SYNTHESIS AND EVALUATION OF QUINOLINE AND PIPERIDINE DERIVATIVES AS EHMT2 INHIBITORS: PROSPECTS FOR ANTIMALARIAL DRUG DEVELOPMENT

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Gassama et al. World Journal of Pharmaceutical and Life Science
SYNTHESIS AND EVALUATION OF QUINOLINE AND PIPERIDINE DERIVATIVES
AS EHMT2 INHIBITORS: PROSPECTS FOR ANTIMALARIAL DRUG DEVELOPMENT
Moussa Toure1, Oumar Sambou1, Abdoulaye Gassama1,2*, Christian Cave2 and Sandrine Cojean2,3
1Laboratory of Chemistry and Physics of Materials (LCPM), Assane SECK University Ziguinchor, BP 523,
Ziguinchor, Senegal.
2Antiparasitic Chemotherapy, UMR 8076 CNRS BioCIS, Paris-Sud University, Paris-Saclay University, 17 rue avenue
des sciences, 91400 Orsay, France.
3National Malaria Reference Center, Hôpital Bichat-Claude Bernard, APHP, 75018 Paris, France.
3National Malaria Reference Center, Bichat-Claude Bernard Hospital, APHP, Paris, France.
Article Received on 25/08/2023 Article Revised on 15/09/2023 Article Accepted on 05/10/2023
INTRODUCTION
Malaria is a potentially fatal parasitic disease affecting
millions of people worldwide.[1] It is mainly caused by
parasites of the genus Plasmodium, transmitted to
humans by the bites of infected female Anopheles
mosquitoes.[2] The emergence and spread of resistance to
artemisinin and its related drugs[3,4] - the most widely
used combination of antimalarial drugs[5] - threaten to
wipe out gains and could have devastating consequences
worldwide. This calls for the urgent development of new
therapeutic agents with distinct modes of action to
overcome resistance and control multi-resistant
Plasmodium parasites.[6]
Quinolines are heterocycles that have emerged as a
promising class of compounds with significant
antimalarial activity.[7,8] Aminoquinoline derivatives with
amide function play a key role in interaction with target
receptors or enzymes,[9] which may influence their
pharmacological activity.[10] A number of organic and
natural products containing peptide bonds possess
interesting biological activities.[9] For this reason, the
development of new peptide bonds containing the
quinoline ring using simple reactions has become a
fascinating area of research.
As part of our research into antimalarial quinoline
derivatives, the present study focuses on the synthesis of
N-benzyl-N-(8-quinolyl)-2-phenoxyacetamide analogues,
containing an amide linkage (-CONR-), using an
approach based on alkylation and acylation reactions
starting from aminoquinoline and acyl chloride. We
carried out an in vitro biological evaluation of the
antimalarial activity of these compounds. In addition,
cell viability tests were carried out to determine the
effect of the compounds on cell survival (HUVEC).
An in silico study was also carried out on the ADME
(Absorption Distribution Metabolism and Elimination)
properties of the synthesized compounds, enabling us to
estimate the ADME properties of the compounds, such
as their intestinal absorption, solubility, metabolic
stability and bioavailability.
Molecular docking appears to be an important and
necessary step in understanding the process of biological
reactions and in drug design. We performed molecular
docking with proteins of interest involved in malaria, in
order to predict the binding affinity of compounds and
understand their potential mechanism of action. The
Molecular Operating Environment (MOE), an open
*Corresponding Author: Pr. Abdoulaye Gassama
Laboratory of Chemistry and Physics of Materials (LCPM), Assane SECK University Ziguinchor, BP 523, Ziguinchor, Senegal.
ABSTRACT
In this study, we report the synthesis of a set of quinoline and piperidine derivatives and the in vitro evaluation of
their antimalarial activity against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfW2) P. falciparum
strains. The in vitro cytotoxicity of these compounds was assessed to determine their impact on human cells.
Preliminary in vitro results showed that these compounds displayed selective cytotoxicity and potent activity
against both strains. In particular, compound 8 showed promising activity, with CI50 values of 1.36 µM for strain
3D7 and 6.57 µM for strain W2. An in silico approach was used in parallel, such as molecular docking and
pharmacological and pharmacokinetic properties prediction (ADME) to study the ability of these compounds to
bind to the target of interest and to predict their efficacy and safety in the context of oral administration.
KEYWORDS: antimalarial, plasmodium falciparum, in vitro, in silico, quinoline, piperidine.
Research Article
ISSN 2454-2229
wjpls, 2023, Vol. 9, Issue 11, 01-11
World Journal of Pharmaceutical and Life Sciences
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Gassama et al. World Journal of Pharmaceutical and Life Science
access software package, was used to dock our
compounds.[11]
MATERIALS AND METHODES
General
NMR spectra 1H and 13C were recorded at room
temperature on a BRUKER UltraShield 300
spectrometer and tetramethylsilane (TMS) was used as
internal reference. Analyses 1H were obtained at 300
MHz and analyses 13C were obtained at 75 MHz.
Chemical shifts δ are expressed in parts per million
relatives to TMS (δ = 0.00). Different deuterated solvents
were used depending on the solubility of the products.
For 1H spectra, the abbreviations s, d, t, q, dd and m refer
to signals in singlet, doublet, triplet, quadruplet, split
doublet and multiplet form. Coupling constants J are
expressed in Hertz (Hz). Mass spectroscopy analyses
were carried out on a Waters Micromass Quattro
quadrupole/Q-TOF time-of-flight instrument equipped
with ESI electrospray ionization or APCI atmospheric
pressure chemical ionization. Reactions were monitored
by Macherey-Nagel Polygram Sil G/UV254 silica gel
thin-layer chromatography (TLC) and products were
detected under ultraviolet illumination at 254 nm.
Product purification by column chromatography was
carried out on silica gel (Merck Kieselgel 60).
General procedure for the synthesis of 3a-c
A mixture of 8-aminoquinoline 1 (500 mg, 3.47 mmol)
and 10.40 mmol triethylamine (Et3N) in 20 mL THF was
stirred for 30 min at room temperature. The
corresponding acetyl chloride (1.5 equiv) was added
dropwise to the reaction mixture at 0°C. The mixture was
stirred for 3 h at room temperature. 20 mL of an aqueous
solution of NaOH (10%) was added to the mixture. The
aqueous phase was extracted with ethyl acetate (3x10
mL). The organic phases were washed with NaCl salt
solution (20 mL), dried over Na2SO4 and then
concentrated, under reduced pressure. The residue
obtained required further purification on column
chromatography with the eluent cyclohexane/AcOEt
ratio 7:3. The product was obtained as a white solid.
General procedure synthesis for 5(a-d)
A mixture of phenoxy-N-(quinolin-8-yl)acetamide 2 (100
mg, 0.37 mmol) and 3 equivalents of iPr2NEt is
dissolved in 20 mL THF. After addition of 2 equivalents
of the corresponding substituted benzyl bromide (0.9
mmol), the reaction mixture is kept under stirring at
room temperature for 24 to 48 hrs. The solvent was
removed and the residue soaked in 20 mL of an aqueous
solution of NaHCO3. The aqueous phase was extracted
with CH2Cl2 (3 x 10 mL). The organic phases were dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue obtained was purified by silica gel
column chromatography with the eluent
cyclohexane/ethyl acetate (6/4) to give compounds 5(a-
d) as a yellowish powder.
