Nonclassical Zwitterions as a Design Principle to Reduce Lipophilicity without Impacting Permeability

The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic pK_a is significantly lower than the basic pK_a. Through concordance of measured and calculated pK_a and log P, we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative ΔpK_a. These nonclassical zwitterions are characterized by a weak acidic and basic pK_a and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry.