Anti-malarial, cytotoxicity and molecular docking studies of quinolinyl chalcones as potential anti-malarial agent

Article abstract of DOI:10.1007/s10822-019-00210-2

Abstract: The quinolinyl chalcones series (A₁–A₁₄) were screened for antimalarial activity. According to in vitro antimalarial studies, many quinolinyl chalcones are potentially active against CQ-sensitive and resistance P. falciparum strains with no toxicity against Vero cell lines. The most active quinolinyl chalcones A₄ (with IC₅₀ 0.031?μM) made a stable A₄–heme complex with ??25?kcal/mole binding energy and also showed strong π–π interaction at 3.5??. Thus, the stable A₄–heme complex formation suggested that these quinolinyl chalcones act as a blocker for heme polymerization. The docking results of quinolinyl chalcones with Pf-DHFR showed that the halogenated benzene part of quinolinyl chalcones made strong interaction with Pf-DHFR as compared to quinoline part. A strong A₄–Pf-DHFR complex was formed with low binding energy (??11.04?kcal/mole). The ADMET properties of quinolinyl chalcones were also studied. The in vivo antimalarial studies also confirmed the A₄ as an active antimalarial agent. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10822-019-00210-2

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Journal of Computer-Aided Molecular Design
https://doi.org/10.1007/s10822-019-00210-2
Anti‑malarial, cytotoxicity and molecular docking studies of quinolinyl
chalcones as potential anti‑malarial agent
Asima Hameed1 · Sara Masood3,4 · Aamir Hameed5 · Ejaz Ahmed1 · Ahsan Sharif1 · Muhammad Imran Abdullah1,2
Received: 9 January 2019 / Accepted: 31 May 2019
© Springer Nature Switzerland AG 2019
Abstract
The quinolinyl chalcones series (A1–A14) were screened for antimalarial activity. According to in vitro antimalarial studies,
many quinolinyl chalcones are potentially active against CQ-sensitive and resistance P. falciparum strains with no toxicity
against Vero cell lines. The most active quinolinyl chalcones A4 (with IC50 0.031 μM) made a stable A4–heme complex with
− 25 kcal/mole binding energy and also showed strong π–π interaction at 3.5 Å. Thus, the stable A4–heme complex forma-
tion suggested that these quinolinyl chalcones act as a blocker for heme polymerization. The docking results of quinolinyl
chalcones with Pf-DHFR showed that the halogenated benzene part of quinolinyl chalcones made strong interaction with
Pf-DHFR as compared to quinoline part. A strong A4–Pf-DHFR complex was formed with low binding energy (− 11.04 kcal/
mole). The ADMET properties of quinolinyl chalcones were also studied. The in vivo antimalarial studies also confrmed
the A4 as an active antimalarial agent.
* Ejaz Ahmed
dr.ejaz.ahmed@gmail.com
* Muhammad Imran Abdullah
imranchemist.ali@gmail.com
1
Institute of Chemistry, University of the Punjab, P.O 54590,
Lahore, Pakistan
2
University of Science and Technology of China
(USTC), 96 Jinzhai Road, Hefei 230026, Anhui,
People’s Republic of China
3
Sheikh Zayed Madical College & Hospital, Rahim Yar Khan,
Pakistan
4
Islam Madical College & Hospital, Gujranwala, Pakistan
5
Fatima Memorial Hospital College of Medicine
and Dentistry, Punjab, Pakistan
Vol.:(0123456789)
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Graphical abstract
Keywords Quinolinyl chalcones · Heme binder · Acetophenone · Antimalarial · Pf-DHFR
in the B-ring of the chalcones and reported that the activity
Introduction
is largely depends on the kind of substituent on ring B of
the chalcones. The chloro group on the para-position of the
4-phenylurenyl chalcones plays a very important role in the
anti-malarial activity and the chloro-substituted phenylure-
nyl chalcones showed good anti-malarial activity [5].
The tropical and subtropical countries of the world have
a foremost health problem is malaria. Malaria affected
400–900 million people each year in the world and also
becomes the cause of death of about one to three million
people annually [1]. The malaria caused in humans by the
parasites such as Plasmodium falciparum, P. malariae,
P. vivax and P. ovale. However, one of the most danger-
ous parasite is Plasmodium falciparum, the 80% of infec-
tion and 90% of deaths caused by Plasmodium falciparum
parasite [2]. For the treatment of malaria, researcher have
been developed many drugs, the chloroquine is one of most
commonly used drug against malaria. The chloroquine is
not the efective drug because Plasmodium falciparum has
become resistant to chloroquine and other conventional
anti-malarial drugs, so there is search for efective anti-
malarial drug is still under process [3, 4]. Domínguez et al.
reported potent phenylurenyl substituted chalcones with
(IC50=1.76–10 μM) as a growth inhibitors for in vitro cul-
tured P. falciparum. They did variation of the substituents
Moreover, after a lot of research work, there is no avail-
able vaccine made against malaria for commercial uses.
The GlaxoSmithKline pharmaceuticals recently developed
a RTS, S/AS01 vaccine candidate, which is in Phase lll
clinical trials. This vaccine provided only mild protection
in young infant against both severe and clinical malaria [6,
7]. Thus, the treatment of malaria through chemotherapy
remains the main procedure to deal with malarial problems.
The drug resistance development against antimalarial
medicines such as amodioquine, chloroquine, artemisinin
and anti-folates is turn out to be a severe health issue that
stimulates the researcher to synthesize novel antimalarial
compounds [8]. There is a need to develop new safe and
affordable anti-malarial agents to overcome the grow-
ing malarial resistance against drugs. The twelve novel
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quinolinyl chalcones synthesized by Domínguez et al. and
screened these chalcones against chloroquine resistant strain
