Effect of water solvation on the lipophilicity of isomeric pyrimidine-carboxamides

Maria Angelica Linton; Benjamin J Burke; Ted W Johnson; Sacha Ninkovic; Ketan S Gajiwala; Paul Richardson; Phuong T Le

doi:10.1016/j.bmc.2015.04.041

Effect of water solvation on the lipophilicity of isomeric pyrimidine-carboxamides

Bioorg Med Chem. 2015 Jul 1;23(13):3408-13. doi: 10.1016/j.bmc.2015.04.041. Epub 2015 Apr 22.

Authors

Maria Angelica Linton¹, Benjamin J Burke², Ted W Johnson², Sacha Ninkovic², Ketan S Gajiwala², Paul Richardson², Phuong T Le²

Affiliations

¹ Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States. Electronic address: [email protected].
² Pfizer Global Research and Development, Department of Chemistry, La Jolla, CA, United States.

PMID: 25963824
DOI: 10.1016/j.bmc.2015.04.041

Abstract

Incorporation of nitrogen is a common medicinal chemistry tactic to reduce logD values. Neighboring group participation influences logD, so the results are isomer dependent. The logD and logP differences observed between isomeric pyrimidines 1, 2 and 3 presumably result when the carbonyl or ether lone pairs are in close proximity to a heterocyclic nitrogen lone pair, recruiting water to bridge between the electron rich atoms. Various lipophilicity calculators did not discriminate between 1 (logD=2.6) and 3 (logD=1.0), but solvation energies using Poisson-Boltzmann and 3D-RISM methods rationalize the observed differences in lipophilicity among pyrimidine carboxamide isomers.

Keywords: Isomers; Lipophilicity; Lipophilicity calculators; LogD; LogP; Pyrimidines; Water solvation.

MeSH terms

Amides / chemistry*
Electrons*
Hydrogen-Ion Concentration
Hydrophobic and Hydrophilic Interactions
Isomerism
Models, Molecular
Nitrogen / chemistry*
Pyrimidines / chemistry*
Solubility
Thermodynamics
Water / chemistry*

Substances

Amides
Pyrimidines
Water
Nitrogen