Synthesis of N-[(3-bromobenzyl)quinolin-8-amine (6)
A mixture of 8-aminoquinoline 1 (3.5 mmol) and 3-
bromobenzyl bromide 4 (5.25 mmol) was dissolved in
acetonitrile (20 mL). Potassium carbonate (14 mmol)
was added in excess and the mixture was stirred for 5
hours. The liquid was removed and the residue cooled in
a basic solution of sodium bicarbonate. The aqueous
phase was extracted three times with ethyl acetate. The
organic phases are dried over Na2SO4. The solvents are
evaporated under reduced pressure. The residue obtained
is purified on a silica chromatography column using a
mixture of ethyl acetate and petroleum ether (1/9) as
eluent to give the product as a white solid.
Synthesis of N-(3-bromobenzyl)-2-chloro-N-(8-
quinolyl) benzamide (8)
In a round-bottomed flask, 100mg (0.32mmol) of N-[(3-
bromobenzyl) quinolin-8-amine 6 and 100µL of DIPEA
in 10ml THF were stirred for ½ hour. 81µL (0.64mmol)
of 3-bromobenzyl bromide 2c was added dropwise to the
solution containing 6. After stirring at room temperature
for 24 hours, the reaction was concentrated and then
quenched with saturated NaHCO3. The aqueous phase
was extracted three times with ethyl acetate. The organic
phase was dried over MgSO4 and then concentrated in
vacuo. The residue obtained was purified on a silica gel
chromatography column with the eluent
cyclohexane/ethyl acetate in the ratio 6:4 to give pure
compound 8 as a brown solid.
Synthesis of 1-Boc-4-(3,4-dichloroanilino) piperidine
(11)
In a nitrogen fed reaction vessel 4-oxo-piperidine-1-
carboxylic acid tert-butyl ester 9 (0.3g, 1.5 mmol) and
3,4-dichloro-phenylanine 10 (0.20 g, 1.23 mmol) were
dissolved in dichloroethane (15 ml) and acetic acid (1.2
eq). Sodium triacetoxyborohydride (1.4 eq) was added at
room temperature. The reaction was stirred overnight
and then poured into a sodium hydroxyd solution (10%).
The water phase was shaken three times with ethyl
acetate (EtOAc). The combined organic phase was dried
over sodium sulfate, evaporated and purified by flash
chromatography (DCM 100% and DCM/MeOH 9,8/0,2)
giving pure compound.
Synthesis of t-butyl 4-(3,4-dichloro-N-[(E)-3-
phenylprop-2-enoyl]anilino)piperidine-1-carboxylate
(12)
A mixture of 11 (50mg; 0.15 mmol) and
diisopropylethylamine (0.3 mmol) is dissolved in
dichloromethane (10 mL). Cinnamoyl chloride 2 (0.22
mmol) is added in excess and the mixture is stirred for 48
hours at room temperature. The reaction is concentrated
and cooled in sodium bicarbonate solution. The aqueous
phase is then extracted three times with ethyl acetate.
The organic phase is washed with an aqueous solution
saturated with NaCl (40 mL) and dried over MgSO4. The
solvents are evaporated under reduced pressure. The
residue obtained is purified on a silica chromatography

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Gassama et al. World Journal of Pharmaceutical and Life Science
column using ethyl acetate/cyclohexane (3/7) as eluent to
give the product as a white solid.
General procedure for the synthesis of 14a-c
A mixture of piperidine (3.25 mmol) and excess
potassium carbonate (8 mmol) is dissolved in
dichloromethane (10 mL). After 40 minutes stirring,
corresponding acyl chloride (6.5 mmol) is added
dropwise at 0°C. The mixture is stirred for 24 to 48 hours
in the presence of 100µL triethylamine at room
temperature. The liquid is removed and the residue
cooled with sodium bicarbonate solution. The aqueous
phase is then extracted three times with ethyl acetate.
The organic phase is washed with an aqueous solution
saturated with NaCl (40 mL) and dried over Na2SO4. The
solvents are evaporated under reduced pressure. The
residue obtained is purified on a silica chromatography
column using ethyl acetate/cyclohexane (3/7) as eluent to
give the product as a white powder.
General procedure for the synthesis of 16a-b
A mixture of t-butyl 4-(aminomethyl)piperidine-1-
carboxylate 15 (2.33 mmol) and excess triethylamine (5
mmol) is dissolved in THF (15 mL). After 30 minutes
stirring, corresponding cinnamoyl chloride 2 (3.5 mmol)
is added dropwise at 0°C. The mixture is stirred for 3 h at
room temperature. The solvent is removed and the
residue cooled with sodium bicarbonate solution. The
aqueous phase is then extracted three times with
dichloromethane. The organic phase is washed with an
aqueous solution saturated with NaCl (30 mL) and dried
over Na2SO4. Solvents are evaporated under reduced
pressure. The residue obtained is purified on a silica
chromatography column using ethyl acetate/cyclohexane
(3/7) as eluent to give the product as a light yellow
powder.
BIOLOGICAL PROCEDURE
In vitro test for growth and proliferation of P. falciparum
The compounds were tested against parasites of the
susceptible P. falciparum strain 3D7 and the resistant P.
falciparum strain W2, using the two-day fluorescence-
based SYBR Green I approach.[12] Parasites were grown
under standard conditions with minor modifications at
2.5% hematocrit in RPMI 1640 medium with an initial
parasitemia of 1%. Compounds and negative control
were prepared by double dilution, in the range 0.098-100
μg/mL, in a 96-well flat-bottom plate to give a final
volume in each well of.[13] After 48 h incubation, the
plates were subjected to 3 freeze-thaw cycles to achieve
complete hemolysis. The parasite lysis suspension was
diluted 1:5 in SYBR Green I lysis buffer. Plates were
then incubated for a further hour at room temperature in
the dark and examined for relative fluorescence units per
well using epRealplex Master.[14] IC50 values of active
compounds were calculated by non-linear regression
using ICEstimator Server version 1.2.[15]
In vitro cytotoxicity test
HUVEC cells were cultured in RPMI 1640 medium
supplemented with 10% fetal bovine serum and 1 mM L-
glutamine and incubated in 5% CO2 at 37°C. Host cell
cytotoxicity was assessed using the SYBR Green I assay
as previously described. HUVEC cells were seeded in a
96-well plate at 100,000 cells/well and incubated for 24
h to adhere. After discarding the old medium, cells were
incubated in medium containing eight concentrations
(0.78-100 μg/mL) of each extract in duplicate. After 48 h
incubation, cells were visualized using an inverted
microscope to check morphology or cell viability. The
medium was then removed and replaced with SYBR
Green I-free lysis buffer, and the plates subjected to 3
freeze-thaw cycles. The cell lysis suspension was diluted
1:2 in SYBR Green I lysis buffer. Incorporation of
SYBR Green I into cellular DNA and IC50 analysis were
obtained as before.