of P. falciparum. Only one compound out of twelve showed
promising activity against chloroquine resistant strain with
IC50 =19.0 μM [9].
In search of new drugs for malarial parasites, the most
important target for drugs are to bind with Pf-DHFR (Plas-
modium falciparum dihydrofolate reductase) or heme. Dur-
ing the life cycle of malarial parasite at pathogenic blood
stage, the malarial parasite catabolizes the hemoglobin as a
key reserve of amino acids, dismissing free heme that is sup-
posed to be poisonous to the malarial parasite [10, 11]. The
parasite has developed a detoxifcation path to confscate
free heme into inert and insoluble compound recognized
as hemozoin or malaria pigment. Quinoline based antima-
larial agents, for example quinacrine (QA), quinine (Q),
mefoquine (MQ) and chloroquine (CQ) are backbones of
chemotherapy against malarial parasite and are thought to
be employed their efect through disturbing the formation of
malarial pigment, therefore producing parasite poisonous-
ness from the accumulation of free heme [10, 12, 13]. The
quinolinyl chalcones were also reported as anti-HIV, anti-
bacterial, and inhibitors of bacterial DNA gyrase and viral
reverse transcriptase enzyme [14, 15]. Herein, we screened
profcient quinolinyl chalcones as antimalarial, Plasmodium
falciparum dihydrofolate reductase (Pf-DHFR) inhibitors
and heme binder. We introduced the substituents such as
Br (bromo) and Cl chloro at diferent position of quinoli-
nyl chalcones, which are highly hydrophobic in nature and
enhance the drug alike features. Thus, these substituents
eases the drug to readily pass cell boundary. The efect of
substituent and its position on antimalarial activity is also
screened by changing the substituent and its location. Nowa-
days, to overawed drug resistance issues the idea of hybrid
molecules have been accessible, in which more than one
pharmacophores are connected together and it is assumed
that these molecules act by impeding instantaneously two
conservative targets. So in our case we linked the quinoline
with benzene (containing various type of substituent such as
–Cl, –Br, –OCH3 and CH3) via chalcone bridge as depicted
in Fig. 1.
Fig. 1 Systematic illustration of quinolinyl chalcones interaction with
Heme and Pf-DHFR
diferent aryl ketones were condensed with formyl quinoline
in the presence of NaOH as shown in Chart 1 [17, 18].
Antimalarial activity
The quinolinyl chalcones were evaluated in vitro for their
antimalarial activity against chloroquine (CQ) sensitive
and resistance (CQ- resistance) strain of P. falciparum
using chloroquine as reference drug (Table 1). The cyto-
toxicity of quinolinyl chalcones drug was also determined
against PBM cell (uninfected PHA stimulated Human),
CEM (T-lympho-blastoid cell line) obtained from American
Type Culture Collection and Vero cells line (obtained from
kidney of green monkey of Africa) as shown in Table 2.
A potent anti-malarial activity was shown by most of the
compounds. Five compounds (A1, A2, A3, A5 and A7) out of
fourteen exhibited ant-malarial activities with an IC50 value
less than 0.05 µM, While A8 and A10 showed anti-malarial
almost equal to reference drug chloroquine against chloro-
quine sensitive strain of P. falciparum. The compound A4
and A6 exhibited better antimalarial activity against chlo-
roquine sensitive strain of P. falciparum than chloroquine.
The entire compounds displayed better antimalarial activity
against chloroquine-resistance strain except A11, A12, A13
and A14, while the compound A4 and A6 showed very good
activity as compared to other compounds against chloro-
quine resistance strain.
Results and discussion
Chemistry
The condensing partner formyl quinoline (2,7-dichloro-
8-methyl-3-formyl quinoline) for aryl ketone was synthe-
sized via meth-chon method [15, 16]. The series of quinoli-
nyl chalcones A1–A14 were synthesized via Claisen–Schmidt
condensation reaction according to previously reported
methods as shown in Scheme 1 [15]. In this reaction the
According to antimalarial studies the phenyl derivative of
quinolinyl chalcones that is A4 is more active than A2 and
A3. The main diference among A2, A3 and A4 is the diferent
location of Br group on the ring C of quinolinyl chalcones.
The antimalarial efect of Br group is less efective at 2 (A2)
and 3 (A3) position of ring C as compared to position 4
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Scheme 1 Reaction protocol for the synthesis of chalcones (A1–A14). a AcOH, H3PO4, refux, 4–6 h, b POCl3, DMF, 80 °C, c Methyl Aryl
Ketones, NaOH, rt, 2 h [15]
Chart 1 Diferent aryl ketones
used in Claisen–Schmidt con-
densation reaction A1–A14
(A4). Conversely, the 4 position of ring C with –Cl, –OCH3
(methoxy) that is A6 and A7 are also less active as compared
to A4, which is due to the greater electronic and lipophilic
efect of Br group at 4 position of ring C (Fig. 1, Table 1).
The thiophene derivatives of quinolinyl chalcones, the
A8 and A10 displayed better antimalarial activity against
chloroquine sensitive and resistance strain as compared to
other thiophene derivatives such as A11, A12, A13 and A14
as illustrated in Table 1. The methyl substituted thiophene
A11, A12 and A13 in quinolinyl chalcones decreases the
antimalarial activity while Cl or Br group at fve position
(A8 and A10) of thiophene ring enhances the antimalarial
activity to a good extent. Conversely, the dimethylated
thiophene A11 is also less active as compared to mono-
methylated thiophene derivatives. Generally, the EDG
(electron donating group) on thiophene or benzene ring
decreased the activity whereas EWD (electron withdraw-
ing groups) enhances the antimalarial activity. The theo-
retical and bioassay studies are also supported the above
conclusions (Tables 1, 2, and 3).
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