Design and synthesis of a new class of 4-aminoquinolinyl- and 9-anilinoacridinyl schiff base hydrazones as potent antimalarial agents

Article abstract of DOI:10.1111/cbdd.12289

A series of novel 4-aminoquinolinyl and 9-anilinoacridinyl Schiff base hydrazones have been synthesized and evaluated for their antimalarial activity. All compounds were evaluated in vitro for their antimalarial activity against chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain of Plasmodium falciparum and for cytotoxicity toward Vero cells. Compounds 17, 20, and 21 displayed good activity against the 3D7 strain with IC₅₀ values ranging from 19.69 to 25.38 nm. Moreover, compounds 16, 17, 21, 24, 32, and 33 exhibited excellent activities (21.64-54.26 nm) against K1 strain and several compounds displayed β-hematin inhibitory activity, suggesting that they act on the heme crystallization process such as CQ. Compounds were also found to be non-toxic with good selectivity index.

Full text of DOI:10.1111/cbdd.12289

Chem Biol Drug Des 2014; 84: 175–181
Research Article
Design and Synthesis of a New Class of
4-Aminoquinolinyl- and 9-Anilinoacridinyl Schiff Base
Hydrazones as Potent Antimalarial Agents
Moni Sharma1, Kuldeep Chauhan1,
such as aminoquinolines (1), anilinoacridines (2), antifolates
(3), and drug combinations on artemisinins (4–6, Figure 1)
(ACTs) (4–8) is driving the rise in global mortality due to
malaria. Owing to emergence of growing resistance, the
Rajeev K. Srivastava2, Shiv V. Singh3, Kumkum
Srivastava2, Jitendra K. Saxena3, Sunil K. Puri2
and Prem M. S. Chauhan1,*
WHO recommends combination therapy as first-line treat-
1Medicinal and Process Chemistry Division, CSIR-Central
ment against resistant malaria (9). Catabolism of hemoglobin
and subsequent detoxification of released heme by the
malaria parasite is one of the most important biochemical
target for drug development (10). To fulfill the requirement of
amino acids, the parasite can degrade as much as 80% of
an infected host’s red blood cell hemoglobin during the
intraerythrocytic phase of its life cycle and producing free
heme (FeIIIPPIX) which is toxic to the parasite. To prevent the
toxic effects of free heme, parasite detoxify it into an insoluble
biomineral known as hemozoin (11,12). Several established
drugs, for example, chloroquine and other quinoline
antimalarials are known to inhibit the formation of hemozoin
and, therefore, make it a target of choice for the development
of new antimalarial chemotype (13–15).
Drug Research Institute, Lucknow 226031, India
2Division of Parasitology, CSIR-Central Drug Research
Institute, Lucknow 226031, India
3Division of Biochemistry, CSIR-Central Drug Research
Institute, Lucknow 226031, India
*Corresponding author: Prem M. S. Chauhan,
prem_chauhan_2000@yahoo.com;
premsc58@hotmail.com
A series of novel 4-aminoquinolinyl and 9-anilinoacridi-
nyl Schiff base hydrazones have been synthesized and
evaluated for their antimalarial activity. All compounds
were evaluated in vitro for their antimalarial activity
against chloroquine-sensitive strain 3D7 and the chlo-
roquine-resistant K1 strain of Plasmodium falciparum
and for cytotoxicity toward Vero cells. Compounds 17,
20, and 21 displayed good activity against the 3D7
strain with IC50 values ranging from 19.69 to 25.38 nM.
Moreover, compounds 16, 17, 21, 24, 32, and 33 exhib-
ited excellent activities (21.64–54.26 nM) against K1
strain and several compounds displayed b-hematin
inhibitory activity, suggesting that they act on the
heme crystallization process such as CQ. Compounds
were also found to be non-toxic with good selectivity
index.
Schiff base hydrazones are interesting scaffolds, possessing
a range of biological activities including antimalarial (16,17),
antitumor (18), antibacterial (19,20), antifungal (21), antitu-
bercular (22), anti-inflammatory (23), antimicrobial (24), anti-
proliferative (25), antiviral (26), and cytotoxic actions (27).