IN SILICO STUDY
In silico drug similarity and ADME analysis
The SwissADME online server was used to predict drug
similarity and ADME parameters.[16]
Molecular docking
The crystal structure of the human malaria drug target
co-crystallized with SAH (PDB ID: 2O8J)[17] was
extracted from the Protein Data Bank
(www.rcsb.org/pdb). The protein was prepared using
Molecular Operating Environment (MOE) version
2015.10 software, eliminating all water molecules. All
compounds were drawn and optimized by the MOE
software, and the resulting molecules were saved in mdb
(molecule data base) format. The protein was considered
to be rigid, but the flexibility of the molecules was taken
into account, so that all possible poses could be
exploited.
In MOE, receptor-ligand binding affinities with all
possible binding geometries are prioritized on the basis
of a numerical value called the S-score. Inhibitor
interactions with receptor proteins are predicted on the
basis of the S-score.[18] Docking results were
manipulated using the GBVI/WSA dG scoring function
with the generalized Born solvation model (GBVI).
GBVI/WSA dG is a force-field-based scoring function
that estimates the ligand's binding free energy from a
given orientation.[19] The binding energy is directly
associated with the conformation adopted by the ligand
within the protein's active site. MOE's "Site Finder"
module detects enzymatic cavities and the most
favorable site in the protein.
The intermolecular interactions between the compounds
and the G9a target (ID:2O8J) were visualized using
Discovery Studio Visualizer software, providing insight
into the molecular mechanisms underlying the
compounds' activity.

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Gassama et al. World Journal of Pharmaceutical and Life Science
RESULTATS AND DISCUSSION
Chemistry
Quinoline-based amide analogues were synthesized by a
simple two-step process according to Scheme 1. The
method involves the reaction of activated carboxylic acid
derivatives, such as chlorides, with amines.[20]
Condensation of 8-aminoquinoline 1 with cinnamoyl
chloride or phenoxyacetyl chloride led to precursors 3a-c
in satisfactory yields. According to Scheme 1, the
previously prepared precursors contain a free NH moiety
attached to the 8-position of the quinoline ring system.
Alkylation of this free NH group with an alkylating agent
such as substituted benzyl bromides, in acetonitrile,
provides di-substituted amides in moderate to high
yields. The results of these condensations are reported in
Table 1.
(a)
5
1
2
3
(b)
4
Scheme 1. Synthesis of quinoline analogues with a peptide bond. Conditions: (a) THF, NEt3, rt, 3h; (b) CH3 CN,
i-Pr2NEt, 90°, 24-48h
Table 1: Synthesized products derived from quinoline with the studied amide linkage.
Compound ID
R1
X
R2
Time (h)
Yield (%)
3a
H
O
/
3
99
3b
4-Br
O
/
3
90
3c
H
C=
/
3
88
5a
H
O
2-Br
4
69
5b
H
O
3-Br
4
60
5c
H
O
4-Br
4
70
5d
H
C=
4-F
48
75
Another quinoline analogue was synthesized in two
steps, N-(3-bromobenzyl)-2-chloro-N-(8-
quinolyl)benzamide (8), in moderate yield. Thus, the
amine of 8-aminoquinoline 1 was first alkylated by
substituted benzyl bromide 4 to give the precursor 6
(monoalkylated). Acylation of 6 with 2-chlorobenzoyl
chloride 7 in THF in the presence of DIPEA gave the
desired compound 8 in 72% yield (Scheme 2).
CH3CN / K2CO3
22h, TA
4
THF / DIPEA
0°C vers TA, 24h
1
7
6
8
Scheme 2: Synthesis of N-[3-bromobenzyl]-2-chloro-N-(8-quinolyl)benzamide 8.
For the synthesis of piperidine analogues, we modified a
methodology adopted from the literature.21,22
Accordingly, the key precursor 11 (rdt = 68%), was
synthesized by reductive amination by condensing Boc-
piperidone 9 with 3,4-dichloroaniline 10 in acid medium
in the presence of sodium triacetoxyborohydride in
dichloroethane. Compound 11 was then treated with
cinnamoyl chloride 2c to give the desired compound 12
in 28% yield (Scheme 3). It is therefore possible to
screen other bases and solvents to optimize yield.
DCM / DIPEA
24h, TA
DCE / AcOH
NaHB(OAc)3
24h, TA
9
11
10
12
2c
Scheme 3: Synthesis of N-(1-boc-piperidin-4-yl)-N-(3,4-dichloro-phenyl)-cinnamamide.

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Gassama et al. World Journal of Pharmaceutical and Life Science
Condensation of various chlorides with piperidine
derivatives such as 4-piperidone hydrochloride hydrate
13 or 1-Boc-4-piperidylmethanamine 15 yielded a series
of five piperidine analog amides in satisfactory yields
(Scheme 4; Table 2).
THF / Et3N, 2h, TA
14
DCM / K2CO3/Et3N
4-24h, TA
16
15
H2O.
HCl .
13
2
Scheme 4: Synthesis of piperidine amide derivatives.
Table 2: Synthesized products derived from
piperidine with the amide bond studied.
Compound ID
R
X
Yield
14a
H
O
72
14b
H
C=
63
14c
4-F
C=
58
16a
4-F
/
80
16b
H
/
87
The final structures of all the compounds synthesized
have been established by the usual spectroscopic
analyses, such as NMR and LC/MS, and the structures
are in line with those expected.
Biological evaluation
The biological activity of each compound was evaluated
on chloroquine-sensitive (3D7) and chloroquine-resistant
(W2) P. falciparum strains, and the lethal dose on
HUVEC cells was assessed.
Table 3: In vitro antimalarial activity, cytotoxicity and selectivity index of compounds.
Cpds ID
In vitro Activity (µM ± SD)
HUVEC cells
Selectivity index : CC50/IC50
CI50 (3D7)
CI50 (W2)
CC50
(3D7)
(W2)
3a
72.45±5.22
>100
88.23±0.31
1.22
< 0.88
3b
>100
>100
>100
>1
>1
3c
33,65±2,55
51,87±3,04
>100
2.97
1.93
5a
>100
>100
89.74±0.21
< 0.90
< 0.90
5b
>100
>100
84.67±0.21
< 0.85
< 0.85
5c
>100
>100
>100
>1
>1
5d
>100
>100
>100
>1
>1
6
7,60±1,30
40,25±3,98
>100
> 13.16
> 2.48
8
1.36±0.61
6.57±1.24
85.78±0.17
63.07
13.06
11
61,71±1,60
>100
65.26±0.52
1.06
< 0.65
12
6,12±1,33
20,62±2,67
92.73±0.13
15.15
4.50
14a
>100
>100
>100
>1
>1
14b
>100
>100
73.34±0.61
< 0.73
< 0.73
14c
/
/
/
/
/
16a
41,02±2,20
33,25±1,61
>100
> 2.44
> 3.01
16b
/
/
/
/
/
CQ
0,0156±0,002
0,238±0,019
>1
> 64.10
> 4.20
Based on Table 3, only seven compounds were active
against the Pf3D7 strain and five against the PfW2 strain.
Compound 8 showed the highest activity against both
strains, with a CI50(3D7) of 1.36 µM and CI50(W2) of 6.57
µM, while compound 3a was the least active (CI50 =
72.45 µM). Compound 6 showed potent activity against
the Pf3D7 strain, with an IC value of50 = 7.60µM. There
was no significant trend when assessing the effect of the
substituent on the benzyl ring. On the other hand, it is
interesting to note the contribution of the 2-
chlorobenzoyl group in the antiproliferative activity of
malaria parasites (compared 6 and 8). Among piperidine
derivatives, only molecule 12 exhibited inhibitory
potency on the susceptible strain, with a CI value50 of
6.12µM. The introduction of cinnamoyl leading to 12
seems to play a crucial role in antiplasmodial activity
(compared 11 and 12).

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Gassama et al. World Journal of Pharmaceutical and Life Science
Evaluation of the cytotoxic activity of all the compounds
studied was relatively good, with a lethal dose ranging
from 65.26 µM to >100, confirming the safety of the
compounds tested. Clearly, compound 8, which showed
the best activity, has the highest selectivity index, with a
value of 63.
Analysis of drug similarity (ADME)
The success of a drug's journey through the human body
is measured in the dimensions of Absorption,
Distribution, Metabolism and Elimination (ADME).[23,24]
Lipinski's Rule of Five (Ro5)[25,26] depends on four
simple physicochemical parameter factors, which are:
molecular weight not exceeding 500 g/mol, lipophilicity
(Log P) less than 5, and a number of hydrogen bond
acceptors and donors that should be less than 10 and 5,
respectively. Taking into account the in vitro assay, the
drug properties of the compounds were evaluated
according to ADMET parameters using the open offline
server SwissADME (http://www.swissadme.ch/)[16] and
the results are summarized in Table 4.
According to the in silico study, all the compounds
synthesized meet Lipinski's Ro5 criteria. They have a
molecular weight of between 274.32 and 475.41 g/mol, 1
to 4 hydrogen bond acceptors, and a hydrogen donor
number of between 0 and 1. The log P partition
coefficient, an important feature in the process of drug
absorption and elimination, is between 1.98 and 5, in
compliance with Ro5. No violation of Lipinski's Ro5 was
observed for these compounds.
Table 4: Drug similarity and Lipinski's rule of our ligands.
Cpds
ID
ABS
TPSA
(Å2)
Molar
refractivity
ROTB
MW
LogP
ALH
DLH
Lipinski
violation
Log S
F
Rule
-
˂140
40-130
≤ 10
˂ 500
≤ 5
˂ 10
˂ 5
˂ 2
≤ 1
>10%
3a
Haute
51,22
82,07
5
278,31
1,98
3
1
0
MS
0,55
3b
Haute
51,22
89,77
5
357,20
2,60
3
1
0
MS
0,55
3c
Haute
41,99
85,67
4
274,32
2,73
2
1
0
MS
0,55
5a
Haute
42,43
119,16
7
447,32
3,91
3
0
0
PS
0,55
5b
Haute
42,43
119,16
7
447,32
3,91
3
0
0
PS
0,55
5c
Haute
42,43
119,16
7
447,32
3,91
3
0
0
PS
0,55
5d
Haute
33,20
115,01
6
382,43
4,42
3
0
0
MS
0,55
6
Haute
24,92
83,24
3
313,19
3,50
1
1
0
MS
0,55
8
Haute
33,20
118,06
5
451,74
5,03
2
0
0
PS
0,55
11
Haute
41,57
95,44
5
345,26
3,47
2
1
0
MS
0,55
12
Haute
49,85
134,96
8
475,41
4,58
3
0
0
PS
0,55
16a
Haute
58,64
103,59
8
362,44
2,91
4
1
0
MS
0,55
ABS: absorption. TPSA: Topological Polar Surface Area. HBA: H-bond acceptor. HBD: H-bond donor n-ROTB:
Number of rotatable bonds. MW: Molecular weight. LogP: logarithm of partition coefficient of compound between n-
octanol and water. F: Bioavailability Score. MS: Moderately soluble. PS: Poorly soluble.
In addition, topological polar area (TPSA) values of less
than 140 Ų indicate good permeability through the cell
plasma membrane.[27] In addition, the number of flexible
bonds is between 4 and 8, which does not adversely
affect the permeation rate. As with the absorption of the
molecule in the gut, all compounds show high
gastrointestinal absorption, indicating that they are
highly absorbed in the gut.
The results of this study show that the compounds meet
the criteria established by ADMET, suggesting that they
can be administered orally. Furthermore, when
comparing in vitro and in silico results, compound 8
stands out for its potential promise in terms of
pharmacological properties, making it a promising
prototype.
Molecular docking
G9a, also known as Euchromatin Histone Lysine Methyl
Transferase 2 (EHMT2), is an enzyme that catalyzes the
addition of methyl groups to histone H3 lysine 9.[28–30]
This epigenetic modification plays a crucial role in many
biological processes. Because of the importance of G9a,
several inhibitors of this enzyme have been
developed.[29,30] Competitive SAM inhibitors bind to the
SAM cofactor binding pocket of G9a, thus preventing
histone methylation and, consequently, reducing the
enzymatic activity of G9a. These inhibitors offer a
promising strategy for disrupting G9a-dependent gene
regulatory pathways.
It's worth noting that histone lysine methyltransferases
(HKMTs) are present not only in mammalian systems,
but also in P. falciparum, one of the agents responsible
for human malaria. In the case of the parasite, these
proteins play an essential role in regulating the gene
transcription pathway. Therefore, by specifically
targeting G9a, it is possible to disrupt these processes in
P. falciparum. To further investigate competitive
inhibitors of G9a, we have chosen the human G9a
receptor (PDB ID:2O8J) as the anchor for our structures.
This will enable us to explore competitive inhibitors
specific to the EHMT2 substrate.

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To explore ligand binding sites on the structure of the
receptor enzyme EHMT2, its 3D structure was
downloaded from RCSB-PDB (www.rcsb.org/pdb).
Ligands and receptor were prepared for docking by
minimizing their energy, followed by 3D protonation in
MOE 2015.10[31] eliminating water molecules on G9a,
facilitating the interaction of ligands with the
receptor.[18,32] MOE uses an empirical swimming
function (GBVI/WSA dG), based on the force field, to
calculate binding affinity.[11]
Table 5: S-score binding energy values of selected
synthesized ligands.
N°
Ligand name
S value (Kcal/mol)
1
5a
-7.3805
2
5b
-7.2362
3
5c
-7.4593
4
6
-6.4672
5
8
-7.1898
6
12
-7.3911
7
CQ
-6.8021
The energy values generated by the MOE-Dock software
(Table 5) showed that the selected compounds had the
lowest binding energy values, ranging from -7.46 to -
6.47 kcal/mol among the compounds tested. All
molecules showed a high affinity for G9a.
Similar to in silico docking, ligand 5c showed a
minimum energy of -7.46 kcal/mol, making it the
strongest interaction to inhibit G9a activity. However, in
vitro, it showed no biological activity (IC50 > 100).
Compound 12 showed the second highest affinity with
the EHMT2 target, exhibiting a lower binding energy
than chloroquine, with a value of -7.39 kcal/mol versus -
6.80 kcal/mol. The analog N-[3-bromobenzyl]-2-chloro-
N-(8-quinolyl)benzamide 8 satisfies all the parameters of
Lipinski's rule, showing a minimum energy of -7.19
kcal/mol, making it a potentially orally active drug.
