 1H, thia-
zolidinone, 2nd position), 5.29 (s, 2H, Thiazolidinone, 4th position),
2.63 (s, 3H, CH3 of quinoline).
2.1.2.2. 2-(4-chlorophenyl)-3-(4-methylquinolin-2-ylamino)thiazoli-
2.1.3.4. 5-(4-methoxybenzylidene)-3-(4-methylquinolin-2-ylamino)-
2-phenylthiazolidin-4-one (5d). Yield 63%, mp 205e206 ꢁC IR (v,
cmꢂ1): 1529 (¼C-H), 2976 (¼C-H), 1573 (C¼N); 1H NMR (400 MHz,
din-4-one (4b). Yield 54%, mp 230e232 ꢁC IR ( , cmꢂ1): 3409.46 (N-
y
H), 1659.32 (C¼O); 1H NMR (400 MHz, DMSO-d6,
d): 8.52 (s, 1H,
NH), 8.14 (s, 1H, H3 of quinoline), 7.20e7.85 (m, 8H), 6.65 (s, 1H,
thiazolidinone, 2nd position), 5.33 (s, 2H, Thiazolidinone, 4th po-
sition), 2.68 (s, 3H, CH3 of quinoline).
DMSO-d6, d): 8.23 (s, 1H, NH), 8.17 (s, 1H, H3 of quinoline), 6.83 (s,
1H, thiazolidinone, 2nd position), 6.77e7.69 (m, 13H), 5.83 (s,
1H, ¼CH-Ar), 4.03 (s, 3H, OCH3 of phenyl), 2.67 (s, 3H, CH3 of
quinoline); MS: m/z ¼ 454.35 (Mþ1); Anal. Calcd for C27H23N3O2S:
C, 71.50; H, 5.11; N, 9.26. Found: C, 71.53; H, 5.16; N, 9.21.
2.1.2.3. 3-(4-methylquinolin-2-ylamino)-2-p-tolylthiazolidin-4-one
(4c). Yield 49%, mp 236e238 ꢁC IR ( , cmꢂ1): 3411.43 (N-H),
y
1659.22 (C¼O); 1H NMR (400 MHz, DMSO-d6,
d):8.41 (s, 1H, NH),
2.1.3.5. 5-Benzylidene-2-(4-chlorophenyl)-3-(4-methylquinolin-2-
ylamino)thiazolidin-4-one (5e). Yield 63%, mp 205e206 ꢁC IR (v,
cmꢂ1): 1531 (¼C-H), 2972 (¼C-H), 1571 (C¼N); 1H NMR (400 MHz,
8.19 (s, 1H, H3 of quinoline), 7.15e7.95 (m, 8H), 6.73 (s, 1H, thiazo-
lidinone, 2nd position), 5.06 (s, 2H, Thiazolidinone, 4th position),
2.65 (s, 3H, CH3 of quinoline), 2.35 (s, 3H, CH3 of phenyl).
DMSO-d6, d): 8.27 (s, 1H, NH), 8.19 (s, 1H, H3 of quinoline), 7.1e7.92
(m, 13H), 6.79 (s, 1H, thiazolidinone, 2nd position), 5.84 (s,
1H, ¼CH-Ar), 2.65 (s, 3H, CH3 of quinoline); MS: m/z ¼ 458.35
(Mþ1); Anal. Calcd for C26H20ClN3OS: C, 68.19; H, 4.40; N, 9.18.
Found: C, 68.21; H, 4.46; N, 9.25.
2.1.2.4. 2-(4-methoxyphenyl)-3-(4-methylquinolin-2-ylamino)thia-
zolidin-4-one (4d). Yield 57%, mp 220e222 ꢁC IR ( , cmꢂ1): 3410.58
y
(N-H), 1654.63 (C¼O); 1H NMR (400 MHz, DMSO-d6,
d): 8.42 (s, 1H,
NH), 8.26 (s, 1H, H3 of quinoline), 7.06e7.80 (m, 8H), 6.54 (s, 1H,
thiazolidinone, 2nd position), 5.15 (s, 2H, Thiazolidinone, 4th po-
sition), 4.35 (s, 3H, OCH3 of phenyl), 2.67 (s, 3H, CH3 of quinoline).
2.1.3.6. 5-(4-chlorobenzylidene)-2-(4-chlorophenyl)-3-(4-
methylquinolin-2-ylamino) thiazolidin -4-one (5f). Yield 61%, mp
217e218 ꢁC IR (v, cmꢂ1): 1527 (¼C-H), 2971 (¼C-H), 1573 (C¼N); 1H
NMR (400 MHz, DMSO-d6, d): 8.29 (s, 1H, NH), 8.18 (s, 1H, H3 of
2.1.2.5. 3-(4-methylquinolin-2-ylamino)-2-(thiophen-2-yl)thiazoli-
din-4-one (4e). Yield 42%, mp 200e202 ꢁC IR ( , cmꢂ1): 3399.18 (N-
y
quinoline), 7.12e7.97 (m, 12H), 6.75 (s, 1H, thiazolidinone, 2nd
position), 5.87 (s, 1H, ¼CH-Ar), 2.68 (s, 3H, CH3 of quinoline). MS:
m/z ¼ 492.45 (Mþ1); Anal. Calcd for C26H19Cl2N3OS: C, 63.42; H,
3.89; N, 8.53. Found: C, 63.52; H, 3.93; N, 8.55.