Among the reported heterocyclic hydrazones, quinolylhyd-
razones are known for their excellent antimalarial and antitu-
bercular activities (28–30). Recently, the Schiff bases of
N4O2 complex were developed as novel antimalarials that
inhibit the aggregation of hemozoin (31). Furthermore,
oxalamide derivatives also represent important substructures
in molecules that show diverse biological activities (32,33).
Key words: 4-aminoquinoline, 9-anilinoacridine, antimalarial,
oxalamide, Schiff base
The contemporary trend of drug discovery is shifted toward
the molecule having multiple ligands instead of single phar-
macophore that provide structural features to modulate
numerous biological targets simultaneously within that mol-
ecule. In this context, hybridization approach is recently
developed which involves the molecular hybridization of
two or more than two different chemical entities in a single
molecule by simple fusion (usually via a covalent linker).
The rational of this approach depends upon the hybridiza-
tion of two drugs, both active compounds and pharmaco-
phoric units recognized and derived from known bioactive
molecules (34,35). Some hybrid molecules based on
Received 30 September 2013, revised 10 December 2013
and accepted for publication 8 January 2014
Malaria, a devastating infectious disease, caused by five
species of Plasmodium, responsible for 216 million clinical
cases in 2010, 65 5000 deaths in children below the age of
5 years and pregnant women (1). Among the five major
species of the malaria parasite Plasmodium falciparum,
P. vivax, P. malariae, P. ovale, and P. knowlesi that infect the
humans, P. falciparum is the most fatal one (2,3). The preva-
lent drug resistance to currently established antimalarials
ª 2014 John Wiley & Sons A/S. doi: 10.1111/cbdd.12289
175

Sharma et al.
(60–120 and 100–200 mesh). All reactions were monitored
by thin-layer chromatography (TLC), and silica gel plates
with fluorescence F254 were used. Melting points were
taken in open capillaries on Complab melting point appa-
ratus and are presented uncorrected. Infrared spectra
were recorded on a Perkin-Elmer AC-1 spectrometer. 1H
NMR and 13C NMR spectra were recorded using Bruker-
Supercon Magnet DRX-300 spectrometer (operating at
200, 300 MHz for 1H and 50, 75 MHz for 13C) using
CDCl3, CD3OD, DMSO-d6, and TFA as solvents and tetra-
methylsilane (TMS) as internal standard. Chemical shifts
are reported in parts per million. Multiplicities are reported
as follows: singlet (s), doublet (d), triplet (t), multiplet (m),
and broad singlet (brs). Some signals for NH proton are
not presented in the few 1H NMR data, and FAB mass
spectra were recorded on JEOL SX 102/DA 6000 mass
spectrometer using argon/xenon (6 Kv, 10 mA) as the
FAB gas. Chemical analysis was carried out on carlo-
Erba-1108 instrument. The melting points were recorded
on an electrically heated melting point apparatus and are
uncorrected.
Cl
N
N
HN
HN
OMe
N
N
H2N
N
NH2
Cl
N
Cl
N
Chloroquine CQ (1)
Cycloguanil (3)
Quinacrine (2)
H
H
H
O
O
O
O
O
O
O
O
O
H
H
H
H
H
H
O
O
O
OH
O
O
Artemether (4)
Dihydroartemisinin (5)
Artemotil (6)
Figure 1: Structure of some traditional (1–3) as well as arte-
misinin-based (4–6) antimalarials.
4-aminoquinoline and 9-anilinoacridine core reported by
us and other groups as potent hybrid antimalarial agents
(Figure 2) (36–41).
Therefore, in continuation of our ongoing anti-infective
research program and in an earlier attempt to introduce
the oxalamide linker as flexible tether in aminoquinoline
(42–44), here we report that the derivatives of 4-amino-
quinolinyl and 9-anilinoacridinyl Schiff base hydrazones
having an oxalamide functionality have antimalarial activity
(14–26 and 31–41).
Bioevaluation methods
In vitro antimalarial assay
The compounds were evaluated for antimalarial activity
against both 3D7 (CQ sensitive) and K1 (CQ resistant)
strains of Plasmodium falciparum using Malaria SYBR
Green I nucleic acid staining dye based fluorescence
(MSF) assay as mentioned by Singh et al. (45). The stock
(5 mg/mL) solution was prepared in DMSO, and test dilu-
tions were prepared in culture medium (RPMI-1640-FBS).