Analysis of the pharmacophore map of compound 8 with
EHMT2 revealed a significant interaction in the form of
a hydrogen bond between the oxygen of the amide
function and residue GLN1019 of the enzyme's C-chain
active site. In addition to this hydrogen bond, pi-anion
and pi-alkyl interactions were observed (fig. 2).
Similarly, compound 12 also showed a significant
interaction with G9a. A hydrogen bond was formed
between this compound and ARG residue B:966, in
addition to electrostatic and hydrophobic interactions
(fig. 3). These results support the hypothesis that
compounds 8 and 12 possess potentially strong
biological activity in blocking the growth of P.
falciparum parasites through their interaction with G9a.
The intermolecular interactions between the compounds
and the G9a target (ID:2O8J) were visualized using
Discovery Studio Visualizer software, providing insight
into the molecular mechanisms underlying the
compounds' activity.
Figure 1: 2D and 3D image of interactions between G9a active site residues and compound 5c.
Figure 2: 2D and 3D image of interactions between G9a active site residues and compound 8.

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Gassama et al. World Journal of Pharmaceutical and Life Science
Figure 3: 2D and 3D image of interactions between G9a active site residues and compound 12.
Characteristics of Synthetic Molecules
2-phenoxy-N-(quinolin-8-yl)acetamide (3a)
Yield: 99%; MS: (ESI, +) for C17H14N2O2 [M+H]
calculated 278.1055 m/z, found 279.1154 m/z; 1H NMR
(300 MHz, CDCl3) δ 10.98 (s, 1H, NH), 8.86 (dd, J =
9.0, 4.9 Hz, 2H, 2CHAr), 8.17 (dd, J = 8.3, 1.7 Hz, 1H,
CH), 7.62 - 7.52 (m, 2H, 2CHAr), 7.47 (dd, J = 8.3, 4.2
Hz, 1H), 7.38 (t, J = 15.1, 6.1 Hz, 2H, 2CH), 7.21 - 7.12
(m, 2H), 7.07 (t, J = 7.3 Hz, 1H), 4.77 (s, 2H, CH2 O).
13C NMR (75 MHz, CDCl3) δ 166.83 (C=O), 157.44 (C-
OAr), 148.66 (C=NAr), 138.80, 136.20, 133.74, 129.79
(2CHAr), 128.00, 127.23, 122.24 (2CHAr), 121.72,
116.80, 115.16 2CHAr), 68.16 (CH2).
2-(4-bromophenoxy)-N-(8-quinolyl)acetamide (3b)
Yield: 90%; MS: (ESI, +) for C13H17BrN2O2 [M+H]
calculated 356.0160 m/z, found 357.0244 m/z; 1H NMR
(300 MHz, Chloroform-d) δ 10.90 (s, 1H), 8.91 - 8.75
(m, 2H), 8.24 - 8.13 (m, 1H), 7.65 - 7.41 (m, 6H), 7.09 -
6.96 (m, 2H), 4.74 (s, 1H).
(2E)-3-phenyl-N-(8-quinolyl)prop-2-enamide (3c)
Yield: 88%; MS: (ESI, +) for C18H14N2 [M+H] calculated
274.1106 m/z, found 275.1186 m/z; 1H NMR (300 MHz,
Chloroform-d) δ 10.03 (s, 1H, NH), 8.94 (dd, J = 7.4, 1.7
Hz, 1H), 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3,
1.7 Hz, 1H), 7.85 (d, J = 15.6 Hz, 1H), 7.64 (dq, J = 6.7,
2.5 Hz, 2H), 7.61 – 7.52 (m, 2H), 7.52 – 7.42 (m, 2H),
7.42 – 7.34 (m, 2H), 6.83 (d, J = 15.6 Hz, 1H). 13C NMR
(75 MHz, Chloroform-d) δ 164.13 (C=O), 148.15,
142.09, 138.51, 136.42, 134.86, 134.68, 129.89, 128.87
(2CHAr), 128.04 (2CHAr), 128.00, 127.51, 121.65,
121.61, 117.37-116.53 (4CH).
N-(2-bromobenzyl)-2-phenoxy-N-(8-
quinolyl)acetamide (5a)
Yield: 69%; MS: (ESI, +) for C24H19BrN2O2
[M+3H]+ calculated 446.0630 m/z, found 449.0713
m/z; 1H NMR (300 MHz, CDCl3) δ 8.78 (dd, J =
4.2, 1.7 Hz, 1H), 8.11 (dd, J = 8.3, 1.7 Hz, 1H),
7.69 – 7.55 (m, 3H), 7.50 – 7.30 (m, 4H), 7.28 –
7.08 (m, 4H), 6.75 (s, 1H), 6.59 (dd, J = 7.7, 1.1
Hz, 1H), 4.75 (s, 2H), 4.67 (d, J = 5.5 Hz, 2H). 13C
NMR (75 MHz, DMSO-d6) δ 164.20, 155.04,
148.77, 147.33, 142.46, 139.82, 138.99, 131.81,
131.69, 127.90, 127.77, 127.00, 123.98, 121.49,
118.11, 117.47, 114.82, 114.54, 112.78, 112.47,
101.74, 56.04.
N-(3-bromobenzyl)-2-phenoxy-N-(8-
quinolyl)acetamide (5b)
Yield: 60%; MS: (ESI, +) for C24H19BrN2O2 [M+3H]+
calculated 446.0630 m/z, found 449.0713 m/z; 1H NMR
(300 MHz, CDCl3) δ 9.03 (dd, J = 4.2, 1.7 Hz, 1H), 8.25
(dd, J = 8.3, 1.7 Hz, 1H), 7.87 (dd, J = 8.3, 1.4 Hz, 1H),
7.59 – 7.41 (m, 2H), 7.44 (s, 1H), 7.36 (d, J = 7.7 Hz,
1H), 7.31 – 7.04 (m, 5H), 6.92 (t, J = 9.0, 6.0 Hz, 1H),
6.77 (d, J = 7.9 Hz, 2H), 5.72 (s, 2H, CH2N), 4.33 (s, 2H,
CH2O). 13C NMR (75 MHz, CDCl3) δ 168.99, 158.01,
151.25, 144.11, 139.84, 137.63, 136.48, 131.98, 130.48,
129.83, 129.61, 129.55, 129.27 (2CHAr), 129.09, 127.66,
126.29, 122.31, 122.22, 121.15, 114.63 (2CHAr), 66.63
(CH2O), 52.76 (CH2N).
N-(4-bromobenzyl)-2-phenoxy-N-(8-
quinolyl)acetamide (5c)
Yield: 40%; MS: (ESI, +) for C24H19BrN2O2 [M+3H]+
calculated 446.0630 m/z, found 449.0687 m/z; 1H NMR
(300 MHz, CDCl3) δ 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.15
(dd, J = 8.3, 1.8 Hz, 1H), 7.77 (dd, J = 8.3, 1.4 Hz, 1H),
7.44 (dd, J = 8.3, 4.2 Hz, 1H), 7.36 (dd, J = 8.3, 7.3 Hz,
1H), 7.31 – 7.21 (m, 2H), 7.11 (td, J = 8.3, 2.1 Hz, 3H),
7.06 – 6.96 (m, 2H), 6.83 (t, J = 7.3 Hz, 1H), 6.66 (d,
2H), 5.64 (s, 2H), 4.31 (s, 2H).
