Xanthone as antimalarial: QSAR analysis, synthesis, molecular docking and in-vitro antimalarial evaluation

Article abstract of DOI:10.13005/ojc/330104

The rational design of eighteen new antimalarial compounds from xanthone derivatives has been conducted based on Quantitative Structure-Activity Relationship (QSAR) calculation using semiempirical AM1 methods. The best equation model obtained from QSAR calculation was Log pIC₅₀ = 2.997 - 29.256 (qO8) - 138.234 (qC9) - 6.882 (qC12) - 107.836 (qC14) + 48.764 (qO15). Among the designed compounds, 3,6-dihydroxy-9H-xanthen-9-one (26) and 3,4,6-trihydroxy-9H-xanthen-9-one (27) have been synthesized and investigated their in-vitro antimalarial activities against the chloroquine-sensitive 3D7 strain. An in-vitro antimalarial activity of compound 26 and 27 showed to be highly potential as antimalarial compounds with IC₅₀ of 0.71 and 0.11 μM respectively. Molecular docking studies of compound 26 and 27 showed the formation of a binding interaction between the compounds with the amino acids Ala16, Ser108, Phe58, Asp54 and Leu46, which is the crucial amino acids for antimalarial activity based on the protein-ligand co-crystal structure of WR99210 (1,3,5-triazine, a pre-clinical molecule as P. falciparum DHFR-TS inhibitor).

Full text of DOI:10.13005/ojc/330104

ISSN: 0970-020 X
CODEN: OJCHEG
017, Vol. 33, No. (1):
Pg. 29-40
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
2
www.orientjchem.org
Xanthone as Antimalarial: QSAR Analysis, Synthesis,
Molecular Docking and In-vitro Antimalarial Evaluation
1
,2
2,3
2
JUFRIzAL SYAHRI *, EMMYYUANITA , BETA ACHROMI NUROHMAH ,
4
1
MUHAMMAD HIzBUL WATHON , RAHMADINI SYAFRI ,
2
2
RIA ARMUNANTO and BAMBANꢀ PURWONO *
1
Department of Chemistry, Universitas Muhammadiyah Riau – Indonesia.
2
Department of Chemistry, Universitas Gadjah Mada - Indonesia.
3
Department of Chemistry, Universitas Mataram – Indonesia.
School of Chemistry, University of Leeds – United Kingdom.
4
*
Corresponding author E-mail: purwono.bambang@ugm.ac.id
http://dx.doi.org/10.13005/ojc/330104
(Received: October 25, 2016; Accepted: January 01, 2017)
ABSTRACT
The rational design of eighteen new antimalarial compounds from xanthone derivatives has
been conducted based on Quantitative Structure-Activity Relationship (QSAR) calculation using semi-
empirical AM1 methods. The best equation model obtained from QSAR calculation was Log pIC50
=
2.997 - 29.256 (qO8) - 138.234 (qC9) - 6.882 (qC12) - 107.836 (qC14) + 48.764 (qO15). Among
the designed compounds, 3,6-dihydroxy-9H-xanthen-9-one (26) and 3,4,6-trihydroxy-9H-xanthen-
-one (27) have been synthesized and investigated their in-vitro antimalarial activities against the
9
chloroquine-sensitive 3D7 strain. An in-vitro antimalarial activity of compound 26 and 27 showed to
be highly potential as antimalarial compounds with IC50 of 0.71 and 0.11 µM respectively. Molecular
docking studies of compound 26 and 27 showed the formation of a binding interaction between the
compounds with the amino acids Ala16, Ser108, Phe58, Asp54 and Leu46, which is the crucial
amino acids for antimalarial activity based on the protein-ligand co-crystal structure of WR99210
(
1,3,5-triazine, a pre-clinical molecule as P. falciparum DHFR-TS inhibitor).
Keywords: Antimalarial, Docking, Semi-empirical AM 1, QSAR, Xanthone.
INTRODUCTION
that cause mild diseases in human and not generally
fatal. The fifth parasite, Plasmodium knowlesi,
is known to cause malaria in monkeys, which is
reported can also infect humans. According to the
WHO report in 2015, mortality number caused by
malaria disease of as many as 438,000 lives from
Therearefivetypesofmalariaparasitesthat
commonly infect humans, the first one is Plasmodium
falciparum, which is the most fatal among other
Plasmodium parasites. Furthermore, Plasmodium
vivax, Plasmodium ovale, and Plasmodium malariae
1
214 million cases of malaria infection in the world.