Chloroquine was used as reference drug. The compounds
Experimental
General chemistry
All reagents were commercial and were used without fur-
ther purification. Chromatography was carried on silica gel
R1
N
R2
HO
CH3
N
O
OH
HN
N
N
H
HN
N
N
N
H
N
H
(7)
(8)
Cl
Cl
O
R
O
NH
NHN
NH
N
HN
N
N
H
HN
N
H
O
O
Cl
Cl
Compounds (14-26)
Aminoquinoline-oxalamide (9)
O
R
NH
NHN
HN
N
H
O
O
Cl
Compounds (31-41)
Figure 2: Hybrid antimalarials.
176
Chem Biol Drug Des 2014; 84: 175–181

Aminoquinolinyl and Anilinoacrydinyl as Antimalarial Agents
were tested in 96-well plate (in duplicate wells). 1.0% par-
asitized cell suspension containing 0.8% parasitaemia was
used. The plates were incubated at 37 °C in CO2 incuba-
tor in an atmosphere of 5% CO2 and air mixture. After
72 h, 100 lL of lysis buffer containing 1 9 concentration
of SYBR Green I (Invitrogen) was added to each well and
incubated for another 1 h at 37 °C. The plates were
examined at 485 Æ 20 nm of excitation and 530 Æ 20 nm
of emission for relative fluorescence units (RFUs) per well
using the fluorescence plate reader (FLUO star; BMG Lab
Technologies). Data were transferred into a graphic pro-
gram (EXCEL), and IC50 values were obtained by logit
regression analysis using preprogrammed Excel spread-
sheet.
Tris-HCl buffer pH (7.4) containing 2.5% SDS. The pellet
obtained after centrifugation was washed thrice with
distilled water (TDW) to remove free hemin attached to
b-hematin. The pellet was solubilized in 50 L of 2 N
NaOH, and volume was made up to 1.0 mL with
TDW. Absorbance was measured at 400 nm3. The 50%
inhibitory concentration (IC50
) was determined using
nonlinear regression analysis dose–response curves (47).
Results and Discussion
Chemistry
Proposed prototypes were prepared in economical way
using inexpensive starting materials. A relatively straightfor-
ward synthetic approach (Schemes 1 and 2) was followed
for the synthesis of target N-(4′-(7-chloroquinolin-4-ylami-
no)aryl)-2″-(benzylidene)hydrazinyl)-2″-oxoacetamide (14–26)
and N-(4′-(6-chloro-2-methoxy-acridine-9-ylamino)phenyl)-
2″-(benzylidene)hydrazinyl)-2″-oxoacetamide (31–41). The
chemistry for the synthesis of compounds 11 and 28 was
described previously (36,39). The so-formed diamines (11)
and (28) on reaction with ethyl 2-chloro-2-oxoacetate give
the corresponding oxoacetate, namely ethyl 2-(4-(7-chloro-
quinolin-4-ylamino)phenylamino)-2-oxoacetate (12) and
ethyl 2-(4-(6-chloro-2-methoxyacridin-9-ylamino)phenylami-
no)-2-oxoacetate (29) in quantitative yield. These interme-
diates with hydrazine hydrate provide the corresponding
hydrazinyl oxoacetamide, N-(4-(7-chloroquinolin-4-ylamino)
phenyl)-2-hydrazinyl-2-oxoacetamide (13) and N-(4-(6-
chloro-2-methoxyacridin-9-ylamino)phenyl)-2-hydrazinyl-2-
oxoacetamide (30) in quantitative yield. Finally, this hydrazi-
nyl oxoacetamide on condensation with various aldehydes
led to the formation of desired prototypes (14–26 and 31–
41) as given in Table 1.