13C NMR (75 MHz, CDCl3) δ 168.91 (C=O), 158.01,
151.27, 144.12, 137.59, 136.59, 136.47, 131.38

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(2CHAr), 130.91, 129.60 (2CHAr), 129.24 (2CHAr),
129.04, 126.26, 122.21, 121.39, 121.14, 114.63
(2CHAr), 66.61 (CH2O), 52.60 (CH2N).
(2E)-N-(2-bromobenzyl)-3-phenyl-N-(8-
quinolyl)prop-2-enamide (5d)
Yield: 75%; MS: (ESI, +) for C25H19FN2O [M+H]+
calculated 382.1481 m/z, found 383.1605 m/z; 1H NMR
(300 MHz, CDCl3) δ 9.00 (dd, J = 4.2, 1.8 Hz, 1H), 8.25
(dd, J = 8.3, 1.8 Hz, 1H), 7.87 (dd, J = 8.3, 1.4 Hz, 1H),
7.77 (d, J = 15.5 Hz, 1H), 7.56 – 7.39 (m, 3H), 7.32 –
7.10 (m, 6H), 6.99 – 6.83 (m, 2H), 6.11 (d, J = 15.6 Hz,
1H), 5.91 (d, J = 14.4 Hz, 1H), 5.31 (s, 2H).
13C NMR (75 MHz, CDCl3) δ 166.83, 162.07 (d, J =
245.0 Hz, CF), 151.07, 144.49, 142.03, 138.70, 136.30,
135.28, 133.89, 130.85, 130.74, 130.62, 129.50, 129.31,
128.59, 128.51, 127.73, 126.07, 121.99, 119.18, 115.12,
114.84, 52.09.
N-[(3-bromobenzyl)quinolin-8-amine (6)
Yield: 69%; MS: (ESI, +) for C16H13BrN2 [M+2H]+
calculated 313.0262 m/z, found 315.0320 m/z; 1H NMR
(300 MHz, CDCl3) δ 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.10
(dd, J = 8.3, 1.7 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.48 –
7.29 (m, 4H), 7.22 (t, J = 7.8 Hz, 1H), 7.10 (dd, J = 8.2,
1.2 Hz, 1H), 6.67 (s, 1H), 6.62 (dd, J = 7.6, 1.2 Hz, 1H),
4.57 (d, J = 5.9 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ
147.03, 144.27 (CIV), 141.86 (CIV), 138.24 (CIV), 136.06
(CH), 130.30, 130.26, 130.18, 128.66, 127.69, 125.82,
122.79 (CIV), 121.48, 114.55, 105.25, 47.20.
N-(3-bromobenzyl)-2-chloro-N-(8-
quinolyl)benzamide (8)
Yield: 72%; MS: (ESI, +) for C23H16BrClN2O [M+2H]+
calculated 451.0135 m/z, found 453.0229 m/z; 1H NMR
(300 MHz, CDCl3) δ 9.07 (dd, J = 4.2, 1.7 Hz, 1H), 8.09
(dd, J = 8.3, 1.7 Hz, 1H), 7.60 (dd, J = 8.2, 1.4 Hz, 1H),
7.53 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 8.3, 4.2 Hz, 1H),
7.41 – 7.25 (m, 3H), 7.22 – 7.07 (m, 2H), 7.01 (dd, J =
7.7, 1.7 Hz, 1H), 6.93 (td, J = 7.8, 1.7 Hz, 1H), 6.68 (td,
J = 7.5, 1.1 Hz, 1H), 6.11 (d, J = 14.8 Hz, 1H), 4.52 (d, J
= 14.8 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 168.80,
150.75, 143.94, 139.91, 138.11, 136.54, 136.35, 131.81,
130.71, 130.39, 129.91, 129.76, 129.62, 129.09, 129.02,
128.72, 127.45, 127.20, 125.85, 125.73, 122.31, 121.81,
51.73.
1-Boc-4-(3,4-dichloroanilino)piperidine (11)
Yield: 68%; MS: (ESI, +) for C16H22Cl2N2O2 [M+H]+
calculated 344.1058 m/z, found 445.1164 m/z; 1H NMR
(300 MHz, Chloroform-d) δ 7.10 (d, J = 8.7 Hz, 1H),
6.58 (d, J = 2.8 Hz, 1H), 6.34 (dd, J = 8.7, 2.8 Hz, 1H),
3.97 (d, J = 13.6 Hz, 2H), 3.54 (s, 1H), 3.35 – 3.21 (m,
2H), 2.85 (q, J = 14.0, 11.4, 2.8 Hz, 1H), 1.99 – 1.87 (m,
2H), 1.39 (s, 9H), 1.36 – 1.16 (m, 2H). 13C NMR (75
MHz, CDCl3) δ 146.28, 132.95, 130.70, 119.85, 114.15,
112.96, 79.73 (CIV), 50.22 (2CH2), 42.54, 32.14 (2CH2),
28.42 (3CH3).
t-butyl 4-(3,4-dichloro-N-[(E)-3-phenylprop-2-
enoyl]anilino)piperidine-1-carboxylate (12)
Yield: 28%; MS: (ESI, +) for C25H28Cl2N2O3 [M+H]+
calculated 474.1477 m/z, found 475.0247 m/z; 1H NMR
(300 MHz, CDCl3) δ 7.62 (d, J = 15.4 Hz, 1H), 7.46 (d, J
= 8.5 Hz, 1H), 7.21 (d, J = 13.0 Hz, 6H), 6.93 (dd, J =
8.4, 2.4 Hz, 1H), 5.98 (d, J = 15.4 Hz, 1H), 4.80 (d, J =
11.9 Hz, 1H), 4.10 (d, J = 13.3 Hz, 2H), 3.32 (q, J = 7.0
Hz, 2H), 1.94 – 1.58 (m, 4H), 1.35 (s, 9H).
1-(2-phenoxyacetyl)piperidin-4-one (14a)
Yield: 72%; MS: (ESI, +) for C13H15NO3 [M+H]+
calculated 233.1052 m/z, found 234.1131 m/z; 1H NMR
(300 MHz, CDCl3) δ 7.39 – 7.25 (m, 2H, 2CH), 7.09 –
6.92 (m, 3H, 3CH), 4.79 (d, J = 1.5 Hz, 2H, CH2), 3.90
(t, J = 6.3 Hz, 4H, 2CH2), 2.49 (q, J = 6.7 Hz, 4H,
2CH2). 13C NMR (75 MHz, CDCl3) δ 206.26 (C=O),
166.99 (NC=O), 157.66 (CIV), 129.77 (2CH), 121.96
(CH), 114.46 (2CH), 68.03 (CH2O), 44.08 (2CH2N),
41.51 (2CH2).