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SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
Parasite resistance to the antimalarial best-predicted antimalarial activity. Actually, QSAR
drugs such as chloroquine and artemisinin has led studies could help to determine what the functional
2-3
to the high number of dead. In order to prevent group should be attached to the compounds in order
more victims caused by malaria disease, searching to get the best activity. Herein, molecular docking
and finding for new candidates of the antimalarial with the crystal structure (1J3I.pdb) of Plasmodium
drug must be conducted continuously because falciparum dihydrofolate reductase-thymidylate
the absence of new antimalarial drugs may cause synthase (DHFR-TS) was conducted to observe
malaria being an uncured disease in the next ten the binding interaction of the xanthone with the
years. One of the strategies to find new antimalarial amino acid. The designed compound was further
drugs is to explore natural products, particularly from synthesized and their in vitro antimalarial activity was
plants, which have been traditionally utilized as an tested to prove the accuracy of QSAR calculation.
antimalarial drug.Xanthone, as one of the secondary
metabolite compounds from nature, has been
MATERIALS AND METHODS
4
-6
reported to have antimalarial activity. However,
further research to find optimum antimalarial activities Data Set
of xanthone compounds is still needed. Hence, the
In QSAR study, data sets used were 25
research to discover xanthone compounds with the reported prenylated xanthone derivatives with its
20-21
best antimalarial activity should be conducted.
antimalarial activity as seen inTable 1. .This data
set was divided into two parts i.e. internal evaluation
Xanthone compound was also reported for (training set) and external evaluation (test set). The
7
-9
10-
having some activities as anticancer, antitumor,
test set compounds were selected manually in order
1
1
12-13
14-16
17
antioxidant,
cytotoxic,
leukemia, anti- to consider the structural diversity and a wide range of
1
8
diabetic. These facts show that xanthone has antimalarial activity.The in vitro antimalarial activities
tremendous potential activities. In general, the expressed as the inhibition concentration [IC50
reported compounds were the result of the isolation (µg/mL)] values were converted to the logarithmic
process, which means it is more difficult to conduct pIC = log IC and used as dependent variables in
50
50
furtherdevelopmentinenhancingtheactivitybecause QSAR analysis.
of the low yield of compounds afforded.Therefore, the
research that can truly maximize the potential of the Instrumentation
xanthone compound is required, such as by making
In this study a PC with Intel® (TM)2
design and synthesis of xanthone compounds that Quad CPU Q8200 @2.33GHz was running under
have optimum activity. This kind of research could a Windows XP Professional operating system. All
generate higher yield of the compounds obtained quantum mechanical calculation was executed
and further modification and their biological activity using Gaussian 09 software. Correlation of QSAR
assay can be conducted effectively.
models was evaluated by multiple linear regression
analysis using SPSS statistics 23.0.Docking studies
QSAR analysis of xanthone as an were performed with the cDOCKER protocol under
antimalarial has been reported by Amanatie the receptor-ligand interaction section in Discovery
1
9
et al (2010) . They have used PM3 method and Studio 3.1 (Accelrys, Inc., San Diego, CA, USA).
concluded the descriptors which influence the Other molecular modeling software was used
antimalarial activity were atom charges of O7, C12, throughout this study including CHIMERA 1.9 and
and C13. However, their research did not report the ChemOffice®.
design of xanthone which had the best antimalarial
activity.
The melting point of the synthesized
compounds was determined using Electrothermal
In this research, QSAR studies were 9100 with temperature gradient 10°C/min.ESI-HRMS
carried out to determine the descriptors which spectra were recorded on a Bruker micrOTOF Mass
1
13
were responsible for the antimalarial activity. QSAR Spectrometer. Meanwhile, H and C-NMR spectra
equation from the resulted descriptor was used to were recorded on a JEOL 500 MHz spectrometer
design new xanthone compounds which have the with TMS as an internal standard. All reagents were

