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European Journal of Applied Sciences – Vol. 10, No. 3
Publication Date: June 25, 2022
DOI:10.14738/aivp.103.12352. Atse, A. J., Diomande, S., Kone, S., & Bamba, E. S. (2022). Lipophilicity and Interactions Properties of a Group of Thirteen
Manzamenones in Comparison with Artemisinin and Quinine Using Quantum Chemical Methods: ONIOM and DFT (B3LYP).
European Journal of Applied Sciences, 10(3). 258-274.
Services for Science and Education – United Kingdom
Lipophilicity and Interactions Properties of a Group of Thirteen
Manzamenones in Comparison with Artemisinin and Quinine
Using Quantum Chemical Methods: ONIOM and DFT (B3LYP)
ATSE Adepo Jacques
Laboratoire de Constitution et de Réaction de la matière de L’UFR
SSMT Université Félix Houphouët Boigny 22 BP 582 Abidjan 22
DIOMANDE Sékou
UFR Agriculture, Ressources Halieutiques et Agro-industrie
Université de San Pedro
KONE Soleymane
Laboratoire de Constitution et de Réaction de la matière de L’UFR
SSMT Université Félix Houphouët Boigny 22 BP 582 Abidjan 22
BAMBA El-Hadji Sawaliho
Laboratoire de Constitution et de Réaction de la matière de L’UFR
SSMT Université Félix Houphouët Boigny 22 BP 582 Abidjan 22
ABSTRACT
This work was undertaken to determine and compare the lipophilic properties of a
group of Manzamenones with those of two antimalarials (Quinine and Artemisinin).
Manzamenones are atypical fatty acid derivatives, belonging to the large family of
lipids. They are extracted from a marine sponge, of the genus Plakortis kenyensis,
used in the treatment of malaria. Three approaches were used to estimate the
lipophilicity values of the molecules. Secondly, we analyzed the intermolecular
interactions between these molecules and each of the two probes: the water
molecule and the 3-aminopropanoic acid molecule (alanine: a protein residue of the
polymerase). Manzamenones are studied with a mixed method: ONIOM 2. The
intermolecular interactions between Manzamenones and water are described at
the B3LYP/6-31++G(d,p) level. The ones between Manzamenones and 3-
aminopropanoic acid are described at B3LYP/6-31+G(d,p). The last part of the
study was the determination of energetic parameters and the estimation of the
relative stabilities of the complexes formed with the two probes. This part allowed
making comparisons with Quinine or Artemisinin.
Keywords: Manzamenone, Artemisinin, Quinine, lipophilicity, hydrogen bond, level of
theory
INTRODUCTION
Malaria is a parasitic disease caused by the infection of erythrocytes by a hematophagous
protozoan of the species Plasmodium. It is transmitted to humans through the bite of an
infected female Anopheles mosquito [1]. Malaria is one of the principal causes of death of
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Atse, A. J., Diomande, S., Kone, S., & Bamba, E. S. (2022). Lipophilicity and Interactions Properties of a Group of Thirteen Manzamenones in
Comparison with Artemisinin and Quinine Using Quantum Chemical Methods: ONIOM and DFT (B3LYP). European Journal of Applied Sciences,
10(3). 258-274.
URL: http://dx.doi.org/10.14738/aivp.103.12352
children in the world . Despite more than a century of control efforts, it remains one of the major
diseases in tropical areas. In Africa, malaria infection is one of the main causes of death [3].
Regardless of WHO's efforts, the African region still accounts for approximately 92% of malaria
cases and deaths worldwide. This disease is caused by five parasites of the genus Plasmodium.
However, the majority of deaths are caused by Plasmodium falciparum and Plasmodium vivax
[4,5-7]. Quinine, Quinoline, Mefloquine and Artemisinin used to be effective treatments for
malaria.
Since about 25 years, the parasite has been developing resistance to the main classes of drugs.