H), 1659.47 (C¼O); 1H NMR (400 MHz, DMSO-d6,
d): 8.48 (s, 1H,
NH), 8.21 (s, 1H, H3 of quinoline), 7.16e7.85 (m, 7H), 5.23 (s, 2H,
Thiazolidinone, 4th position), 6.67 (s, 1H, thiazolidinone, 2nd po-
sition), 2.56 (s, 3H, CH3 of quinoline).
2.1.3.7. 5-(4-methylbenzylidene)-2-(4-chlorophenyl)-3-(4-
methylquinolin-2-ylamino) thiazolidin-4-one (5g). Yield 59%, mp
221e223 ꢁC IR (v, cmꢂ1): 1528 (¼C-H), 2968 (¼C-H),1571 (C¼N); 1H
2.1.3. General experimental procedure for synthesis of arylidine
derivatives
NMR (400 MHz, DMSO-d6, d): 8.33 (s, 1H, NH), 8.17 (s, 1H, H3 of
A well-stirred solution of 3-(4-methylquinolin-2-ylamino)-2-
arylthiazolidin-4-ones (4a-e) in 20 ml glacial acetic acid was buff-
ered with sodium acetate, 0.66 g (8 mmol) followed by addition of
substituted arylaldehyde (6 mmol). The solution was refluxed for
12 h and then poured into ice-cold water to yield titled compounds,
5a-r. The resulting product was purified by recrystallization from
dioxane (Omar et al., 2010; Deep et al., 2014).
quinoline), 7.14e7.93 (m, 12H), 6.79 (s, 1H, thiazolidinone, 2nd
position), 5.80 (s, 1H, ¼CH-Ar), 2.65 (s, 3H, CH3 of quinoline), 2.47
(s, 3H, CH3 of phenyl); MS: m/z ¼ 492.45 (Mþ1); Anal. Calcd for
C27H22ClN3OS C, 68.71; H, 4.70; N, 8.90. Found: C, 68.76; H, 4.73; N,
8.94.
2.1.3.8. 5-(4-methoxybenzylidene)-2-(4-chlorophenyl)-3-(4-
methylquinolin-2-ylamino) thiazolidin-4-one (5h). Yield 65%, mp
198e201 ꢁC IR (v, cmꢂ1): 1532 (¼C-H), 2976 (¼C-H), 1577 (C¼N); 1H
2.1.3.1. 5-Benzylidene-3-(4-methylquinolin-2-ylamino)-2-
phenylthiazolidin-4-one (5a). Yield 62%, mp 212e214 ꢁC IR (v,
Cmꢂ1): 1527 (¼C-H), 2974 (¼C-H), 1565 (C¼N); 1H NMR (400 MHz,
NMR (400 MHz, DMSO-d6, d): 8.31 (s, 1H, NH), 8.20 (s, 1H, H3 of
DMSO-d6,
d
): 8.25 (s, 1H, NH), 8.11 (s, 1H, H3 of quinoline), 6.82 (s,
quinoline), 6.88e7.87 (m, 12H), 6.72 (s, 1H, thiazolidinone, 2nd
position), 5.84 (s, 1H, ¼CH-Ar), 4.12 (s, 3H, OCH3 of phenyl), 2.71 (s,
3H, CH3 of quinoline); MS: m/z ¼ 488.34 (Mþ1); Anal. Calcd for
1H, thiazolidinone, 2nd position), 6.9e7.85 (m, 14H), 5.88 (s,
1H, ¼CH-Ar), 2.70 (s, 3H, CH3 of quinoline); MS: m/z ¼ 424.35
(Mþ1); Anal. Calcd for C26H21N3OS: C, 73.73; H, 5.00; N, 9.92.
Found: C, 73.81; H, 5.02; N, 9.89.
C27H22ClN3O2S; C, 66.45; H, 4.54; N, 8.61. Found: C, 66.47; H, 4.53;
N, 8.64.

110
S. Jain et al. / Experimental Parasitology 185 (2018) 107e114
2.1.3.9. 5-Benzylidene-3-(4-methylquinolin-2-ylamino)-2-p-tolylth-
(Mþ1); Anal. Calcd for C28H25N3O2S; C, 71.92; H, 5.39; N, 8.99.
iazolidin-4-one (5i). Yield 54%, mp 213e215 ꢁC IR (v, cmꢂ1): 1530
Found: C, 71.99; H, 5.45; N, 9.02.
(¼C-H), 2974 (¼C-H), 1573 (C¼N); 1H NMR (400 MHz, DMSO-d6,
d):
8.26 (s, 1H, NH), 8.15 (s, 1H, H3 of quinoline), 7.1e7.92 (m, 13H), 6.71
(s, 1H, thiazolidinone, 2nd position), 5.87 (s, 1H, ¼CH-Ar), 2.66 (s,
3H, CH3 of quinoline), 2.34 (s, 3H, CH3 of phenyl). MS: m/z ¼ 438.47
(Mþ1); Anal. Calcd for C27H23N3OS: C, 74.11; H, 5.30; N, 9.60.
Found: C, 74.19; H, 5.37; N, 9.71.
