Predicting the phospholipophilicity of monoprotic positively charged amines

The sorption affinity of eighty-six charged amine structures to phospholipid monolayers (log K_IAM) was determined using immobilized artificial membrane high-performance liquid chromatography (IAM-HPLC). The amine compounds covered the most prevalent types of polar groups, widely ranged in structural complexity, and included forty-seven pharmaceuticals, as well as several narcotics and pesticides. Amine type specific corrective increments were used to align log K_IAM data with bilayer membrane sorption coefficients (K_MW(IAM)). Using predicted sorption affinities of neutral amines, we evaluated the difference (scaling factor Δ_MW) with the measured log K_MW(IAM) for cationic amines. The Δ_MW values were highly variable, ranging from -2.37 to +2.3 log units. For each amine type, polar amines showed lower Δ_MW values than hydrocarbon based amines (C_xH_yN⁺). COSMOmic software was used to directly calculate the partitioning coefficient of ionic structures into a phospholipid bilayer (K_{DMPC-W,cation}), including quaternary ammonium compounds. The resulting root mean square error (RMSE) between log K_{DMPC-W,cation} and log K_MW(IAM) was 0.83 for all eighty-six polar amines, and 0.47 for sixty-eight C_xH_yN⁺ amines. The polar amines were then split into five groups depending on polarity and structural complexity, and corrective increments for each group were defined to improve COSMOmic predictions. Excluding only the group with sixteen complex amine structures (≥4 polar groups, M_w > 400, including several macrolide antibiotics), the resulting RMSE for corrected K_{DMPC-W,cation} values improved to 0.45 log units for the remaining set of 138 polar and C_xH_yN⁺ amines.