Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties

Abstract

Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH→NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure–property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski’s rule of 5.

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…Studying the impact of stereospecific intramolecular hydrogen bonds on cell permeability and physicochemical properties, Over et al [239] on series of stereoisomeric T. cruzi inhibitors, found an unexpectedly revealed striking influence of stereochemistry on solubility, lipophilicity, and cell permeability. This effect on compound properties was traced to the relative stereochemistry at two adjacent stereocenters where an intramolecular hydrogen bond was favored that reduced the basicity of the tertiary amine of the inhibitors while simultaneously shielding polarity from the surrounding environment.…”

Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein–Protein Interaction

“…This effect has also been showed for other molecular series. 27 For more details on the relationship between pK a and permeability for several compounds in this article, please see the Supporting Information.…”

Novel tactics for designing water-soluble molecules in drug discovery

“…The calculated log P is shown to illustrate the fact that most calculation protocols incorporate the alkyl versus aryl behavior of fluorine. solubilities observed for compounds 19-26, which are identical except for the stereochemistry at C8, C9 and C25 (Table 4) [44]. Four of the diastereomers (23-26) showed favorable solubility as a result of being less hydrophobic (log D £ 3.9) compared to the other four (19)(20)(21)(22), which showed poor solubility and higher log D. The more soluble isomers share the same relative syn-stereochemistry between the stereocenters at C8 and C9, while the poorly soluble isomers are trans.…”