1 Introduction
Malaria is an infectious disease caused by plasmodia, among which Plasmodium
falciparum is the most dangerous and responsible for most deaths. According to
WHO 2014 reports, 97 countries and territories are affected by malaria transmission
[1]. 98 million cases and 584 000 deaths were recorded in 2013 [1] and 212 million
new cases and 429 000 deaths in 2015 [2]. 90% of the cases occurred in African
countries and most of the deaths concern children under 5 years [1, 2].
The major challenge for malaria treatment is the fast development of resistance
to new drugs, just within few years after their introduction into clinical use. Some
drugs have already lost their efficacy and resistance has started appearing for
artemisinin, which is the current drug of choice. The development of new drugs
should at least keep the pace with the rate at which Plasmodium develops resistance
to existing drugs. This implies urgent need for new compounds having original
modes of action. Natural products constitute a potentially immense source of new
compounds, with diverse molecular structures and pharmacophores.
Jozimine A 2 (Fig. 1, denoted by the acronym JZM in the rest of the text) is a
dioncophyllaceae-type naphthylisoquinoline alkaloid isolated from a plant
belonging to the ancistrodaceae family. It has confirmed antimalarial activity, with
the lowest IC 50 (0.0014 μm) among antimalarial naphthylisoquinoline alkaloids [3].
(The IC 50 indicates how much of a particular drug is needed to inhibit 50% of a
given biological process or component of a process such as an enzyme, cell, cell
receptor or microorganism). The molecule has a dimeric structure: it consists of the
two units, each consisting of a naphthalene moiety and an isoquinoline moiety. The
two units are identical (have the same substituents in corresponding positions)
making the molecule a C 2 symmetric dimer [3]. These characteristics make the
computational study of this molecule particularly interesting. The analysis of the
results will give specific attention to symmetry aspects.
The electronic structure of a molecule and the properties related to it—such as
dipole moment, molecular electrostatic potential, molecular orbital energies—provide important information for a better understanding of molecular interactions when
biological recognition processes are involves [4–8]. Some studies have also already
shown relationships between the electronic structure and the antimalarial activity of
alkoxylated and hydroxylated chalcones [9], tetrahydropyridines [10] and the cinchona alkaloids [8]. Some Quantitative Structure-Activity Relationship (QSRA)
studies have shown correlation between electronic structure, antimalarial activity
and phototoxicity of selected quinolinemethanol derivatives and their analogs [11].
The current study is the first study of the electronic structure of JZM, and it is part
of an ongoing computational investigation of naphthylisoquinoline alkaloids [12,
13]. The conformational preferences of JZM were studied in vacuo and in three
solvents with different polarities and different H-bonding abilities (chloroform,
acetonitrile and water). Two levels of theory, Hartree-Fock (HF/6-31G(d,p)) and
Density Functional Theory with the B3LYP functional (DFT/B3LYP/6-31+G(d,p)),
306
M. K. Bilonda and L. Mammino
Malaria is an infectious disease caused by plasmodia, among which Plasmodium
falciparum is the most dangerous and responsible for most deaths. According to
WHO 2014 reports, 97 countries and territories are affected by malaria transmission
[1]. 98 million cases and 584 000 deaths were recorded in 2013 [1] and 212 million
new cases and 429 000 deaths in 2015 [2]. 90% of the cases occurred in African
countries and most of the deaths concern children under 5 years [1, 2].
The major challenge for malaria treatment is the fast development of resistance
to new drugs, just within few years after their introduction into clinical use. Some
drugs have already lost their efficacy and resistance has started appearing for
artemisinin, which is the current drug of choice. The development of new drugs
should at least keep the pace with the rate at which Plasmodium develops resistance
to existing drugs. This implies urgent need for new compounds having original
modes of action. Natural products constitute a potentially immense source of new
compounds, with diverse molecular structures and pharmacophores.
Jozimine A 2 (Fig. 1, denoted by the acronym JZM in the rest of the text) is a
dioncophyllaceae-type naphthylisoquinoline alkaloid isolated from a plant
belonging to the ancistrodaceae family. It has confirmed antimalarial activity, with
the lowest IC 50 (0.0014 μm) among antimalarial naphthylisoquinoline alkaloids [3].
(The IC 50 indicates how much of a particular drug is needed to inhibit 50% of a
given biological process or component of a process such as an enzyme, cell, cell
receptor or microorganism). The molecule has a dimeric structure: it consists of the
two units, each consisting of a naphthalene moiety and an isoquinoline moiety. The
two units are identical (have the same substituents in corresponding positions)
making the molecule a C 2 symmetric dimer [3]. These characteristics make the
computational study of this molecule particularly interesting. The analysis of the
results will give specific attention to symmetry aspects.
The electronic structure of a molecule and the properties related to it—such as
dipole moment, molecular electrostatic potential, molecular orbital energies—provide important information for a better understanding of molecular interactions when
biological recognition processes are involves [4–8]. Some studies have also already
shown relationships between the electronic structure and the antimalarial activity of
alkoxylated and hydroxylated chalcones [9], tetrahydropyridines [10] and the cinchona alkaloids [8]. Some Quantitative Structure-Activity Relationship (QSRA)
studies have shown correlation between electronic structure, antimalarial activity
and phototoxicity of selected quinolinemethanol derivatives and their analogs [11].
The current study is the first study of the electronic structure of JZM, and it is part
of an ongoing computational investigation of naphthylisoquinoline alkaloids [12,
13]. The conformational preferences of JZM were studied in vacuo and in three
solvents with different polarities and different H-bonding abilities (chloroform,
acetonitrile and water). Two levels of theory, Hartree-Fock (HF/6-31G(d,p)) and
Density Functional Theory with the B3LYP functional (DFT/B3LYP/6-31+G(d,p)),
306
M. K. Bilonda and L. Mammino