Stabilization of the hydrophilic sphere of non-ionic monomers: are all protected in a similar way?

Abstract

The present study attempts to investigate whether incorporation of a methyl group as second substituent in the tertiary amido group of the two benzamide side chains of iobitridol (Xenetix) increases the stability of the hydrophilic sphere around this molecule as claimed by its manufacturer, and whether this hydrophilic sphere is unique to this particular molecule or to what extent other monomer non-ionic contrast media show this feature. Five non-ionic monomer contrast medium molecules, ioversol, iohexol, iobitridol, ioxilan and iopromide, were studied. Barriers to the rotation of acetanilide and benzamide side chains, and to the rotation of the amide bond in the benzamide chains, were calculated at a semi-empirical quantum mechanical level of theory with the Mopac/Ampac computer program. The five studied contrast medium molecules showed very similar energy barriers to the rotation of complete substituent chains (benzamide and acetanilide) around their bond with the benzene ring. The magnitude of the barriers fell in the range of values mentioned in the literature. In conclusion, introduction of a methyl group as second substituent in the tertiary amido group of the benzamide substituent chains of iobitridol does not increase the studied rotation barriers, i.e. it does not seem to stabilize the hydrophilic sphere to a greater extent compared with similar monomer non-ionic molecules. The sphere is shown to exist in all five analysed molecules. Introduction of a group with a more hydrophobic character has to be considered and eventually questioned, bearing in mind that a more hydrophilic molecule interacts to a lesser degree with body systems.