2.1.3.16. 5-(4-methoxybenzylidene)-2-(4-methoxyphenyl)-3-(4-
methylquinolin-2-ylamino)thiazolidin-4-one (5p). Yield 52%, mp
229e231 ꢁC IR (v, cmꢂ1): 1527 (¼C-H), 2976 (¼C-H), 1573 (C¼N); 1H
NMR (400 MHz, DMSO-d6, d):8.26 (s, 1H, NH), 8.12 (s, 1H, H3 of
quinoline), 6.98e7.88 (m, 12H), 6.69 (s, 1H, thiazolidinone, 2nd
position), 5.68 (s, 1H, ¼CH-Ar), 4.26 (s, 3H, OCH3 of phenyl), 4.17 (s,
3H, OCH3 of phenyl), 2.72 (s, 3H, CH3 of quinoline). MS: m/
z ¼ 484.25 (Mþ1); Anal. Calcd for C28H25N3O3S; C, 69.54; H, 5.21; N,
8.69. Found: C, 69.58; H, 5.28; N, 8.73.
2.1.3.10. 5-(4-chlorobenzylidene)-3-(4-methylquinolin-2-ylamino)-
2-p-tolylthiazolidin-4-one (5j). Yield 61%, mp 219e220 ꢁC IR (v,
cmꢂ1): 1529 (¼C-H), 2967 (¼C-H), 1569 (C¼N); 1H NMR (400 MHz,
DMSO-d6, d): 8.28 (s,1H, NH), 8.12 (s,1H, H3 of quinoline), 7.12e7.96
(m, 12H), 6.72 (s, 1H, thiazolidinone, 2nd position), 5.80 (s,
1H, ¼CH-Ar), 2.64 (s, 3H, CH3 of quinoline), 2.32 (s, 3H, CH3 of
phenyl). MS: m/z ¼ 492.45 (Mþ1); Anal. Calcd for C27H22ClN3OS C,
68.71; H, 4.70; N, 8.90. Found: C, 68.76; H, 4.73; N, 8.94.
2.1.3.17. 5-Benzylidene-3-(4-methylquinolin-2-ylamino)-2-(thio-
phen-2-yl)thiazolidin-4-one (5q). Yield 67%, mp 189e191 ꢁC IR (v,
cmꢂ1): 1526 (¼C-H), 2979 (¼C-H), 1569 (C¼N); 1H NMR (400 MHz,
DMSO-d6,
d): 8.34 (s, 1H, NH), 8.13 (s, 1H, H3 of quinoline),
6.93e7.75 (m, 12H), 6.72 (s, 1H, thiazolidinone, 2nd position), 5.81
(s, 1H, ¼CH-Ar), 2.76 (s, 3H, CH3 of quinoline). MS: m/z ¼ 430.19
(Mþ1); Anal. Calcd for C24H19N3OS2; C, 67.11; H, 4.46; N, 9.78.
Found: C, 67.18; H, 4.51; N, 9.83.
2.1.3.11. 5-(4-methylbenzylidene)-3-(4-methylquinolin-2-ylamino)-
2-p-tolylthiazolidin-4-one (5k). Yield 49%, mp 209e211 ꢁC IR (v,
cmꢂ1): 1525 (¼C-H), 2965 (¼C-H), 1567 (C¼N); 1H NMR (400 MHz,
DMSO-d6,
d): 8.36 (s, 1H, NH), 8.12 (s, 1H, H3 of quinoline),
6.98e7.81 (m, 12H), 6.59 (s, 1H, thiazolidinone, 2nd position), 5.68
(s, 1H, ¼CH-Ar), 2.68 (s, 3H, CH3 of quinoline), 2.41 (s, 3H, CH3 of
phenyl), 2.34 (s, 3H, CH3 of phenyl). MS: m/z ¼ 452.35 (Mþ1); Anal.
Calcd for C28H25N3OS; C, 74.47; H, 5.58; N, 9.31. Found: C, 74.56; H,
5.62; N, 9.36.
2.1.3.18. 5-(4-methylbenzylidene)-3-(4-methylquinolin-2-ylamino)-
2-(thiophen-2-yl)thiazolidin-4-one (5r). Yield 54%, mp 182e183 ꢁC
IR (v, cmꢂ1): 1531 (¼C-H), 2971 (¼C-H), 1573 (C¼N); 1H NMR
(400 MHz, DMSO-d6, d): 8.36 (s, 1H, NH), 8.17 (s, 1H, H3 of quino-
line), 6.98e7.96 (m, 12H), 6.92 (s, 1H, thiazolidinone, 2nd position),
5.84 (s, 1H, ¼CH-Ar), 2.78 (s, 3H, CH3 of quinoline), 2.36 (s, 3H, CH3
of phenyl). MS: m/z ¼ 444.61 (Mþ1); Anal. Calcd for C25H21N3OS2;
C, 67.69; H, 4.77; N, 9.47. Found: C, 67.68; H, 4.77; N, 9.51.
2.1.3.12. 5-(4-methoxybenzylidene)-3-(4-methylquinolin-2-
ylamino)-2-p-tolylthiazolidin-4-one (5l). Yield 54%, mp 206e207 ꢁC
IR (v, cmꢂ1): 1526 (¼C-H), 2969 (¼C-H), 1572 (C¼N); 1H NMR
(400 MHz, DMSO-d6, d): 8.29 (s, 1H, NH), 8.15 (s, 1H, H3 of quino-
2.2. In vitro antimalarial activity
line), 7.12e7.96 (m, 12H), 6.61 (s, 1H, thiazolidinone, 2nd position),
5.73 (s, 1H, ¼CH-Ar), 4.25 (s, 3H, OCH3 of phenyl), 2.71 (s, 3H, CH3 of
quinoline), 2.38 (s, 3H, CH3 of phenyl). MS: m/z ¼ 468.53 (Mþ1);
Anal. Calcd for C28H25N3O2S; C, 71.92; H, 5.39; N, 8.99. Found: C,
71.99; H, 5.45; N, 9.02.
