Systematic Investigation of Lipophilicity Modulation by Aliphatic Fluorination Motifs

Optimization of compound
lipophilicity is a key aspect of drug
discovery. The aim of this work was to compare the lipophilicity modulations
induced by 16 distinct known and novel fluoroalkyl motifs on three
parent models. Fifty fluorinated compounds, with 28 novel experimental
aliphatic log P values, are involved in discussing
various lipophilicity trends. As well as confirming known trends,
a number of novel lipophilicity-reducing motifs are introduced. Tactics
to reduce lipophilicity are discussed, such as “motif extensions”
and “motif rearrangements”, including with concomitant
extension of the carbon chain, as well as one- and two-fluorine ‘deletions’
within perfluoroalkyl groups. Quantum chemical log P calculations (SMD-MN15) based on solvent-dependent three-dimensional
(3D) conformational analysis gave excellent correlations with experimental
values, superior to Clog P predictions based on 2D structural motifs. The availability of a
systematic collection of data based on a small number of parent molecules
illustrates the relative lipophilicity modulations of aliphatic fluorination
motifs.