In vitro cytotoxicity evaluation assay
Cytotoxicity of the compounds was carried out using Vero
cell line (C1008; Monkey kidney fibroblast) following the
method of Mosmann (46) with certain modifications. The
cells were incubated with compound dilutions for 72 h,
and MTT was used as reagent for the detection of cyto-
toxicity. Fifty percent cytotoxic concentration (CC50) was
determined using nonlinear regression analysis using
preprogrammed Excel spreadsheet. Selectivity index was
calculated as SI = CC50/IC50
.
b-Hematin inhibitory (BHIA) assay
Male Swiss mice, weighing 15–20 g, were inoculated with
1 9 105 P. yoelii infected RBCs. Blood of infected animal
at 50% parasitemia was collected by cardiac puncture in
2.0% citrate buffer and centrifuged at 1844 9 g for
10 min at 4 °C. The plasma was used in assay of
b-hematin formation. The assay mixture contained 100 mM
sodium acetate buffer pH (5.1), 50 lL plasma, 100 lM
hemin as the substrate, and 1–20 lg compound/drug in a
total volume of 1.0 mL. The control tube contained all
reagents except compound. The reaction mixture in tripli-
cate was incubated at 37 °C for 16 h in a rotary shaker.
The reaction was stopped by centrifugation at 7378 9 g
for 10 min at 30 °C. The pellet was suspended in 100 mM
In vitro antimalarial evaluation
Analogues 14–26 and 31–41, based on 4-aminoquinoline
and 9-anilinoacridine nuclei, were designed and synthe-
sized for the study of SARs (structure–activity relationship).
The in vitro antiplasmodial SAR initially involved in the
O
NH
OC2H5
Cl
HN
N
NH2
b
HN
N
O
a
l
C
N
l
C
Cl
11
12
10
c
Scheme 1: Reagents and
conditions: (a) p-phenylenediamine,
p-TSA, EtOH, 3 h., (b) ethyl
chlorooxoacetate, DMF, Et3N, rt.,
(c) hydrazine hydrate 80%, EtOH,
rt., (d) different aldehydes, EtOH,
HCl, rt.
O
R
O
NH
NH
NHN
NHNH2
HN
HN
N
H
O
O
d
Cl
N
l
C
13
-
14 26
Chem Biol Drug Des 2014; 84: 175–181
177

Sharma et al.
NH2
O
NH
OC2H5
Cl
NH
N
HN
O
O
O
O
b
a
Cl
N
Cl
Cl
N
29
28
27
c
O
O
Scheme 2: Reagents and
conditions: (a) p-phenylenediamine,
p-TSA, EtOH, 3 h., (b) ethyl
chlorooxoacetate, DMF, Et3N, rt.,
(c) hydrazine hydrate 80%, EtOH,
rt., (d) different aldehydes, EtOH,
HCl, rt.
R
NH
NH
NHNH2
NHN
HN
N
HN
H
O
O
O
O
d
Cl
Cl
N
31-41
30
Table 1: In vitro antimalarial activity of compounds against 3D7 and K1 strains of Plasmodium falciparum and their cytotoxicity against
Vero cell line
IC50 (nM)a
R
Compound no.
Linker (L)
3D7
38.34
K1
SIb
55.37
131.81
65.55
229.91
15.87
146.10
316.71
185.81
39.63
968.60
274.88
155.16
155.68
1569.97
1866.02
2668.70
875.35
43.87
14
15
16
17
18
19
20
21
22
23
24
25
26
31
32
33
34
35
36
37
38
39
40
41
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
p-Phenylene diamine
CQ (mean Æ SD)
4-Ethylphenyl
168.74
110.18
21.64
51.96
ND
155.03
85.68
22.52
185.83
422.47
34.10
431.57
293.67
201.98
54.26
53.05
510.09
ND
406.54
ND
ND
677.31
200.55
131.56
495.94 Æ 127.1
4-Propylphenyl
4-Isopropylphenyl
4-t-butylphenyl
2-Fluorophenyl
4-Fluorophenyl
4-Bromophenyl
4-Trifluoromethylphenyl
4-Methoxyphenyl
3,4,5-Trimethoxyphenyl
4-Thiomethylphenyl
3-Pyridyl
37.07
40.88
19.69
261.06
43.94
20.78
25.38
91.75
47.74
43.81
152.35
81.47
43.30
94.84
42.43
211.16
665.15
105.89
NA
2-Fluoro, 3-Pyridyl
Phenyl
4-Isopropylphenyl
4-t-butylphenyl
2-Fluorophenyl
4-Fluorophenyl
4-Bromophenyl
4-Methoxyphenyl
3,4,5-Trimethoxyphenyl
4-Thiomethylphenyl
2-Fluoro, 3-Pyridyl
3-Indolyl
578.35
ND
627.83
51.22
44.92
71.49
259.41
1065.71
4106.77
398.25
8983.00
4.16 Æ 2.09
aIC50 (nM): concentration corresponding to 50% growth inhibition of the parasite.