Schizont Maturation Inhibition (SMI) assay was performed
against Chloroquine sensitive strain, 3D7 and Chloroquine resistant
strain, RKL9 of Plasmodium falciparum in RPMI medium (Rieckmann
et al., 1978). The cultures of both strains were synchronized using
5% aqueous sorbitol solution. All stages except trophozoites (ring
form) of parasite were degenerated and removed by centrifugation
at 1500 rpm for 5 min. The test solutions were prepared in 0.1 ml
DMSO and further diluted to produce concentration of
2.1.3.13. 5-Benzylidene-2-(4-methoxyphenyl)-3-(4-methylquinolin-
2-ylamino)thiazolidin-4-one (5m). Yield 61%, mp 202e203 ꢁC IR (v,
cmꢂ1): 1527 (¼C-H), 2974 (¼C-H), 1576 (C¼N); 1H NMR (400 MHz,
DMSO-d6, d): 8.37 (s, 1H, NH), 8.20 (s, 1H, H3 of quinoline), 7.1e7.92
1.98e500 mg/ml with RPMI 1640 medium. 96 well plates were used
(m,13H), 6.71 (s,1H, thiazolidinone, 2nd position), 5.74 (s,1H, ¼CH-
Ar), 4.27 (s, 3H, OCH3 of phenyl), 2.68 (s, 3H, CH3 of quinoline), MS:
m/z ¼ 454.35 (Mþ1); Anal. Calcd for C27H23N3O2S: C, 71.50; H, 5.11;
N, 9.26. Found: C, 71.53; H, 5.16; N, 9.21.
for both cultures and inoculated with synchronized parasites. The
plates were kept for 24e30 h in 5% CO2 incubator at 37 ꢁC. Thick
smear was prepared for each well, stained with Giemsa stain and
examined microscopically. EC50 was calculated for evaluation of
antimalarial potential (Saini et al., 2016).
2.1.3.14. 5-(4-chlorobenzylidene)-2-(4-methoxyphenyl)-3-(4-
methylquinolin-2-ylamino) thiazolidin-4-one (5n). Yield 56%, mp
199e201 ꢁC IR (v, cmꢂ1): 1526 (¼C-H), 2972 (¼C-H),1575 (C¼N); 1H
2.3. In vivo antimalarial screening
NMR (400 MHz, DMSO-d6, d): 8.33 (s, 1H, NH), 8.21 (s, 1H, H3 of
Acute toxicity study was performed by following OECD guide-
lines 423. Overnight fasted 4e6 week old using Swiss Albino Mice
were used. The mice was observed for any symptom of toxicity such
as change in colour of eyes, fur, urination, defecation, posture
alteration, aggressiveness or any lethal response for first 4 h and
examined for 24 h. If no lethal response was found, then second
animal was administered with higher dose and observed as earlier.
The animal were given dose for 14 days and kept under observation
for the calculation of LD50 (Ecobichon, 1977).
In vivo antimalarial potential was investigated by 4-day sup-
pressive test using Swiss Albino Mice of 4e6 week (22 5 g, 5 ani-
mal/group) against P. berghei. Each mice was inoculated with 0.2 ml
of 1 ꢃ 106 parasitized RBC (from donor mice) intraperitoneally on
day 0. Two hour post-infection, all the test groups were
quinoline), 6.92e7.94 (m, 12H), 6.74 (s, 1H, thiazolidinone, 2nd
position), 5.79 (s, 1H, ¼CH-Ar), 4.27 (s, 3H, OCH3 of phenyl), 2.67 (s,
3H, CH3 of quinoline). MS: m/z ¼ 488.34 (Mþ1); Anal. Calcd for
C
27H22ClN3O2S; C, 66.45; H, 4.54; N, 8.61. Found: C, 66.47; H, 4.53;
N, 8.64.
2.1.3.15. 5-(4-methylbenzylidene)-2-(4-methoxyphenyl)-3-(4-
methylquinolin-2-ylamino)thiazolidin-4-one (5o). Yield 53%, mp
210e211 ꢁC IR (v, cmꢂ1): 1522 (¼C-H), 2976 (¼C-H), 1577 (C¼N); 1H
NMR (400 MHz, DMSO-d6, d): 8.38 (s, 1H, NH), 8.16 (s, 1H, H3 of
quinoline), 6.98e7.90 (m, 12H), 6.72 (s, 1H, thiazolidinone, 2nd
position), 5.72 (s, 1H, ¼CH-Ar), 4.18 (s, 3H, OCH3 of phenyl), 2.62 (s,
3H, CH3 of quinoline), 2.38 (s, 3H, CH3 of phenyl). MS: m/z ¼ 468.53

S. Jain et al. / Experimental Parasitology 185 (2018) 107e114
111
administered with test drug at 200 mg/kg and standard at 5 mg/kg
3.2. In vitro antimalarial evaluation and structure-activity
relationship
for 4 consecutive days. On day 4, thin smears were prepared from
tail vein and were stained using Giemsa stain for evaluation of
parasitemia microscopically. The mortality was observed for 7 days
to check the survival rate. Percentage of parasitemia inhibition was
calculated by (A-B)/A ꢃ 100, where A is the parasitemia of negative
control (without any treatment) and B is the parasitemia of each
test group (Devi et al., 2001; Manohar et al., 2012).
