Structure-property relationships of fluorinated carboxylic acid bioisosteres

Fluorinated alcohols and phenols are potentially useful as bioisosteres of the carboxylic acid functional group. To enable a direct comparison of the properties of fluorinated carboxylic acid surrogates with those of other commonly used, non-fluorinated bioisosteres, we conducted a structure-property relationship (SPR) study based on matched molecular pair (MMP) analyses. A series of representative examples have been characterized by experimentally determining physicochemical properties, such as acidity (pKa), lipophilicity (logD7.4), and permeability (PAMPA). The results presented can help estimate the relative changes in physicochemical properties that may be attainable by replacing the carboxylic acid functional group with fluorine containing surrogate structures.

Automated summary

In this study, fluorinated alcohols and phenols were investigated as bioisosteres of the carboxylic acid functional group. A structure-property relationship analysis was conducted using matched molecular pair analyses to compare their properties with other commonly used non-fluorinated bioisosteres. Physicochemical properties, such as acidity, lipophilicity, and permeability, were experimentally determined for representative examples. The results provide insights into the relative changes in physicochemical properties achievable by replacing the carboxylic acid functional group with fluorine-containing surrogate structures.