moieties. The O−H⋯O IHBs are the dominant factor determining conformational
preferences and energetics.
The low relative energy of many conformers in water solution suggests that a
comparatively high number of conformers may be potential responsibles for the
molecule’s biological activity. The values of the free energy of solvation suggest
greater solubility in water than in the other two solvents considered in this study,
which would be consistent with the high polarity of the JZM molecule, but not with
the octanol/water partition coefficient of JZM or with its high molecular mass.
It is interesting to note that (differently from a number of other molecules), JZM
appears to respond to the three solvents considered according to their increasing
dipole moment, so that the responses to water are slightly smaller than those to
acetonitrile.
A typical feature of this molecule is the presence of axial chirality (stereoisomerism resulting from the non-planar arrangement of four groups in pairs about a
chirality axis). The presence of axial chirality suggests that rotation about the C13
−C21 bond is not free because of steric hindrance. A space-filling visualisation with
Chem3D [47] appears to confirm the hindrance, at least for lower energy conformers. On the other hand, the rotation scans about this bond (and about the other
two biaryl bonds) were not disrupted (i.e., the steric hindrance did not appear in the
bond-rotation model). A possible reason is the fact that the rotation scan input was a
conformer with 12.811 kcal/mol relative energy (2.32 × 10
−8 population);
although expedient to identify minima in the orientation of the moieties, this
conformer is poorly populated and, therefore, it does not contribute to the molecule’s actual (or experimentally determined) behaviour.
An analysis of the differences with the behaviours and properties of michellamine A may be useful for a better understanding of the difference in the biological
activities of these largely similar molecules.
Acknowledgements M. K. Bilonda expresses her gratitude to the National Research Foundation
(NRF) of South Africa for a bursary to support her Ph.D. studies.
References
1. World Health Organization (2014) World malaria report 2014 summary. http://www.who.int/
malaria/publications/world_malaria_report_2014/wmr-2014-no-profiles.pdf
2. World Health Organization (2016) World malaria report 2016. http://www.who.int/malaria/
media/world-malaria-report-2016/en/
3. Bringmann G, Zhang G, Büttner T, Bauckmann G, Kupfer T, Braunschweig H, Brun R,
Mudogo V (2013) Chem Eur J 19:916–923
4. Bierer DE, Dener JM, Dubenko LG, Gerber RE, Litvak J, Peterli S, Peterli-Roth P,
Truong TV, Mao G, Bauer BE (1995) J Med Chem 38:2628
5. Ganellin CR, Mitchell RC, Young RC (1988) In: Melchiorre C, Giannella M (eds) Recent
advances in receptor chemistry. Elsevier Science Publishers B.V., Amsterdam, pp 289–306
6. Guha S, Majumdar D, Bhattacharjee AK (1992) J Mol Struct (Theochem) 256:61
7. Sjoberg P, Murray JS, Brinck T, Evans P, Politzer P (1990) J Mol Graph 8:81
326
M. K. Bilonda and L. Mammino
preferences and energetics.
The low relative energy of many conformers in water solution suggests that a
comparatively high number of conformers may be potential responsibles for the
molecule’s biological activity. The values of the free energy of solvation suggest
greater solubility in water than in the other two solvents considered in this study,
which would be consistent with the high polarity of the JZM molecule, but not with
the octanol/water partition coefficient of JZM or with its high molecular mass.
It is interesting to note that (differently from a number of other molecules), JZM
appears to respond to the three solvents considered according to their increasing
dipole moment, so that the responses to water are slightly smaller than those to
acetonitrile.
A typical feature of this molecule is the presence of axial chirality (stereoisomerism resulting from the non-planar arrangement of four groups in pairs about a
chirality axis). The presence of axial chirality suggests that rotation about the C13
−C21 bond is not free because of steric hindrance. A space-filling visualisation with
Chem3D [47] appears to confirm the hindrance, at least for lower energy conformers. On the other hand, the rotation scans about this bond (and about the other
two biaryl bonds) were not disrupted (i.e., the steric hindrance did not appear in the
bond-rotation model). A possible reason is the fact that the rotation scan input was a
conformer with 12.811 kcal/mol relative energy (2.32 × 10
−8 population);
although expedient to identify minima in the orientation of the moieties, this
conformer is poorly populated and, therefore, it does not contribute to the molecule’s actual (or experimentally determined) behaviour.
An analysis of the differences with the behaviours and properties of michellamine A may be useful for a better understanding of the difference in the biological
activities of these largely similar molecules.
Acknowledgements M. K. Bilonda expresses her gratitude to the National Research Foundation
(NRF) of South Africa for a bursary to support her Ph.D. studies.
References
1. World Health Organization (2014) World malaria report 2014 summary. http://www.who.int/
malaria/publications/world_malaria_report_2014/wmr-2014-no-profiles.pdf
2. World Health Organization (2016) World malaria report 2016. http://www.who.int/malaria/
media/world-malaria-report-2016/en/
3. Bringmann G, Zhang G, Büttner T, Bauckmann G, Kupfer T, Braunschweig H, Brun R,
Mudogo V (2013) Chem Eur J 19:916–923
4. Bierer DE, Dener JM, Dubenko LG, Gerber RE, Litvak J, Peterli S, Peterli-Roth P,
Truong TV, Mao G, Bauer BE (1995) J Med Chem 38:2628
5. Ganellin CR, Mitchell RC, Young RC (1988) In: Melchiorre C, Giannella M (eds) Recent
advances in receptor chemistry. Elsevier Science Publishers B.V., Amsterdam, pp 289–306
6. Guha S, Majumdar D, Bhattacharjee AK (1992) J Mol Struct (Theochem) 256:61
7. Sjoberg P, Murray JS, Brinck T, Evans P, Politzer P (1990) J Mol Graph 8:81
326
M. K. Bilonda and L. Mammino