The antimalarial potential of entire set of synthesized analogues
was assessed by in vitro antimalarial assay against Chloroquine-
sensitive, 3D7 and Chloroquine-resistant, RKL9 strains of Plasmo-
dium falciparum. The activity results of the target molecules have
been displayed in Table 1. All compounds exhibited good antima-
larial potency with EC50 range 0.432e2.672
mg/ml against 3D7
while against RKL-9 EC50 varies from 0.824 to 11.451
mg/ml. EC50
value for all the synthesized derivatives against both Chloroquine
sensitive and Chloroquine resistant strain has also been repre-
sented graphically in Fig. 1. Compound 5g was found to be most
2.4. Docking study
In an effort to get insight the factors determining the bioactivity
of novel arylidene derivatives of thiazolidinone-quinoline hybrids,
docking simulations were performed in the active sight of Plas-
modium falciparum lactate dehydrogenase (Singh et al., 2016;
Prathiban et al., 2015). The molecular docking study was done by
AutodockVina and autodock tools using Lamarckian Genetic Algo-
rithm (Trott and Olson, 2010). The crystal structure of protein (PDB
ID: 1CET) was obtained from Protein Data Bank (www.rcsb.org)
(Kaushik et al., 2015). The structures of five ligands were prepared
using ChemDrawUltra 8.0.3. Then the structures were converted
into required. pdbqt format using ADT 1.5.6. During protein prep-
aration, all the water molecules were removed; polar hydrogen and
partial charges were added and saved as. pdbqt. The active grid was
generated for docking with size 40 ꢃ 40 ꢃ 40 along x, y & z centres,
25.8, 26.829 & 9.405 respectively with 0.375 Å grid spacing.
Further, ADT and Python were used for visualisation and identifi-
cation of residues involved in binding.
potent among the series with EC50 of 0.423 mg/ml and 0.824 mg/ml
against 3D7 and RKL-9 respectively. Compound 5r displayed
maximum EC50 against both the strains and hence considered as
least active compound of the series. Compounds 5b, 5e, 5g, 5j and
5n were found to be five most potent analogues among the series
with EC50 (3D7/RKL-9) values of 0.731/1.617, 0.734/2.011, 0.423/
0.824, 0.562/0.992 and 0.632/1.211 mg/ml respectively. From in vitro
study, we have concluded the results in structure-activity
relationship.
3.2.1. Structure-activity relationship
It has been revealed that the presence of chloro group at p-po-
sition of either ring led to the development of best candidate for
malaria as compounds 5b, 5e, 5g, 5h, 5j and 5n were found to have
EC50 less than 1 mg/ml. Unfortunately, 5f, substitution of both rings
with chloro group didn't meet the expectation of enhanced potency
and was found to be less active than above given (substitution with
chloro group at one ring only) derivatives. Incorporation of methyl
group along with chloro group was proven to be best match and
hence 5g was the most potent derivative among the series.
Furthermore, it was also indicated that the presence of methyl
group was more preferred as compared to methoxy group at p-
position of phenyl rings. The effect of ring size was also established
by replacing phenyl ring with five membered sulphur containing
thienyl ring, the activity was reduced by many folds, even com-
pound 5r, least active among the series, belongs to this category.
The complete Structure-activity relationship study regarding
various substitution around arylidene derivatives suggested that p-
position of rings should be occupied by chloro group at one ring
while methyl ring at another to get remarkable antimalarial activ-
ity. The SAR study of series is depicted in Fig. 2.
3. Result and discussion
3.1. Chemistry
The synthetic protocol was successfully followed for the syn-
thesis of thiazolidinone and their respective arylidene derivatives.
The first step, compounds (3a-e) were prepared in good yield by
condensation of 2-hydrazino-4-methylquinoline with different ar-
omatic aldehyde in acidic conditions. In next step, hydrazone in-
termediates were converted into thiazolidinone (4a-e) by reacting
with thioglycolic acid in dioxane. Finally the target compounds, 5-
Arylidene-3-(4-methylquinolin-2-ylamino)-2-arylthiazolidin-4-
one, were obtained by reacting equimolar amount of (4a-e) and aryl
aldehyde in Glacial acetic acid.
Characteristic data from FTIR and 1H NMR was studied for the
progression of reaction. A strong band in range of 3200e3400 cmꢂ1
is attributed to secondary amine present in all the intermediates
and final compounds. Similarly, 1H NMR of all the derivatives were
supported by the presence of one broad singlet corresponding to
3.3. In vivo antimalarial activity
No mortality was observed during acute toxicity study. At the
end of study, the dose calculated for all the synthetic derivatives
was 200 mg/kg. Among the synthesized analogues 5 a-r, five most
potent compounds, 5b, 5e, 5g, 5j and 5n, were further selected for
in vivo antimalarial evaluation. Compounds were screened against
P. berghei in swiss albino mice using 4-day suppressive test. Com-
pound 5g, bearing p-chloro group in one ring and p-methyl group
in another, showed best activity with 73.38% of parasitemia inhi-
bition. Four mice out of five were found to be alive on 7th day.
Antimalarial potential displayed by 5 selected compounds has been
presented in Table 2. Microscopic examination of thin smears of
control group, standard (Chloroquine), 5g (most active) and 5e
(least active) from in vivo study has been displayed in Fig. 3. Further
the plausible route for antimalarial activity of compounds was
studied through in-silico approach.