31
SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
Table 1: Xanthone derivatives compound used as data set for QSAR analysis
R7
O
OH
R3
R6
R5
R1
R2
O
R4
Comp
R1
R2
R3
R4
R5
R6
R7
Log IC50
1
OH
H
H
H
0.114
O
O
(
(
2
O in R )
2
3
Prenyl
H
H
H
H
H
OH
OH
Prenyl
Prenyl
-0.046
0.000
2
O in R )
O
(O in R2)
4
a
Prenyl
OH
OH
H
H
H
H
H
O
0.431
(
O in R7)
H
O
7
(O in R )
5
6
H
H
0.643
0.279
H
OH
OH
H
H
O
(
O in R2)
7
8
Prenyl
H
OH
H
H
H
H
H
H
OH
OH
H
0.623
0.204
-0.097
0.623
9
1
H
H
OH
OH
OH
H
H
H
0.505
0.362
0.204
0.505
0
OMe
OH
1
1
1
2
H
H
OH
OH
OH
OH
OH
H
H
0.544
H
0.362
0.544
O
(
O in R2)
1
1
1
1
1
3
4a
5
6
7a
H
H
Prenyl
Prenyl
H
H
OH
H
H
Prenyl
Prenyl
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
0.690
0.255
0.568
0.820
1.170
0.544
1.393
0.690
0.255
0.613
OH
OH
OH
OH
18
OH
H
OH
H
H
0.732
0.568
OH

32
SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
1
9
H
H
OH
OH
H
H
0.633
0.820
OH
O
2
2
0a
1
(O in R2)
OH
OH
H
H
H
H
H
H
0.146
1.170
OH
OH
OH
O
22
(O in R2)
OH
H
H
H
0.732
OH
2
2
3
4
H
OMe
H
H
OH
OH
OH
H
Geranyl
H
H
H
0.633
0.672
OH
O
25a
(O in R
2
)
OH
OH
O
H
0.672
(
O in R5)
a) Test set
purchased from Aldrich, Acros, and Merck and were the values of the regression coefficients by applying
used without further purification.All the solvents used least square curve fitting method. The model for
in the synthesis were analar and synthesis grade. QSAR calculation was chosen based on some
2
The solvents used in spectroscopic measurements statistical parameters such as r , standard estimation
were spectroscopic grade.
of error (SEE), F-ratio between the variance of
prediction and observation activity, and PRESS value
(predictive residual sum of square), where:PRESS =
Procedure
QSAR Analysis
2,22
2
S (predicted value-observed value) in criteria r >
23
24
25
In order to find the best calculation method, 0.6, ;SEE < 0.3, ;Fcal/Ftab ≥ 1. The best-selected
one of the xanthone compounds (24) was calculated model obtained from the previous step was used to
1
for H-NMR chemical shift using the semi-empirical predict the log IC50 of the test set and the model was
2
26
method of Austin Model 1 (AM1), Parameterized validated by criteria r prediction > 0.5.
Model (PM3 and PM6), and Gaussian 09 software.
The chemical shift data were then compared to the
General procedure for the synthesis of
1
data of H-NMR from the experiment. AM1, PM3 or compounds 3,6-dihydroxy-9H-xanthen-9-one (26)
PM6 calculation methods which gave the closest and 3,4,6-trihydroxy-9H-xanthen-9-one (27)
values to the experimental data was selected as a
method of study throughout the investigation.
A mixture of 2,4-dihydroxybenzoic acid (5
mmol) and resorcinol or pyrogallol (5 mmol) was
stirred in Eaton’s acid (5 ml) and heated to 80 °C
Statistical analysis
Thepredominantdescriptorswhichaffecting for 3 h. After the completion of reaction (monitored
the antimalarial activity of the prenylated xanthone by TLC), the product was poured into an ice water
analogues were selected according to the correlation and the precipitate formed was filtered, washed
analysis by SPSS 23.0 statistical software. In this with water and 5% NaHCO . The dried product
3
process, each electronic descriptor was appointed was purified by silica gel column chromatography
as independent variables and pIC as the dependent with n-hexane/ethyl acetate (gradient 0–30% ethyl
50
variable.Moreover, this regression method estimates acetate) to afford compound 26 and 27.

SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
33
3
,6-dihydroxy-9H-xanthen-9-one (26).
Data Bank (PDB codes: 1J3I).The protein was pre-
treated before the docking process.Hydrogen atoms
were added to the protein structure, and all ionizable
residues were set at their default protonation of pH
7.2 while the ligands were prepared and minimized.
During the docking process, the receptor was held
rigid while the ligands were allowed to flex during the
refinement. A number of polar or nonpolar receptor
hotspots for conformer matching starting were set
at 500 with the docking tolerance of 0.25 Å. The
conformations ligands generated from the process
was set to 500 within the threshold of relative energy
of 20 kcal/mol.
1
Reddish crystals, yield 43%, mp 247 °C; H-NMR
500 MHz, CDCl ) d (ppm): 7.37 (d, J = 8.5 Hz,
H), 6.37 (d, J = 8.4 Hz, 2H), 6.35 (s, 2H). HRESI-
MS calcd. for C H O , [M+H] 229.0522, found
(
2
3
+
1
3
8
4
2
29.0517.
3
,4,6-trihydroxy-9H-xanthen-9-one (27).
1
Reddish crystals, yield 44%, mp 254 °C; H-NMR
500 MHz, CDCl ) d (ppm): 7.37 (d, J = 8.5 Hz,
H), 6.41 (d, J=8.4 Hz, 2H), 6.35 (s, 1H). HRESI-
MS calcd. for C H O , [M+H] 245.0421, found
(
2
3
+
1
3
8
5
2
45.0411.
Molecular Docking Studies
The protein crystal structure of the inhibitor-
bound DHFR was retrieved from Brookhaven Protein
In-vitro Antimalarial activity Assay
Anin-vitroantimalarialassaywasconducted
against Plasmodium falciparum 3D7 strain which
1
Table 2:The differences of the H NMR chemical shifts by
experimental and computational methods (δ, ppm)
1
5
16
1
8
O
OH
20
1
3
1
3
1
7
1
4
2
21
12
1
4
19
11
5
9
7
0
O
6
8
OH
OH
22
2
3
No Atom H δ Experiment
δ AM1
δ PM3
δPM6
5
1
1
1
1
2
2
7.72
7.53
7.27
7.99
1.66
6.47
5.15
2.13
7.50
6.22
6.97
8.26
1.69
6.03
5.20
3.53
7.60
6.10
6.82
7.68
0.81
5.87
4.84
3.56
7.23
6.01
6.79
7.99
1.07
5.92
4.76
1
2
3
8 and 19
0
1
PRESS
O
O
CO2
a
OH
+
HO
OH
b
HO
OH
HO
OH
HO
O
OH
R
R
Resorcinol or
Pyrogallol
Resorcinol
2,4-dihydroxybenzoic acid
2
2
6 R=H
7 R=OH
Scheme 1: Reagents and conditions of synthesis: (a) KHCO3,
Aquadest, reflux, 4 h; (b) Eaton’s acid, heated to 80°C, 3 h