Quinine, usually used in severe cases, has shown resistance [8, 9, 10]. Manzamenones from
marine sources derived from sponges are becoming increasingly extracted and used in drug
diversification for the treatment of malaria [11]. They are atypical fatty acid derivatives,
belonging to the large family of lipids. These molecules have antifungal, anticancer,
antimicrobial, enzymatic and antibacterial activities [12, 13]. Some work has shown that
Manzamenone A is a potent inhibitor of β DNA polymerase and only weakly active against the
α form of the enzyme [11, 14, 15, 16]. A previous study allowed us to compare some molecular
parameters including the interaction sites of Manzamenones with those of Quinine and
Artemisinin [17]. The present study first compares the lipophilic properties of thirteen
Manzamenones with two antimalarials. These results will allow knowing the ability of these
molecules to migrate to the blood lipoproteins. The lipophilic properties are estimated with
three different software. In a second part, a more elaborate analysis of intermolecular
interactions was performed. The aim of this part is to specify the binding mode(s) in biological
sites. The interactions are calculated between the studied molecules and a water molecule
(complexes) and then the 3-aminopropanoic acid (Alanine) a protein residue of the
polymerase. The calculations also allow examining the relative stability of the complexes. Some
similarities between the Manzamenones and the selected antimalarial drugs are investigated.
All calculations are performed in the gas phase. A mixed method of quantum chemistry is used
for the calculations of Manzamenones; ONIOM 2. Quinine and Artemisinin are described with
the DFT method (B3LYP).
STUDIED MOLECULES AND CALCULATION METHODS
Studied molecules
The studied molecules in this work are the two antimalarials Quinine and Artemisinin used as
references figure 1 and the fourteen (14) Manzamenones listed in the literature figure 2.
Artemisinin
Figure 1 : Structures of Quinine and Artemisinin
N
O
HO
N
H
Quinine
H3C H
O
O
CH3
H
H CH3
O
H3C O
O
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A B C D
E F
H
L M N
G J K O
Figure 2: 2D structures and refcodes of the fourteen Manzamenones listed in the literature.
Calculation methods
Partition coefficient or molecular lipophilicity
The logarithm of the partition coefficient (logP) is a parameter combining several effects such
as non-covalent interactions, solvation and an entropic component. For a studied substance, it
is expressed by the logarithm of the ratio of the concentrations in octanol and in water.
���� = ��� %
!!"#$%!&
!'$(
&
This value allows understanding the hydrophilic or hydrophobic (lipophilic) character of a
molecule. Indeed, if logP is positive (logP > 0) and very high then the considered molecule is
much more soluble in octanol than in water. The various theoretical methods used to determine
theoretically lipophilicity are briefly described.
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Atse, A. J., Diomande, S., Kone, S., & Bamba, E. S. (2022). Lipophilicity and Interactions Properties of a Group of Thirteen Manzamenones in
Comparison with Artemisinin and Quinine Using Quantum Chemical Methods: ONIOM and DFT (B3LYP). European Journal of Applied Sciences,
10(3). 258-274.
URL: http://dx.doi.org/10.14738/aivp.103.12352
Three freeware programs were used to perform these calculations. They are
MOLINSPIRATION, ACD/ChemSketch(Freeware)2016.2.2 and EPIWEB [18, 19, 20]. These
programs are known respectively under the names: MI/logP, ACD/logP and KowWIN/logP. The
mi/logP software is available from vcclab.org. This calculation approach is based on functional
groups. It takes into account intramolecular H-bonds and charge interactions. The ACD/logP
approach is based on the contributions of the atoms and structural fragments taken separately.
It takes into account the intramolecular interactions between the different fragments.
KowWIN/logP is a method that takes into account steric interactions between atoms, the H
bond and polar substructure effects.
With the ACD/logP approach, if fragmentary and interaction contributions are not in the
internal database, a special secondary algorithm is used to calculate them. The values from the
ACD/logP calculations are provided with an error equal to 0.6 [19]. Any greater error reflects
that the compound studied is not the database of the ACD/logP program. It is a new compound.
ONIOM method
The ONIOM method consists in dividing the studied system into several layers, each of them
being treated at a different level of calculation. In our case, the system is two-layered (ONIOM2)
as shown in Figure 3. The interactions between the water molecule or the alanine molecule and
the model system are studied at two different ONIOM levels (B3LYP / Base). In both types of
complexes, the real system is studied with the AM1 method. In a previous work [17], we have
shown the compatibility of the two levels of theory chosen to study these two layers in
Manzamenones.