1-[(E)-3-phenylprop-2-enoyl]piperidin-4-one (14b)
Yield: 63%; MS: (ESI, +) for C14H15NO2 [M+H]+
calculated 229.1103 m/z, found 230.1174 m/z; 1H NMR
(300 MHz, CDCl3) δ 7.77 (d, J = 15.5 Hz, 1H), 7.66 –
7.49 (m, 4H), 7.41 (dd, J = 7.4, 2.8 Hz, 1H), 6.96 (dd, J
= 15.4, 2.5 Hz, 1H), 3.99 (d, J = 7.9 Hz, 4H), 2.57 (dd, J
= 7.5, 5.0 Hz, 4H). 13C NMR (75 MHz, MD3OD) δ
207.76 (C=O), 166.31 (NC=O), 143.29 (CH), 135.13
(CIV), 129.59 (CHAr), 128.47 (2CHAr), 127.55 (2CHAr),
117.09 (CH), 39.58 (2CH2), 34.80 (2CH2).
1-[(E)-3-(4-fluorophenyl)prop-2-enoyl]piperidin-4-
one (14c)
Yield: 58%; MS: (ESI, +) for C14H14NFO2 [M+H]+
calculated 247.1009 m/z, found 248.1247 m/z; 1H NMR
(300 MHz, CDCl3) δ 7.77 (d, J = 15.3 Hz, 1H), 7.66 –
7.49 (m, 2H), 7.41 (dd, J = 7.4, 3.2 Hz, 2H), 6.98 (dd, J
= 14.9, 2.5 Hz, 1H), 3.89 (d, J = 8.3 Hz, 4H), 2.67 (dd, J
= 7.5, 5.0 Hz, 4H). 13C NMR (75 MHz, MD3OD) δ
207.56 (C=O), 166.38 (NC=O), 161.80 (CF), 134.23
(CIV), 130.59 (CH), 129.47 (2CHAr), 125.5 (2CHAr),
118.49 (CH), 40.58 (2CH2), 34.70 (2CH2).
t-butyl 4-[(E)-(4-
fluorocinnamoyl)aminomethyl]piperidine-1-
carboxylate (16a)
Yield: 80%; MS: (ESI, +) for C20H27FN2O3.H2O
[M+5H]+ calculated 380.2111 m/z, found 385.1900 m/z;
1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 15.6 Hz, 1H),
7.49 (dd, J = 8.3, 5.6 Hz, 2H), 7.15 – 7.01 (m, 2H), 6.33
(d, J = 15.5 Hz, 1H), 5.83 (s, 1H), 4.22 – 4.05 (m, 2H),
3.31 (s, 2H), 2.71 (t, J = 12.7 Hz, 2H), 2.10 (m, 1H), 2.08
(dd, J = 13.2, 1.2 Hz, 4H), 1.28 (s, 9H).
t-butyl 4-[[(E)-cinnamoyl]aminomethyl]piperidine-1-
carboxylate (16b)
Yield: 65%; MS: (ESI, +) for C20H28N2O3 [M+H]
calculated 344.2100 m/z, found 345.2308 m/z; 1H
NMR (300 MHz, CDCl3) δ 7.58 (dd, J = 9.7, 5.3

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Gassama et al. World Journal of Pharmaceutical and Life Science
Hz, 2H), 7.53 (d, J = 15.4 Hz, 1H), 7.41 – 7.37 (m,
3H), 6.55 (d, J = 15.2 Hz, 1H), 5.83 (s, 1H), 3.68
(dt, J = 12.4, 7.0 Hz, 2H), 3.41 (dt, J = 12.4, 7.1 Hz,
2H), 3.18 (d, J = 9.2 Hz, 2H), 1.89 – 1.80 (m, 4H),
1.75 (m, 1H), 1.46 (s, 9H).
CONCLUSION
This multidisciplinary study combines the synthesis of
quinoline and piperidine derivatives, in vitro methods to
assess antimalarial and cytotoxic activity, and in silico
molecular modeling. Compounds 8 and 12 showed
interesting properties against Pf3D7 and PfW2 strains.
The predictive ADME properties identified promising
compounds that could be potential therapeutic agents in
drug discovery and development. Compounds 8 and 12
can also be used to develop orally active drugs for the
treatment of malaria. This study provides a clearer
insight into the interaction properties of synthetic
inhibitors with the EHMT2 protein. The results obtained
could contribute to the development of new, more
effective, safe and targeted antimalarial drugs, paving the
way for new strategies in the fight against malaria.
ACKNOWLEDGMENTS
We would like to express our deep gratitude to the
Senegalese government. We would also like to thank the
French Cooperation for having made this thesis work
possible by granting a 12-month scholarship. We are also
grateful to the BioCIS laboratory at the Université Paris-
Saclay for their invaluable collaboration. Their expertise
and access to state-of-the-art equipment, notably for
bioactive assays, LC/MS and NMR analysis, greatly
contributed to the success of this study.
REFERENCES
1. WHO. WHO Guidelines for Malaria - 3 June
2022||Targeted Testing and Treatment (TTaT).
Geneva: World Health Organization, 2022; 2022:
396.
2. Taylor, H. M.; Triglia, T.; Thompson, J.; Sajid, M.;
Fowler, R.; Wickham, M. E.; Cowman, A. F.;
Holder, A. A. Plasmodium Falciparum Homologue
of the Genes for Plasmodium Vivax and
Plasmodium yoeliiAdhesive Proteins, Which Is
Transcribed but Not Translated. Infect. Immun,
2001; 69(6).
3. Dondorp, A. M.; Nosten, F.; Yi, P.; Das, D.; Phyo,
A. P.; Tarning, J.; Lwin, K. M.; Ariey, F.;
Hanpithakpong, W.; Lee, S. J.; Ringwald, P.;
Silamut, K.; Imwong, M.; Chotivanich, K.; Lim, P.;
Herdman, T.; An, S. S.; Yeung, S.; Singhasivanon,
P.; Day, N. P. J.; Lindegardh, N.; Socheat, D.;
White, N. J. Artemisinin Resistance in Plasmodium
Falciparum Malaria. N. Engl. J. Med., 2009; 361(5):
455–467.
4. Noedl, H.; Socheat, D.; Satimai, W. Artemisinin-
Resistant Malaria in Asia. N. Engl. J. Med., 2009;
361(5): 540–541.
5. Gogtay, N.; Kannan, S.; Thatte, U. M.; Olliaro, P.
L.; Sinclair, D. Artemisinin-Based Combination
Therapy for Treating Uncomplicated Plasmodium
Vivax Malaria. Cochrane Database Syst. Rev., 2013;
2013(10): CD008492.
6. Flannery, E. L.; Chatterjee, A. K.; Winzeler, E. A.
Antimalarial Drug Discovery - Approaches and
Progress towards New Medicines. Nat. Rev.
Microbiol, 2013; 11(12): 849–862.
7. Burrows, J. N.; Hooft van Huijsduijnen, R.; Möhrle,
J. J.; Oeuvray, C.; Wells, T. N. Designing the next
Generation of Medicines for Malaria Control and
Eradication. Malar. J., 2013; 12(1): 187.
8. Van de Walle, T.; Cools, L.; Mangelinckx, S.;
D’hooghe, M. Recent Contributions of Quinolines to
Antimalarial and Anticancer Drug Discovery
Research. Eur. J. Med. Chem., 2021; 226: 113865.
9. Dolezal, M.; Palek, L.; Vinsova, J.; Buchta, V.;
Jampilek, J.; Kralova, K. Substituted
Pyrazinecarboxamides: Synthesis and Biological
Evaluation. Molecules, 2006; 11(4): 242–256.
