184
M. K. Bilonda and L. Mammino
1 Introduction
Malaria is a transmittable disease caused by plasmodia, among which Plasmodium
falciparum is the most dangerous and responsible for most deaths. According to
WHO 2018 reports [1], 219 million cases were recorded in 2017, and the disease still
causes more than 435 000 deaths each year. African countries still have the highest
burden of malaria cases, and children under five years are the most vulnerable [1]. In
terms of drugs viability, the major problem is the high rate with which Plasmodium
falciparum develops resistance few years after a new drug enters into clinical use;
this implies the need that new drugs, with different molecular structures and different
modes of actions, become available to replace the currently-in-use ones as soon as
the parasite’s resistance lowers their efficacy.
Natural products represent a potentially immense source of new biologically active
compounds, with diverse molecular structures and pharmacophores and, therefore,
diverse mechanisms of action. For this reason, they are considered important for the
identification of new lead compounds for drug development.
Shuangancistrotectorines A, B, C, D and E are naphthylisoquinoline alkaloids
isolated from the twigs of Ancistrocladus tectorius, a plant indigenous in China and
South East Asia [2]. Their molecules have a dimeric structure, i.e., they consist of two
units, with each unit consisting of a naphthalene moiety and an isoquinoline moiety.
The two units are identical, which make the molecules C 2 -symmetric dimers. Shuangancistrotectorine B and E are atropo-diastereomers of shuangancistrotectorine A
and D respectively [2]. Shuangancistrotectorine A, B and D show very good antimalarial activity, with shuangancistrotectorine A being the most active and having
the lowest IC 50 , 0.052 μM [2]. (The IC 50 indicates the amount of a particular drug
that 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 current work is part of an ongoing computational study of naphthylisoquinoline (NIQ) alkaloids [3–6], with major focus on those having antimalarial
activity. It investigates the conformational preferences of shuangancistrotectorine
A (Fig. 1, hereafter denoted by the acronym SHA) in the gas phase and in three
solvents with different polarities and different H-bonding abilities (chloroform, acetonitrile and water). SHA is selected because it has the strongest antimalarial activity
among shuangancistrotectorines. Calculations were performed at 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)). Calculations in solution used the Polarizable
Continuum Model (PCM).
The results show that the conformational preferences are primarily influenced by
the presence of intramolecular interactions, chiefly intramolecular hydrogen bonds
(IHBs), followed by the mutual orientations of the four moieties. O–H···O IHBs
have the dominant stabilizing effect. Other H-bond-type intramolecular interactions,
such as O–H···π interactions, also have significant stabilizing effect. All the moieties
prefer to be perpendicular to each other.
M. K. Bilonda and L. Mammino
1 Introduction
Malaria is a transmittable disease caused by plasmodia, among which Plasmodium
falciparum is the most dangerous and responsible for most deaths. According to
WHO 2018 reports [1], 219 million cases were recorded in 2017, and the disease still
causes more than 435 000 deaths each year. African countries still have the highest
burden of malaria cases, and children under five years are the most vulnerable [1]. In
terms of drugs viability, the major problem is the high rate with which Plasmodium
falciparum develops resistance few years after a new drug enters into clinical use;
this implies the need that new drugs, with different molecular structures and different
modes of actions, become available to replace the currently-in-use ones as soon as
the parasite’s resistance lowers their efficacy.
Natural products represent a potentially immense source of new biologically active
compounds, with diverse molecular structures and pharmacophores and, therefore,
diverse mechanisms of action. For this reason, they are considered important for the
identification of new lead compounds for drug development.
Shuangancistrotectorines A, B, C, D and E are naphthylisoquinoline alkaloids
isolated from the twigs of Ancistrocladus tectorius, a plant indigenous in China and
South East Asia [2]. Their molecules have a dimeric structure, i.e., they consist of two
units, with each unit consisting of a naphthalene moiety and an isoquinoline moiety.
The two units are identical, which make the molecules C 2 -symmetric dimers. Shuangancistrotectorine B and E are atropo-diastereomers of shuangancistrotectorine A
and D respectively [2]. Shuangancistrotectorine A, B and D show very good antimalarial activity, with shuangancistrotectorine A being the most active and having
the lowest IC 50 , 0.052 μM [2]. (The IC 50 indicates the amount of a particular drug
that 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 current work is part of an ongoing computational study of naphthylisoquinoline (NIQ) alkaloids [3–6], with major focus on those having antimalarial
activity. It investigates the conformational preferences of shuangancistrotectorine
A (Fig. 1, hereafter denoted by the acronym SHA) in the gas phase and in three
solvents with different polarities and different H-bonding abilities (chloroform, acetonitrile and water). SHA is selected because it has the strongest antimalarial activity
among shuangancistrotectorines. Calculations were performed at 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)). Calculations in solution used the Polarizable
Continuum Model (PCM).
The results show that the conformational preferences are primarily influenced by
the presence of intramolecular interactions, chiefly intramolecular hydrogen bonds
(IHBs), followed by the mutual orientations of the four moieties. O–H···O IHBs
have the dominant stabilizing effect. Other H-bond-type intramolecular interactions,
such as O–H···π interactions, also have significant stabilizing effect. All the moieties
prefer to be perpendicular to each other.