34
SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
sensitive to chloroquine according to the microassay
by Rieckmann et al. in 96 well microtitre plates with
RESULTS AND DISCUSSION
27
slight modifications. For this assay, the compounds Validation method
were dissolved in DMSO and prepared in a series of
Calculation of H-NMR chemical shift of
1
concentration, i.e. 100, 10, 1, 0.1 and 0.01 µg/mL in compound 24 using AM1, PM3, and PM6 method
RPMI-1640 media.Into the sample, Parasitemia and showed that AM1 method was the best method,
hematocrit, ±1% and 5% were added respectively. which gives the closest result to the experimental
The culture was incubated for 48 hours at 37 °C, data. This result is clearly shown by the PRESS
treated with 20% Giemsa dyes and made it as thin value of AM1 method (2.13) which is smaller than
blood layer.After that, the percentage of parasitemia PM3 (3.53) and PM6 (3.57) as presented in Table 2.
and also the inhibition percentage of P. falciparum Therefore, AM1 method was used to calculate the
growth were determined by calculating the number of descriptors of each compound.
the infected erythrocytes for every 1000 erythrocytes.
Based on the inhibition percentage data, analysis Selection of the Best Model
of the correlation between concentrations of the
Statistical multi-linear regression calculation
compound with the inhibition percentage was of the descriptors using SPPS give 5 QSAR models
conducted using probit log analysis to determine the as shown in Table 3. It shows that all models depict
IC .
the linear correlation between biological activity and
descriptors as can be seen by the r-value of each
5
0
Table 3: Statistical model and parameter of molecular properties
and antimalarial activity of xanthone derivatives
Model Variables
r
r2 Adjusted SEE Fcalc/Ftable Press
2
r
1
2
qC1, qO8, qC9, qC12, qC13,
qC14 , qO15, EHOMO, ELUMO
qC1, qO8, qC9, qC12,
0.942 0.888 0.787 0.148 2.921
0.935 0.874 0.783 0.150 3.167
2.791
2.469
qC13, qC14 , qO15, EHOMO
3
4
5
qC1, qO8, qC9, qC12, qC14 , qO15, EHOMO 0.919 0.845 0.755 0.159 3.101
1.602
0.998
0.921
qC1, qO8, qC9, qC12, qC14 , qO15
qO8, qC9, qC12, qC14 , qO15
0.904 0.817 0.733 0.166 3.207
0.888 0.789 0.714 0. 172 3.471
Table 4:The comparison between calculated
model.Basically, the best model is determined by the
number of variable and statistical parameters which
belong to that model.
and experimental antimalarial activity (log IC )
50
of 5 test set calculated by model 4 and 5
Comp
Experimental
log IC )
Calculated (log pIC )
Table 3 also show that model 4 and model
5 are considered to be the best models because
those models have the lowest number of variable, the
highest Fcalc/tab and the lowest PRESS (predictive
residual sum of square) value. Furthermore, model
4 and 5 were used to design of new xanthones
derivatives with a better antimalarial activity. The
complete QSAR equations of model 4 [1] and 5 [2]
are:
50
(
Model 4
Model 5
50
4
0.431
0.411
1.466
0.888
0.459
0.993
0.962
0.570
1.309
0.858
0.466
0.874
0.821
1
1
2
2
4
7
0
5
1.393
0.613
0.146
0.672
Press

SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
35
Log pIC50 = 67.987 (qC1) - 37.297 (qO8) - 169.104
qC9) - 10.330 (qC12) - 127.091 (qC14) + 86.740
qO15) - 10.827 ...(1)
Validation Model
QSAR equation [1] and [2] were used
to predict antimalarial activity (log pIC ) of 5
(
(
5
0
test compounds in order to find the best model
in predicting the antimalarial activity of xanthone
derivatives (Table 4). The predicted antimalarial
activity of 5 test set generated from model 4
Log pIC50 = 2.997 - 29.256 (qO8) - 138.234 (qC9)
6.882 (qC12) - 107.836 (qC14) + 48.764 (qO15)
-
.
..(2)
Fig. 1: Plot of experimental result versus predicted antimalarial
IC50 value of 5 test set compounds by model 4 and 5

SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
36
and 5 was compared and then plotted with the
experimental data by linear regression calculation
to see the correlation for each equation, as shown
in Fig. 1.
new xanthone compounds with better antimalarial
activity.
Furthermore, by introducing the descriptor
of qC9, qC14, and qO15 as an active center of
antimalarial in xanthone derivatives, it revealed that
conjugated double bond with carbonyl group was
an important feature on the antimalarial activity.This
result showed the similarity with the reported QSAR
Table 4 shows that PRESS value of model
5
(0.821) is smaller than model 4 (0.962), which
mean model 5 give a closer result to experimental
data compared to model 4. This result is supported
2
28
by Fig. 1 where model 4 has r = 0.887 while model
study conducted et al for chalcone derivatives.
2
5
has r = 0.963. These numbers mean that there
is a significant correlation between an independent
variable (in equation 2) and antimalarial activity of
xanthone compound. As for model 5, the r value of
Design of New Antimalarial
Model 5 as the best QSAR model was used
2
as a guidance to predict the antimalarial activity in
the rational design of the new antimalarial compound
from xanthone derivatives. R substituents were
introduced to the new molecule as a descriptor
which will influence the antimalarial activity. From
equation 2, it can be shown that in order to get the
0
(
.963 means the changing of independent variable
atomic charges of qO8, qC9, qC12, qC14 and
qO15) could influence 96.3% of antimalarial activity
log IC ) of xanthone derivate. Therefore, it can be
(
5
0
concluded that model 5 is the best model to design
Table 5: Design of xanthone derivatives and its predicted
antimalarial activity calculated using the best QSAR model
R8
3
O
R1
3
1
R7
R6
14
9
2
7
R2
R3
4
5
1
1
2
1
1
O
10
6
R4
8
R5
Comp
R1
R2
R3
R4
R5
R6
R7
R8
Log IC50
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
Prenyl
Prenyl
H
H
H
H
H
H
OH
OH
OH
OH
OH
OH
OH
H
H
H
OH
OH
H
H
OH
H
OH
OH
OH
OH
H
H
H
H
Prenyl
H
H
H
H
H
H
H
H
Cl
OH
OH
OH
OH
H
H
H
H
H
OH
OH
OH
OH
H
H
H
OH
Cl
Cl
Cl
Cl
H
H
OH
OH
OH
OH
H
H
Cl
H
OH
OH
OH
Cl
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
Cl
-0.74
-1.32
-2.14
-1.16
-2.69
-4.09
-5.17
-0.54
-0.76
-2.40
-1.13
-4.39
-8.76
-9.31
-10.83
-21.18
-19.97
-10.42
H
NO2
H
H
H
Prenyl
NO2
OH
OH
H
OH
OH
OH
H
H
H
OH
OH
H
H
H
SO H
3
H
H
H
H
SO H
3
SO H
3
SO H
SO H
3
3
SO H
SO H
3
3
H
NO2
NO2

37
SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
best antimalarial activity, atomic charges of O8, C9, the significant influence which leads to the better
C12 and C14 should have a positive charge while the antimalarial activity.
atomic charge of O15 should be negative. A positive
charge in atom C12 can be obtained by adding
Synthesis and an in-vitro antimalarialactivity
electronegative substituents or donating electrons assay of compound 26 and 27 against chloroquine-
groups such as hydroxyl and halogen. Since C9 and sensitive 3D7 strain have been successfully
C14 were C quarter atom which cannot be added conducted.The experimental antimalarial activity of
with any R substituents, so the substituents must be 26 and 27 are close to the results from the QSAR
bonded in C10 and C13. In order to get a positive analysis (Table 6). This result proves the accuracy
partial charge of C9 and C14, withdrawing electron of the generated QSAR equation to predict the
group could be added in C10 and C13 since the antimalarial activity of xanthone derivatives.Also, the
resonance could make an atomic charge of atom antimalarial activity of compound 26 and 27 could
C9 and C14 becomes more positive.
be categorized as a good antimalarial although their
IC50 are slightly higher than the chloroquine as a
The designed new antimalarial compounds control.
of xanthone derivatives based on the best QSAR
model were listed in Table 5. Indeed, this study
The active synthesized compound 26 and
shows that R substituents variation gives a difference 27 as antimalarial was docked to the active site of the
antimalarial activity. It can be seen in Table 5 that P. falciparum DHFR crystal structure to confirm their
there is a very significant change of the predicted mechanism as an antimalarial drug.Thus, the protein
antimalarial activity occurred when substituent crystal structure of DHFR (1J3I:2.33Å) was retrieved
was changed to SO H and NO at C10 and C13. In from Brookhaven Protein Data Bank. P. falciparum
3
2
addition, removing of SO H from the compound gives dihydrofolate reductases– thymidylate synthase
3
significant influence in decreasing the antimalarial (PfDHFR-TS) is an important target of antimalarial
29
activity. This result is similar to the previously drugs. The inhibition of this enzyme could prevent
28
reported study, that substitution of SO H functional the dTMP production and DNA synthesis since
3
group is able to provide the best antimalarial activity it involved in the catalysis sequential reactions
3
0
towards chalcone compound. Meanwhile, electron in the thymidylate cycle. The docking studies of
donating group OH is a substituent that also gives compounds 26 and 27 displayed favorable binding
Table 6:The antimalarial activity (IC ) of compound
50
26 and 27 based on experimental assay and QSAR analysis
Comp QSAR Analysis Data Experiment In vitro (3D7)
Log pIC50
pIC (µg/ml)
IC (µg/ml)
IC (µM)
50
50
50
2
2
CQ
6
7
-0.74
-1.32
-
0.182
0.048
-
0.162
0.027
0.012
0.71
0.11
0.04
Table 7: Docking interaction of compounds 26 and 27 in Pf-DHFR-TS
Wild-type Pf-DHFR-TS
Comp
Binding interaction
Binding Energy
2
2
6
7
Ala16, Ser108, Phe58, Asp54, Leu46, Cys15
Ala16, Ser108, Phe58, Met55, Leu46, Tyr170
-27.586
-30.991
-54,3237
WR99210 Ala16, Ser108, Phe58, Met55, Asp54, Ile14, Ile164, Trp48, and Thr185

SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
38
affinity towards DHFR with –cDOCKER energy
shown inTable 7 and the docking interaction showed
in Figure 2.
Docking studies revealed the binding site
of 26 and 27 form interactions with Ala16, Ser108,
Asp54, Met55, and Phe58 amino acid which is the
Fig. 2: Predicted binding mode from docking simulation of 26 and 27 into the active site of P.
falciparum DHFR-TS (PDB ID: 1J3I).The coloring atom for the compound is in order as follows:
carbons in gray, oxygen in red, nitrogen in blue, and hydrogen in white.The green line indicates
hydrogen-bonding interaction with distance ascribed in angstroms, Å.

39
SꢀAHRI et al., Orient. J. Chem., Vol. 33(1), 29-40 (2017)
crucial interactions for antimalarial activity based the relevancies between QSAR calculation and the
on the binding interactions displayed by the ligand experimental IC50 data. Molecular docking showed
co-crystal of WR99210 (1,3,5-triazine containing the binding interaction of 26 and 27 with the crucial
pre-clinical molecule as Pf-DHFR-TS inhibitor), a amino acid for antimalarial activity.
potent antimalarial compound. On the other hand,
26 and 27 are well-positioned in the DHFR active
ACKNOWLEDꢀMENT
site, constituting of residues Ile14, Ala16, Trp48,
Asp54, Met55, Phe58, Ser108, Ile164 and Thr185
Authors gratitude to Ministry of Research,
Technology, and Higher Education-Indonesia for the
financial support of this work through competing
for research project grant, contract number 92A/
(
Figure 2).
CONCLUSION
KONTRAK-PENELITIAN BATCH II/010/KM/2016,
nd
A semi-empirical molecular orbital date February 22 , 2016 (Skim Hibah Bersaing).
calculation AM1 was used to study the correlation Gratitude also for Austrian Indonesian Centre (AIC),
between structure and the antimalarial activity Universitas Gadjah Mada who provided the gaussian
of xanthone derivatives series. Correlation of 09 licenses. The authors also acknowledge the
antimalarial activity with the structure has shown Discovery studio 3.1 by CADD Laboratory, Faculty
by atom charge of qC9, qC12, qC14 and qO15 as of Pharmacy, Universiti Kebangsaan Malaysia, for
the active site of antimalarial. Antimalarial activity the Discovery Studio 3.1 licenses.
of the synthesized compounds 26 and 27 proved
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