Figure 3: Splitting model of a Manzamenone A complex with the ONIOM 2 method
.
Software and levels of quantum computation theory
The calculations are performed with the Gaussian 09 software [21]. The method used is the
density functional theory (DFT) [22]. Previous theoretical work on molecular properties
calculations has shown that hybrid functionals such as B3LYP and others, combined with an
extended base of functions lead to values in good agreement with experimental results [23]. An
optimization calculation of the molecular geometry is followed by the vibration frequencies for
each structure.
The calculations of the complexes with the water molecule are performed using the ONIOM
method (B3LYP / 6-31 ++ G (d, p): AM1). Those of the complexes formed with the alanine
External
layer (real
system)
Internal layer
(model
system)
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molecule are carried out using ONIOM (B3LYP / 6-31+G (d, p): AM1). The choice of the ONIOM
method, developed by Morokuma et al [24-26], is justified by the fact that it has been
successfully used to study big size molecules [27-30].
Description of the hydrogen bond
Hydrogen bond (HB) results from an attractive interaction between a hydrogen atom
covalently bonded to a strongly electronegative donor atom such as nitrogen, oxygen, fluorine
or carbon and a similar acceptor atom, which may or may not be part of the same molecule as
the donor. The geometric analysis of this bond is performed according to the recommendations
of Desiraju and Steiner [31], which suggest the characteristic parameters α, θ, d and D defined
in Figure 4.
Figure 4: Geometric parameters α, θ, d and D to describe hydrogen bond.
Energy parameters of interactions
The formation of a hydrogen bond between a donor molecule H ̶X and an acceptor molecule Y ̶
A results in the reaction 1. The hydrogen bond complex Y ̶A--- H ̶X is the product. The variation
of the energy, at 298.15 K is given by equation (2).
Y ̶A + H ̶X → Y ̶A···H ̶X (1)
Δ� = �(Y ̶A···H ̶X) − [E(Y ̶A) + E(H ̶Y)] (2)
The internal energy, at 298.15 K, corresponds to the sum of the electronic, rotational,
translational and vibrational contributions, so that its variation can be written according to
equation (3):
Δ�"#$ = Δ�%&%'+ Δ�()*+ Δ�+,- (3)
The optimization of the reactant and product geometry gives access to all contributions. The
translational contributions are given by equation (4):
Δ�*(./0= Δ�()* = ̶ 1
"
RT (4)
ΔE_vib includes the Zero Point Vibrational Energy (ZPVE), which is the energy of the lowest
vibrational level at 0 K. Taking into account the additional energy due to the vibrational levels
of the population, the increase in temperature from 0 to 298.15 K thus leads to equation (5),
from which the term E can be derived:
�+,-,*3%(4.&= R ∑ 3+)/6
%*+)⁄,-./78
197:
,;8 (5)
Therefore, the internal energy variation at 298.15 K is given by equation (6):
Δ�"#$ = Δ�%&%' + ΔZPVE + Δ�+,-,*3%(4.& ̶ 3RT (6)
atome
donneur
(C,N, O,...)
H
atome
accepteur
(N, O, F,...)
D
d
X Y
a
q
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Atse, A. J., Diomande, S., Kone, S., & Bamba, E. S. (2022). Lipophilicity and Interactions Properties of a Group of Thirteen Manzamenones in
Comparison with Artemisinin and Quinine Using Quantum Chemical Methods: ONIOM and DFT (B3LYP). European Journal of Applied Sciences,
10(3). 258-274.
URL: http://dx.doi.org/10.14738/aivp.103.12352
The variations, at 298.15 K, of enthalpy and free enthalpy are respectively given by equations
(7) and (8), and the variation of entropy, by equation (9)
Δ�"#$<
= = Δ�"#$< ̶ RT (7)
Δ�"#$<
= = Δ�"#$<
= ̶ TΔ�"#$<
= (8)
Where
Δ�"#$<
= = Δ�*(./0
= + Δ�()*
= + Δ�+,-
= (10)
Results and discussion
The molecular lipophilicity
The calculated lipophilic values of the two antimalarials (Artemisinin and Quinine) and the
Manzamenones are reported in Table 1.