bSI: (IC50 values of cytotoxic activity/IC50 values of antimalarial activity).
evaluation of analogues against the CQ-sensitive 3D7
strain and CQ-resistant K1 strain (MRA-159, MR4, ATCC,
Manassas, Virginia) of P. falciparum using a standardized
inexpensive assay based on SYBR Green I nucleic acid
staining dye based fluorescence (MSF) assay as men-
tioned by Singh et al. (45). The in vitro antiplasmodial
activities as indicated by their IC50 values are shown in
Table 1. The test compounds showed superior or compa-
rable activity to the control drug (CQ) against K1 strain of
P. falciparum. However, compounds (17, 20, and 21)
showed a good antimalarial activity with IC50s ranging from
19.69 to 25.38 nM against the 3D7 strain. These results
encourage us to prepare a series of compounds to investi-
gate the antimalarial effect of various substituents of arylid-
ene and heterocycles. Previously, we have reported that
lipophilicity appears to be an important factor influencing
178
Chem Biol Drug Des 2014; 84: 175–181

Aminoquinolinyl and Anilinoacrydinyl as Antimalarial Agents
Table 2: b-hematin inhibitory activity of selected moleculesa
in vitro activity and selectivity (36). Furthermore, for the
study of SAR, we synthesized the 9-anilinoacridine deriva-
tives (31–41); all showed a good selectivity index except
compounds 35 and 37 and were found to be non-toxic.
Compound no.
IC50 (lg/mL)
Compound no.
IC50 (lg/mL)
14
15
16
17
19
20
21
22
23
24
3.43
3.92
2.80
2.70
6.90
5.98
3.35
5.41
3.14
2.96
26
31
33
39
40
41
CQ
3.48
5.25
4.71
10.2
6.10
2.68
3.80
The 4-aminoaryl quinoline analogue 17, having t-butyl group
at the 4-position of arylidene moiety, showed the best
potency among all the synthesized molecules having IC50
19.69 nM against the CQ-sensitive strain. 4-bromo- and 4-
trifluoromethyl-substituted analogues have shown the
comparable potency (20, IC50 = 20.78 nM; 21, IC50
=
25.38 nM). Alkyl groups such as ethyl, propyl, and isopropyl
at the para position of arylidene equally affect the antimalar-
ial potency of their corresponding analogues 14, 15, and
16 (IC50 = 38.34 nM; IC50 = 37.07 nM; IC50 = 40.88 nM).
Para-fluoro-substituted compound 19 showed moderate
activity (IC50 = 43.94 nM), whereas ortho-fluoro-substituted
analogue 18 found to be inactive (IC50 = 261.06 nM). In
the quinoline series (14–26), the arylidene substituent gave
rise to compounds generally more active than the hetero-
cyclic counterparts. In particular, the introduction of a 3-
aThe IC50 represents the concentration of compound that inhibit
b-hematin formation by 50%.
exhibited good potency, IC50 = 51.96 and 34.10 nM,
respectively. Therefore, SAR studies showed that substitu-
tion at the para position is essential for antiplasmodial
activity.
pyridyl ring (25) led to
(IC50 = 152.35 nM) compared with the compound bearing
2-fluoro-3-pyridyl moiety, IC50 = 81.47 nM (26, Table 1).
a
twofold drop in potency
The cytotoxicity of all the synthesized hybrid molecules
(14–26) and (31–41) was carried out using Vero cell line
(C1008; monkey kidney fibroblast) following the method of
Mosmann (46) with certain modifications. The cells were
incubated with compound dilutions for 72 h, and MTT was
used as reagent for the detection of cytotoxicity. The 50%
cytotoxic concentration (CC50) was determined using non-
linear regression analysis using preprogrammed Excel
spreadsheet. Most of the compounds have low cytotoxic-
ity with fairly high selectivity index. Eight compounds 23,
31–34, 36, 39, and 40 exhibited good selectivity having SI
value ranging from 578.35 to 4106.77. Compound 40
showed the highest selectivity index (SI = 4106.77) among
the tested compounds. Therefore, these compounds dem-
onstrated the promising safe and good activity profile for
further lead optimization (Table 1).
