in this discussion). The first five lowest energy conformers have relative energy
below 1 kcal/mol in chloroform and acetonitrile, and below 0.24 kcal/mol in water.
The identification of the lowest energy conformer does not change in chloroform
and acetonitrile with respect to in vacuo, but may be different in water; however, the
relative energies of the five lower-energy conformers are so small in water that a
different identification of the lowest-energy one among them does not affect the
interpretation of the results. Major changes in water occur for some conformers
having relative energy in vacuo greater than 5 kcal/mol. These cases concern
conformers in which O41−H50 or O46−H60 are not engaged in the O−H⋯π
interaction and, therefore, are available to form H-bonds with water molecules.
Although PCM does not take into explicit account solute-solvent H-bonds, it
appears sometimes to take it into account implicitly through the energetics (possibly
as the effect of the point-charges distribution in the areas of the cavity surface
corresponding to an H-bond donor or acceptor) [46]. A confirmation about the
interactions of these conformers with water molecules can be obtained through the
consideration of adducts with explicit water molecules, which might be the object
of a separate study.
The five lowest energy conformers account for 99.89% of the population in
chloroform, 99.66% in acetonitrile and 90.71% in water. The population distribution
of the other conformers (besides the five lowest energy ones) is also different. In
vacuo, no other conformer has a population greater than 0.003%; in chloroform,
there are two conformers with population of 0.02 and 0.01% respectively, and all
the other populations are <0.007%; in acetonitrile, ten other conformers have a
population between 0.02 and 0.05%; in water, three other conformers have population between 1.0 and 1.3% and seven conformers between 0.1 and 0.9%.
Conformers of S/S′ symmetric may have slightly different relative energy in
solution, suggesting that the effect of their symmetric situation may somewhat
decrease in solution.
If 3.5 kcal/mol is taken as a cautious threshold value for conformers which
might be responsible for the biological activity, the results in water solution suggest
that most conformers of JZM (all those with relative energy ≤ 3.5 kcal/mol in water
solution) might be considered as potential responsibles for the antimalarial activity
of JZM.
Table 8 reports the solvent effect (free energy of solvation, ΔG solv ) for the
conformers listed in Table 2. ΔG solv is positive in chloroform and acetonitrile and
negative in water for all the conformers. The values in acetonitrile are considerably
greater than those in chloroform. The electrostatic component of ΔG solv (G el ) has
negative values in all the three solvents, but considerably more negative in water.
A quick estimation of the octanol/water partition coefficient of JZM (6.3743, [47])
suggests that JZM could be more soluble in non-polar solvents than in water. This
could be due to presence of many aromatic rings and to the high molecular mass.
On the other hand, the negative values of ΔG solv in water suggest the possibility of
some (although limited) solubility in water or, at least, the possibility that the
molecule may be present also in the water phases of living organisms cannot be
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below 1 kcal/mol in chloroform and acetonitrile, and below 0.24 kcal/mol in water.
The identification of the lowest energy conformer does not change in chloroform
and acetonitrile with respect to in vacuo, but may be different in water; however, the
relative energies of the five lower-energy conformers are so small in water that a
different identification of the lowest-energy one among them does not affect the
interpretation of the results. Major changes in water occur for some conformers
having relative energy in vacuo greater than 5 kcal/mol. These cases concern
conformers in which O41−H50 or O46−H60 are not engaged in the O−H⋯π
interaction and, therefore, are available to form H-bonds with water molecules.
Although PCM does not take into explicit account solute-solvent H-bonds, it
appears sometimes to take it into account implicitly through the energetics (possibly
as the effect of the point-charges distribution in the areas of the cavity surface
corresponding to an H-bond donor or acceptor) [46]. A confirmation about the
interactions of these conformers with water molecules can be obtained through the
consideration of adducts with explicit water molecules, which might be the object
of a separate study.
The five lowest energy conformers account for 99.89% of the population in
chloroform, 99.66% in acetonitrile and 90.71% in water. The population distribution
of the other conformers (besides the five lowest energy ones) is also different. In
vacuo, no other conformer has a population greater than 0.003%; in chloroform,
there are two conformers with population of 0.02 and 0.01% respectively, and all
the other populations are <0.007%; in acetonitrile, ten other conformers have a
population between 0.02 and 0.05%; in water, three other conformers have population between 1.0 and 1.3% and seven conformers between 0.1 and 0.9%.
Conformers of S/S′ symmetric may have slightly different relative energy in
solution, suggesting that the effect of their symmetric situation may somewhat
decrease in solution.
If 3.5 kcal/mol is taken as a cautious threshold value for conformers which
might be responsible for the biological activity, the results in water solution suggest
that most conformers of JZM (all those with relative energy ≤ 3.5 kcal/mol in water
solution) might be considered as potential responsibles for the antimalarial activity
of JZM.
Table 8 reports the solvent effect (free energy of solvation, ΔG solv ) for the
conformers listed in Table 2. ΔG solv is positive in chloroform and acetonitrile and
negative in water for all the conformers. The values in acetonitrile are considerably
greater than those in chloroform. The electrostatic component of ΔG solv (G el ) has
negative values in all the three solvents, but considerably more negative in water.
A quick estimation of the octanol/water partition coefficient of JZM (6.3743, [47])
suggests that JZM could be more soluble in non-polar solvents than in water. This
could be due to presence of many aromatic rings and to the high molecular mass.
On the other hand, the negative values of ΔG solv in water suggest the possibility of
some (although limited) solubility in water or, at least, the possibility that the
molecule may be present also in the water phases of living organisms cannot be
Computational Study of Jozimine A 2 , a Naphthylisoquinoline …
323