NH nearly at d 8.3e8.6 and a sharp singlet for proton at 3rd position
in quinoline ring around
d 8.2. Characteristic peak in FTIR of com-
pounds (4a-e) was observed in range of 1650e1660 cmꢂ1 due to the
presence of carbonyl group. In 1H NMR, two distinct singlets cor-
responding to C-CH2-S and N-CH-S at
respectively, confirmed the synthesis of thiazolidinone ring.
Further, disappearance of singlet at 5.29 for two protons with
emergence of new singlet in 5.88 for single proton authenticated
the progression of reaction from thiazolidinone to target arylidene
derivatives. Eventually, all the structures of synthesized com-
pounds were found in accordance with mass and elemental
analysis.
d 5.29 and 6.77 ppm
d
d

112
S. Jain et al. / Experimental Parasitology 185 (2018) 107e114
Table 1
In vitro antimalarial activity of synthetic derivatives 5(a-r) against CQ-sensitive (3d7) and CQ-resistant (RKL-9) strain of P. falciparum.
S. No.
Compounds
Ar1
Ar2
EC50 (3D7,
mg/ml)
EC50 (RKL-9, mg/ml)
1.
2.
3.
4.
5.
6.
7.
8.
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5ꢁ
5p
5q
5r
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
1.012
0.731
1.212
1.230
0.734
0.783
0.423
0.791
1.501
0.562
1.732
1.621
1.414
0.632
1.536
1.801
1.931
2.672
0.375
3.121
1.617
4.723
5.123
2.011
2.026
0.824
2.114
6.726
0.992
9.001
7.992
6.023
1.211
7.231
9.373
9.921
11.451
0.80
p-Cl C6H4-
p-CH3C6H4-
p-OCH3C6H4-
C6H5-
p-Cl C6H4-
p-CH3C6H4-
p-OCH3C6H4-
C6H5-
p-Cl C6H4-
p-CH3C6H4-
p-OCH3C6H4-
C6H5-
p-Cl C6H4-
p-CH3C6H4-
p-OCH3C6H4-
C6H5-
p-Cl C6H4-
p-Cl C6H4-
p-Cl C6H4-
p-Cl C6H4-
p-CH3C6H4-
p-CH3C6H4-
p-CH3C6H4-
p-CH3C6H4-
p-OCH3C6H4-
p-OCH3C6H4-
p-OCH3C6H4-
p-OCH3C6H4-
2-thienyl
2-thienyl
e
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
p-CH3C6H4-
e
CQ
Fig. 1. EC50 of synthesized derivatives, 5a-r, against 3D7 and RKL-9 of Plasmodium falciparum.
Fig. 2. Structure-Activity Relationship of Arylidene derivatives of Thiazolidinone-quinoline hybrids.

S. Jain et al. / Experimental Parasitology 185 (2018) 107e114
113
Table 2
Effect of five selected compounds on parasitemia of P. berghei infected mice.
S. No.
Drug treatment
Dose\kg
No. Of animals
%parasitemia
Percentage inhibition
Survival on 7th day
1.
2.
3.
4.
5.
6.
7.
Control
Standard
5b
5e
5g
5j
e
5
5
5
5
5
5
5
49.62 0.304
e
e
0/5
5/5
2/5
3/5
4/5
4/5
3/5
5 mg/kg
100
200 mg/kga
200 mg/kga
200 mg/kga
200 mg/kga
200 mg/kga
29.43 0.312
35.72 0.403
13.21 0.126
17.34 0.301
21.21 0.116
40.68**
28.01
73.38**
65.05**
57.26**
5n
N ¼ 5, Values are expressed as Mean SEM and analyze by ANOVA. **p < .01(significant). Values are compared with control group.
a
Dose calculated by acute toxicity method.
Fig. 4. Binding interaction of most potent synthesized ligand, 5g, with active site of
Lactate dehydrogenase (PDB ID: 1CET).
Fig. 3. Photomicrographs of blood smears of different groups showing parasitemia
(encircled) (a) parasite infected RBCs in control group (b) parasitemia after treatment
with standard drug, chloroquine c) parasitemia after treatment with 5g (Most active)
c) parasitemia after treatment with 5e (Least active).
derivatives of quinoline-thiazolidinone hybrids as antimalarial
agents.
4. Conclusion
3.4. Docking study
In summary, we have synthesized novel series comprised of
arylidene derivatives of quinoline-thiazolidinone hybrids, where
compound 5g exhibited promising in vitro antimalarial potency
against both 3D7 and RKL-9 strains of Plasmodium falciparum. It
also showed highest suppression of parasitemia against P. berghei
during in vivo antimalarial screening. The present study also por-
trayed the utility of docking simulations to get a deep insight of
interaction of synthesized scaffold with target proteins. From
structure-activity relationship, 5g may be utilised as a lead mole-
cule for further investigation to improve their pharmacological
potential. Thus, the current study serves as an encouragement for
the development of new hybrids of thiazolidinone pharmacophore
as antimalarial agent.