To validate our hypothesis, we exploited the effect of
p-phenylenediamine linker on antimalarial potency of acridinyl
Schiff base system (31–41). Compound 31, having unsub-
stituted arylidene moiety, showed the IC50 = 43.30 nM.
Introduction of electron releasing groups such as t-butyl at
the para position of arylidene moiety 33 showed the rea-
sonable activity (IC50 = 42.43 nM), whereas an isopropyl
group reduced the antiplasmodial activity of molecule 32
(IC50 = 94.84 nM). In contrast, a thiomethyl group on the
arylidene increased the activity of the analogue 39,
IC50 = 51.22 nM as compared to the 32. Compound 40
bearing the 2-fluoro-3-pyridyl as part of R showed better
antimalarial activity (IC50 = 44.92 nM) than the compound
26 with the same substituent (IC50 = 81.47 nM). Replace-
ment of 2-fluoro-3-pyridyl with 3-Indolyl, significantly low-
ered the activity of analogue 41, IC50 = 71.49 nM.
Analogously, introduction of the 4-Br, 2-F, and 4-F substit-
uents in 36, 34, and 35 dropped down the activity against
the strains tested.
b-hematin inhibitory activity
Moreover, to find out the mechanism of inhibition, several
molecules found to be active in primary screening were
further evaluated for b-hematin inhibitory activity using the
b-hematin inhibitory (BHIA) assay as previously described
(47). The 50% inhibitory concentration (IC50) was deter-
mined using nonlinear regression analysis dose–response
curves. Eight compounds 14, 16, 17, 21, 23, 24, 26, and
41 showed a better dose dependent inhibition in the BHIA
assay (IC50 ranging from 2.68 to 3.72 lg/mL) than CQ
(IC50 = 3.80 lg/mL) in inhibiting hemozoin formation as
depicted in Table 2.
On further screening of molecules against the K1 strain of
P. falciparum, we found several molecules showed greater
potency than the standard (CQ). Among these, analogues
16, 17, 21, 24, 32, and 33 showed many fold better activ-
ity with IC50 ranging from 21.64 to 54.26 nM, as compared
to CQ (IC50 = 495.94 nM) (Table 1). Compounds 16 and
21 having the isopropyl and trifluoromethyl substituents at
the 4-position of arylidene moiety were the most prominent
in growth inhibition with IC50 value of 21.64 and 22.52 nM.
Whereas, compounds 32 and 33 with the same substitu-
ents showed moderate activity (IC50 = 54.26 nM and 53.05
nM, respectively). Compounds 17 and 24, which contained
the 4-t-butyl and 4-thiomethyl substituents as part of R,
Conclusion
In summary, a novel series of 4-aminoquinolinyl and 9-ani-
linoacridinyl Schiff base hydrazones with oxalamide
functionality have been identified. In vitro inhibitory effects
Chem Biol Drug Des 2014; 84: 175–181
179

Sharma et al.
of compounds proved their better effectiveness against
the K1 strain of P. falciparum. Moreover, compounds
were able to maintain safe selectivity profile and excellent
b-hematin inhibitory activity. We believe that these
derivatives might be an innovative avenue for the treatment
of multi-drug-resistant malaria and open up possibilities for
further derivatization in future.
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Conflict of Interest
The authors declare no competing financial interest.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article:
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Appendix S1. General procedure for the synthesis of
compounds 12, 29, 13, 30, 14–26 and 31–41 and the
characterization of compounds 1H, 13C and CHN data for
14–26 and 31–41.
Chem Biol Drug Des 2014; 84: 175–181
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