Effect of Water Solvation on the Lipophilicity of Isomeric Pyrimidine-Carboxamides
Bioorganic & medicinal chemistry(2015)
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.
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Key words
LogD,LogP,Lipophilicity,Lipophilicity calculators,Water solvation,Pyrimidines,Isomers
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