Anaerobic life cycle of parasite Plasmodium falciparum is sup-
ported by Plasmodium falciparum Lactate Dehydrogenase (PfLDH),
being the terminal enzyme that leads the regeneration of NADþ
from NADH for continual glycolysis. From the literature, it has been
revealed that inhibition of PfLDH may lead a pathway for designing
of antimalarial agents and this has been illustrated in the present
study by docking simulations using 1CET, Pf Lactate dehydrogenase
enzyme complex as target protein. The docked confirmation and
results of ligands in binding pocket is demonstrated in Table 3. The
main amino acid residue that has played a vital role in interaction of
ligands with target protein was ARG171. The biological evaluation
was corroborated by in silico study as compound 5g formed a stable
interaction with PfLDH enzyme having binding affinity ꢂ9.4 kCal/
mol and hydrogen bond as well, depicted in Fig. 4. The results from
docking study justified our preceding research of arylidene
Conflicts of interest
The authors report no conflict of interest.
Table 3
Docking simulations of 5b, 5e, 5g, 5j and 5n in active site of Lactate dehydrogenase receptor (PDB ID: 1CET).
S. No.
Compound
Dock Score (kCal/mol)
Number of hydrogen bonds
Amino Acid involved
Group of ligand involved
1.
2.
3.
4.
5.
5b
5e
5g
5j
ꢂ9.0
ꢂ9.0
ꢂ9.4
ꢂ9.2
ꢂ9.2
1
e
ARG171
e
O of C¼O (thiazolidinone)
e
1
1
ARG171
ARG171
e
O of C¼O (thiazolidinone)
O of C¼O (thiazolidinone)
e
5n
e

114
S. Jain et al. / Experimental Parasitology 185 (2018) 107e114
Saini, D., Jain, S., Kumar, A., Jain, N., 2016. Synthesis and antimalarial potential of
Acknowledgement
some novel quinoline-pyrazolopyridine derivatives. EXCLI J. 15, 730e737.
Singh, B., Maheshwari, A., Dak, G., Sharma, K., Talesara, G.L., 2010. Studies of anti-
microbial activities of some 4-thiazolidinone fused pyrimidines, [1,5]-
Benzodiazepines and their oxygen substituted hydroxylamine derivatives. In-
dian J. Der Pharm. Sin. 72, 607e612.
Singh, S., Agarwal, D., Sharma, K., Sharma, M., Nielsen, M.A., Alifrangis, M.,
Singh, A.K., Gupta, R.D., Awasthi, S.K., 2016. 4-Aminoquinoline derivatives:
synthesis, in vitro and in vivo antiplasmodial activity against chlorquine-
resistant parasites. Eur. J. Med. Chem. 122, 394e407.
The authors gratefully acknowledge financial assistance from
Department of Science and Technology, New Delhi (Letter no. DST/
INSPIRE Fellowship/2013/480).
References
Sinha, S., Medhi, B., Sehgal, R., 2014. Challenges of drug-resistant malaria. Parasite
21, 61.
Teixeira, C., Vale, N., Perez, B., Gomes, A., Gomes, J.R.B., Gomes, P., 2014. Recycling
classical drugs for malaria. Chem. Rev. 114, 11164e11220.
Bekhit, A.A., Hymete, A., Damtew, A., Mohamed, A.M.I., Bekhit, A.E.-D.A., 2012.
Synthesis and biological screening of some pyridine derivatives as anti-malarial
agents. J. Enzym. Inhib. Med. Chem. 27, 69e77.
Deep, A., Jain, S., Sharma, P.C., Mittal, S.K., Phogat, P., Malhotra, M., 2014. Synthesis,
characterization and antimicrobial evaluation of 2,5-disubstituted-4-
thiazolidinone derivatives. Arab. J. Chem. 7, 287e291.
Desai, N.C., Dodiya, A.M., 2014. Synthesis, characterization and antimicrobial
screening of quinoline based quinazolinone-4-thiazolidinone heterocycles.
Arab. J. Chem. 7, 906e913.
Devi, U.C., Neena, V., Atul, P.K., Pillai, C.R., 2001. Antiplasmodial effect of three
medicinal plants: a preliminary study. Curr. Sci. 80, 917e919.
Dorn, A., Stoffel, R., Matile, H., Bubendorf, A., Ridley, R.G., 1995. Malarial haemozoin/
beta-haematin supports haem polymerization in the absence of protein. Nature
374, 269e271.
Ecobichon, D.J., 1977. The Basis of Toxicology Testing. CRC Press, New York.
Foley, M., Tilley, L., 1998. Quinoline antimalarials: mechanisms of action and
resistance and prospects for new agents. Pharmacol. Ther. 79, 55e87.
Kaushik, D., Paliwal, D., Kumar, A., 2015. 2D QSAR and Molecular docking studies of
chloroquine-thiazolidinone derivatives as potential pfLDH inhibitors of Plas-
modium falciparum. Int. J. Pharm. Pharmaceut. Sci. 5, 42e53.
Trott, O., Olson, A.J., 2010. AutoDock Vina: improving the speed and accuracy of
docking with a new scoring function, efficient optimization and multithreading.
J. Comp. Chem. 31, 455e461.
Unsal-Tan, O., Azadali, K., Piskin, K., Balkan, A., 2012. Molecular modeling, synthesis
and screening of some new 4-thiazolidinone derivatives with promising se-
lective COX-2 inhibitory activity. Eur. J. Med. Chem. 57, 59e64.
Warhurst, D.C., Steele, J.C., Adagu, I.S., Craig, J.C., Cullander, C., 2003. Hydroxy-
chloroquine is much less active than chloroquine against chloroquine-resistant
Plasmodium falciparum, in agreement with its physicochemical properties.
