LAUSR

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 in total 28 novel experimental aliphatic logP values, are involved in discussing various lipophilicity trends. Next to 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. In addition, one- and two-fluorine 'deletions' within perfluoroalkyl groups are shown to significantly reduce lipophilicity. Quantum chemical logP calculation (SMD-MN15) and common web-based ClogP calculation methods gave excellent correlations with experimental values. The availability of a large collection of data based on a small number of parent molecules nicely illustrates the relative lipophilicity modulations of aliphatic fluorination motifs.