Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties.
J Med Chem
; 57(6): 2746-54, 2014 Mar 27.
Article
em En
| MEDLINE
| ID: mdl-24524242
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 NHâNR3 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.
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1
Base de dados:
MEDLINE
Assunto principal:
Trypanosoma cruzi
/
Permeabilidade da Membrana Celular
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Suécia