10. Tiglani, D.; Salahuddin; Mazumder, A.; Yar, M. S.;
Kumar, R.; Ahsan, M. J. Benzimidazole-Quinoline
Hybrid Scaffold as Promising Pharmacological
Agents: A Review. Polycycl. Aromat. Compd.,
2022; 42(8): 5044–5066.
11. Attique, S. A.; Hassan, M.; Usman, M.; Atif, R. M.;
Mahboob, S.; Al-Ghanim, K. A.; Bilal, M.; Nawaz,
M. Z. A Molecular Docking Approach to Evaluate
the Pharmacological Properties of Natural and
Synthetic Treatment Candidates for Use against
Hypertension. Int. J. Environ. Res. Public. Health,
2019; 16(6): 923.
12. Manga, A.; Gassama, A.; Diatta, K.; Bassène, E.;
Cojean, S.; Cavé, C. Antiplasmodial Activity of
Extracts of Khaya Senegalensis (Ders.) A. Jus
(Meliaceae) and Melia Azedarach L., Plants of
Senegalese Traditional Medecine, 2018.
13. Smilkstein, M.; Sriwilaijaroen, N.; Kelly, J. X.;
Wilairat, P.; Riscoe, M. Simple and Inexpensive
Fluorescence-Based Technique for High-
Throughput Antimalarial Drug Screening.
Antimicrob. Agents Chemother, 2004; 48(5): 1803–
1806.
14. Johnson, J. D.; Dennull, R. A.; Gerena, L.; Lopez-
Sanchez, M.; Roncal, N. E.; Eaux, N. C. Assessment
and Continued Validation of the Malaria SYBR
Green I-Based Fluorescence Assay for Use in
Malaria Drug Screening. Antimicrob. Agents
Chemother, 2007; 51(6): 1926–1933.
15. GLACE. Introduction à la méthode.
http://www.antimalarial-
icestimator.net/MethodIntro.htm (accessed 2023-09-
05).
16. Daina, A.; Michielin, O.; Zoete, V. SwissADME: A
Free Web Tool to Evaluate Pharmacokinetics, Drug-
Likeness and Medicinal Chemistry Friendliness of
Small Molecules. Sci. Rep., 2017; 7(1): 42717.
17. Wu, H.; Min, J.; Lunin, V. V.; Antoshenko, T.;
Dombrovski, L.; Zeng, H.; Allali-Hassani, A.;

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Gassama et al. World Journal of Pharmaceutical and Life Science
Campagna-Slater, V.; Vedadi, M.; Arrowsmith, C.
H.; Plotnikov, A. N.; Schapira, M. Structural
Biology of Human H3K9 Methyltransferases. PloS
One, 2010; 5(1): e8570.
18. Clark, A. M.; Labute, P. 2D Depiction of
Protein−Ligand Complexes. J. Chem. Inf. Model.,
2007; 47(5): 1933–1944.
19. Inc, C. C. G. Molecular Operating Environment
(MOE). Chem. Comput. Group Inc, 2016; 1010.
20. Carlsen, L.; Dopp, D.; Dopp, H.; Duus, F.;
Hartmann, H.; Lang-Fugmann, S.; Schulze, B.;
Smalley, R. K.; Wakefield, B. J. Houben-Weyl
Methods in Organic Chemistry, 1992.
21. Khan, S. N.; Bae, S.-Y.; Kim, H.-S. A Highly
Stereoselective Reductive Amination of 3-
Ketosteroid with Amines: An Improved Synthesis of
3α-Aminosteroid. Tetrahedron Lett., 2005; 46(45):
7675–7678.
22. Boros, E. E.; Thompson, J. B.; Katamreddy, S. R.;
Carpenter, A. J. Facile Reductive Amination of
Aldehydes with Electron-Deficient Anilines by
Acyloxyborohydrides in TFA: Application to a
Diazaindoline Scale-Up. J. Org. Chem., 2009; 74(9):
3587–3590.
23. Hospital, A.; Goñi, J. R.; Orozco, M.; Gelpí, J. L.
Molecular Dynamics Simulations: Advances and
Applications. Adv. Appl. Bioinforma. Chem., 2015;
8: 37–47.
24. Freire, A. C.; Podczeck, F.; Sousa, J.; Veiga, F.
Liberação específica de fármacos para administração
no cólon por via oral. I - O cólon como local de
liberação de fármacos. Rev. Bras. Ciênc. Farm,
2006; 42: 319–335.
25. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.;
Feeney, P. J. Experimental and Computational
Approaches to Estimate Solubility and Permeability
in Drug Discovery and Development Settings. Adv.
Drug Deliv. Rev., 2001; 46(1–3): 3–26.
26. Fidelis Toloyi Ndombera; Geoffrey K. K. Maiyoh;
Vivian C. Tuei. Pharmacokinetic, Physicochemical
and Medicinal Properties of N-Glycoside Anti-
Cancer Agent More Potent than 2-Deoxy-D-Glucose
in Lung Cancer Cells. J. Pharm. Pharmacol, 2019;
7(4).
27. Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith,
B. R.; Ward, K. W.; Kopple, K. D. Molecular
Properties That Influence the Oral Bioavailability of
Drug Candidates. J. Med. Chem., 2002; 45(12):
2615–2623.
28. Ding, J.; Li, T.; Wang, X.; Zhao, E.; Choi, J.-H.;
Yang, L.; Zha, Y.; Dong, Z.; Huang, S.; Asara, J.
M.; Cui, H.; Ding, H.-F. The Histone H3
Methyltransferase G9A Epigenetically Activates the
Serine-Glycine Synthesis Pathway to Sustain Cancer
Cell Survival and Proliferation. Cell Metab, 2013;
18(6): 896–907.
29. Wood, A.; Shilatifard, A. Posttranslational
Modifications of Histones by Methylation. Adv.
Protein Chem., 2004; 67: 201–222.
30. Branscombe, T. L.; Frankel, A.; Lee, J. H.; Cook, J.
R.; Yang, Z.; Pestka, S.; Clarke, S. PRMT5 (Janus
Kinase-Binding Protein 1) Catalyzes the Formation
of Symmetric Dimethylarginine Residues in
Proteins. J. Biol. Chem., 2001; 276 (35): 32971–
32976.
31. Scholz, C.; Knorr, S.; Hamacher, K.; Schmidt, B.
DOCKTITE—A Highly Versatile Step-by-Step
Workflow for Covalent Docking and Virtual
Screening in the Molecular Operating Environment.
J. Chem. Inf. Model, 2015; 55(2): 398–406.
32. Laleu, B.; Akao, Y.; Ochida, A.; Duffy, S.;
Lucantoni, L.; Shackleford, D. M.; Chen, G.;
Katneni, K.; Chiu, F. C. K.; White, K. L.; Chen, X.;
Sturm, A.; Dechering, K. J.; Crespo, B.; Sanz, L.
M.; Wang, B.; Wittlin, S.; Charman, S. A.; Avery,
V. M.; Cho, N.; Kamaura, M. Discovery and
Structure–Activity Relationships of Quinazolinone-
2-Carboxamide Derivatives as Novel Orally
Efficacious Antimalarials. J. Med. Chem., 2021;
64(17): 12582–12602.