J. Antimicrob. Chemother. 52, 188e193.
World Malaria Report, 2016. http://www.who.int/malaria/media/world-malaria-
report-2016/en/. (Accessed 17 April 2017).
Dr. Sandeep Jain: He is associate professor (Pharmaceu-
tical Chemistry) in Guru Jambheshwar University of Sci-
ence and Technology, Hisar. He has more than 20 years'
experience of teaching and research. He has supervised 6
Ph.D. and about 50 M.Pharm students. He has about 100
research papers in his credit.
Kumar, A., Paliwal, D., Saini, D., Thakur, A., Aggarwal, S., Kaushik, D., 2014.
A comprehensive review on synthetic approach for antimalarial agents. Eur. J.
Med. Chem. 85, 147e178.
Kumar, A., Rajput, C.S., Bhati, S.K., 2007. Synthesis of 3-[40-(p-chlorophenyl)-thiazol-
20-yl]-2-[(substituted azetidinone/thiazolidinone)-aminomethyl]-6-bromo qui-
nazolin-4-ones as anti-inflammatory agent. Bioorg. Med. Chem. 15, 3089e3096.
Kumar, D., Khan, S.I., Tekwani, B.L., Ponnan, P., Rawat, D.S., 2015. 4-Aminoquinoline-
Pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking
studies. Eur. J. Med. Chem. 89, 490e502.
Manohar, S., Rajesh, U.C., Khan, S.I., Tekwani, B.L., Rawat, D.S., 2012. Novel 4-
aminoquinoline-pyrimidine based hybrids with improved in vitro and in vivo
antimalarial activity. ACS Med. Chem. Lett. 3, 555e559.
Manohar, S., Tripathi, M., Rawat, D.S., 2014. 4-Aminoquinoline based molecular
hybrids as antimalarials: an overview. Curr. Top. Med. Chem. 14, 1706e1733.
Mishra, V.K., Mishra, M., Kashaw, V., Kashaw, S.K., 2017. Synthesis of 1,3,5-
trisubstituted pyrazolines as potential antimalarial and antimicrobial agents.
Bioorg. Med. Chem. 6, 1949e1962.
Nagalakshmi, G., Maity, T.K., Maiti, B.C., 2013. Synthesis, characterization and anti-
HIV evaluation of some novel 2-(substitutedphenyl)-5-methyl-3-(phenyl-
amino)-1,3- thiazolidin-4-ones. Int. J. Chem. Tech. Res. 5, 2068e2078.
Olson, J.E., Lee, G.K., Semenov, A., Rosenthal, P.J., 1999. Antimalarial effects in mice of
orally administered peptidyl cysteine protease inhibitors. Bioorg. Med. Chem. 7,
633e638.
Dr. Ajay Kumar: He is assistant professor (Organic
Chemistry) in Institute of Pharmaceutical Sciences, Kur-
ukshetra University Kurukshetra. He has more than 10
years' experience of teaching and research. He has super-
vised 4 Ph.D. and about 22 M. Pharm students. He has
about 30 research papers in his credit. He has been
awarded with Young Scientist Award by ISCA.
Omar, K., Geronikaki, A., Zoumpoulakis, P., Camoutsis, C., Sokovic, M., Ciric, A.,
Glamoclija, J., 2010. Novel 4-thiazolidinone derivatives as potential antifungal
and antibacterial drugs. Bioorg. Med. Chem. 18, 426e432.
Prathiban, A., Muthukumaran, J., Manhas, A., Srivastava, K., Krishna, R., Prakash
Rao, H.S., 2015. Synthesis, in vitro and in silico antimalarial of 7-chloroquinoline
and 4H-chromene conjugates. Bioorg. Med. Chem. 25, 4657e4663.
Rieckmann, K.H., Campbell, G.H., Sax, L.J., Mrema, J.E., 1978. Drug sensitivity of
Plasmodium falciparum: an in-vitro microtechnique. Lancet 1, 22e23.
Ms. Deepika Saini: She is Senior Research Fellow, DST
INSPIRE at Department of Pharmaceutical Sciences, Guru
Jambheshwar University of Science and Technology, Hisar.
She is Gold Medalist during her post-graduation, M. Phar-
macy (Pharmaceutical Chemistry). She has 10 research pa-
pers, 3 reviews and 2 books in her credit.
ꢀ
~
ꢀ
Rojas Ruiz, F.A., García-Sanchez, R.N., Estupinan, S.V., Gomez-Barrio, A.,
ꢀ
ꢀ
ꢀ
Amado, D.F.T., Perez-Solorzano, B.M., Nogal-Ruiz, J.J., Martínez-Fernandez, A.R.,
Kouznetsov, V.V., 2011. Synthesis and antimalarial activity of new heterocyclic
hybrids based on chloroquine and thiazolidinone scaffolds. Bioorg. Med. Chem.
19, 4562e4573.
Rosenthal, P.J., Sijwali, P.S., Singh, A., Shenai, B.R., 2002. Cysteine proteases of ma-
laria parasites, target for chemotherapy. Curr. Pharmaceut. Des. 8, 1659e1672.
Sahu, S., Ghosh, S.K., Kalita, J., Dutta, A., Bhat, H.R., 2016. Design, synthesis and
antimalarial screening of some hybrid 4-aminoquinoline-triazine derivatives
against pf-DHFR-TS. Exp. Parasitol. 163, 38e45.