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J Med Chem DOI:10.1021/jm500059t

Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties.

Publication TypeJournal Article
Year of Publication2014
AuthorsOver, B, McCarren, P, Artursson, P, Foley, M, Giordanetto, F, Grönberg, G, Hilgendorf, C, Lee, MD, Matsson, P, Muncipinto, G, Pellisson, M, Perry, MWD, Svensson, R, Duvall, JR, Kihlberg, J
JournalJ Med Chem
Date Published2014 Mar 27
KeywordsAlgorithms, Animals, Caco-2 Cells, Cell Membrane Permeability, Computational Biology, Drug Design, Humans, Hydrogen Bonding, Hydrogen-Ion Concentration, Kinetics, Lipids, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, Small Molecule Libraries, Solubility, Stereoisomerism, Structure-Activity Relationship, Trypanosoma cruzi

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.


Alternate JournalJ. Med. Chem.
PubMed ID24524242
PubMed Central IDPMC3968888
Grant ListP50 GM069721 / GM / NIGMS NIH HHS / United States