Table 1: Lipophilic values of Artemisinin, Quinine and Manzamenones calculated with the three
software
softwares ACD/logP KOWWIN/logP Mi/logP logP (average)
Artemisinin 2.27±0.68 2.85 3.32 2.81
Quinine 3.44±0.43 3.29 3.06 3.26
A(B) 17.17±0.39 15.93 10.25 14.45
C 17.59±0.39 16.71 10.35 14.88
D 15.69±0.40 14.68 10.20 13.52
E 16.82±0.38 16.55 10.15 14.51
F 18.66±0.39 17.69 10.45 15.60
G 17.70±0.41 16.71 10.34 14.92
H 16.32±0.45 17.75 10.25 14.77
J 16.25±0.41 14.81 10.18 13.75
K 15.46±0.51 13.57 10.00 13.01
L 17.35±0.43 14.71 10.22 14.09
M 16.39±0.42 14.43 10.15 13.66
N 17.66±0.40 16.34 10.30 14.77
O 22.33±0.57 20.48 10.73 17.85
The errors are less than 0.6 except for Artemisinin where the uncertainty is equal to 0.68. Only
this molecule is not in the ACD/Labs software database. All calculated lipophilicity values are
positive. These molecules (Manzamenones and antimalarials) are therefore naturally lipophilic.
They are then potentially biologically active.
For each molecule, the ACD/LogP method predicts a higher value of lipophilicity. The MI/LogP
approach suggests the smallest value. The ACD/LogP and KOWWIN/logP calculations give
closer values. The average values of the three calculation approaches are between 13 and 17.
They are therefore high. The comparison with the two antimalarials shows very clearly that
Manzamenones are much more lipophilic than Artemisinin and Quinine. According to the
theoretical values obtained, Manzamenones are 3 to 6 times more lipophilic. All three
calculation approaches classify Manzamenone O as more lipophilic.
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Lipophilicity is an important molecular property in predicting the pharmacological activity of a
molecule. Its division between a lipidic phase and an aqueous phase [32, 33] can condition its
transport, its transit through the membranes. Biological membranes being lipophilic, the
greater the degree of lipophilicity, the better the molecule crosses them and migrates to the
lipoproteins of the blood. The role of blood lipoproteins is to supply cells with lipid substances.
According to our calculations, the model systems of Manzamenones are excellent "candidates"
to ensure this function.
Geometric characteristics of hydrogen bonds
The numbers assigned to the heteroatoms and hydrogen-carrying carbon atoms of Artemisinin,
Quinine and the Manzamenone model system are specified on the optimized (3D) structures
shown in Figure 5.
Artemisinin Quinine A(B), C, D, E, F et H
L, M et N G J
K O
Figure 5: 3D structures showing the numbers of the heteroatoms of the hydrogen-carrying
carbons
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determined [17]. The results in Table 2 confirm the implication of these sites of the two
reference molecules. Especially with Quinine, the oxygen O39 as acceptor and the hydrogen of
the group O22H as donor interact with the water molecule. We obtain for this complex a
multicentric interaction. For most of the Manzamenones (10/13), the interaction takes place
on the oxygen O11 as acceptor. However, this oxygen is not always identified as a preferred
acceptor site from electrostatic interaction potential calculations [17]. The oxygen O11 and the
acceptor oxygens O13 and O25 of the Manzamenones G and K respectively are carbonyl functions.
In these Manzamenones, this function is always conjugated with a double bond of a ring with
five members (cyclopentenone) except Manzamenone G for which the ring is with six members
(cyclohexenone). The interaction study reveals that the bond always involves the carbonyl of
each of the Manzamenones. The preferred acceptor site for Artemisinin is also a carbonyl
oxygen. This oxygen is also responsible for the interaction with the water molecule. Figure 6
gives an illustration of these interactions between the studied molecules and the water
molecule.
Quinine---H2O Artemisinin---H2O
A(B)---H2O M---H2O
K---H2O G---H2O
Figure 6: Optimized structures of the complexes of Quinine, Artemisinin, Manzamenones A(B),
M, K and G with the water molecule