200
M. K. Bilonda and L. Mammino
the four lowest energy conformers). The difference is likely due to the presence
of IHBs between moieties in MCA, whose stabilising effect overrides that of the
perpendicularity of aromatic systems.
Fig. S3 compares the relative energies of the four lowest energy conformers of the
three molecules in the media considered. The values show that the energy gaps are
smallest for MCA (the four lowest energy conformers of MCA have relative energies
below 1 kcal/mol in all the media), greater for JZM and greatest for SHA. The values
remain below 1.9 kcal/mol for all these conformers, and the values in water solution
remain below 1.0 kcal/mol.
Fig. S4, S5 and S6 respectively compare the dipole moments, the HOMO-LUMO
energy gaps and the free energy of solvation (G solv ) of the four lowest energy
conformers of the three molecules. The conformers of SHA have the smallest dipole
moments values, while the conformers of MCA have the greatest values, and the
conformers of JZM have intermediate values. The conformers of MCA have smaller
values of the HOMO-LUMO energy gap, and the conformers of SHA and JZM have
comparable values-ranges. G solv is negative in water for MCA, JZM and only the
fourth lowest energy conformer of SHA, with considerably greater magnitude for
MCA; it is positive in chloroform and acetonitrile for all the conformers of the three
molecules. For each solvent, G solv is lowest for MCA, higher for JZM and highest
for SHA.
The comparison of the molecular properties considered in this section is not
sufficient to understand the difference in the biological activities of these molecules
(antimalarial for SHA and JZM, anti-HIV for MCA), and the investigation of possible
activity mechanism will be crucial for better understanding. However, the comparison highlights some features that are worthy of further consideration, such as the
smaller energy gaps between low-energy conformers in MCA (which increases the
number of conformers with sufficient population to have non-negligible roles in the
biological activity), the presence of cooperative IHBs in MCA (IHB cooperativity
may considerably influence the properties and behaviour of a molecule [40–44]), the
greater dipole moments (the dipole moment may have a role in the biological activity, as shown, e.g., by the case of anthracyclines [45]), the smaller HOMO-LUMO
energy gap (which might favour certain types of reactivity) and the greater magnitude
of G solv in water.
4 Discussion and Conclusions
A computational study of shuangancistrotectorine A- a naphthylisoquinoline alkaloid with antimalarial activity—has been carried out at the HF/6-31G(d,p) and
DFT/B3LP/6-31+G(d,p) levels in vacuo and at the HF/6-31G(d,p) level in chloroform, acetonitrile and water. The results show that the conformational preferences
and other properties are influenced by the presence of O–H···O IHBs (which can
form within the naphthalene moieties) and other IHB-type interactions, such as O–
H···π (which can form between an OH in one moiety and a π ring in another moiety)
M. K. Bilonda and L. Mammino
the four lowest energy conformers). The difference is likely due to the presence
of IHBs between moieties in MCA, whose stabilising effect overrides that of the
perpendicularity of aromatic systems.
Fig. S3 compares the relative energies of the four lowest energy conformers of the
three molecules in the media considered. The values show that the energy gaps are
smallest for MCA (the four lowest energy conformers of MCA have relative energies
below 1 kcal/mol in all the media), greater for JZM and greatest for SHA. The values
remain below 1.9 kcal/mol for all these conformers, and the values in water solution
remain below 1.0 kcal/mol.
Fig. S4, S5 and S6 respectively compare the dipole moments, the HOMO-LUMO
energy gaps and the free energy of solvation (G solv ) of the four lowest energy
conformers of the three molecules. The conformers of SHA have the smallest dipole
moments values, while the conformers of MCA have the greatest values, and the
conformers of JZM have intermediate values. The conformers of MCA have smaller
values of the HOMO-LUMO energy gap, and the conformers of SHA and JZM have
comparable values-ranges. G solv is negative in water for MCA, JZM and only the
fourth lowest energy conformer of SHA, with considerably greater magnitude for
MCA; it is positive in chloroform and acetonitrile for all the conformers of the three
molecules. For each solvent, G solv is lowest for MCA, higher for JZM and highest
for SHA.
The comparison of the molecular properties considered in this section is not
sufficient to understand the difference in the biological activities of these molecules
(antimalarial for SHA and JZM, anti-HIV for MCA), and the investigation of possible
activity mechanism will be crucial for better understanding. However, the comparison highlights some features that are worthy of further consideration, such as the
smaller energy gaps between low-energy conformers in MCA (which increases the
number of conformers with sufficient population to have non-negligible roles in the
biological activity), the presence of cooperative IHBs in MCA (IHB cooperativity
may considerably influence the properties and behaviour of a molecule [40–44]), the
greater dipole moments (the dipole moment may have a role in the biological activity, as shown, e.g., by the case of anthracyclines [45]), the smaller HOMO-LUMO
energy gap (which might favour certain types of reactivity) and the greater magnitude
of G solv in water.
4 Discussion and Conclusions
A computational study of shuangancistrotectorine A- a naphthylisoquinoline alkaloid with antimalarial activity—has been carried out at the HF/6-31G(d,p) and
DFT/B3LP/6-31+G(d,p) levels in vacuo and at the HF/6-31G(d,p) level in chloroform, acetonitrile and water. The results show that the conformational preferences
and other properties are influenced by the presence of O–H···O IHBs (which can
form within the naphthalene moieties) and other IHB-type interactions, such as O–
H···π (which can form between an OH in one moiety and a π ring in another moiety)