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

Area of Science:

• Medicinal Chemistry
• Physical Chemistry
• Drug Discovery

Background:

• Ionization of bioactive molecules significantly influences ADME-relevant properties like solubility, lipophilicity, and permeability.
• Ampholytes, possessing both acidic and basic groups, are classified as ordinary ampholytes or zwitterions.
• A prevailing view suggests zwitterions only form when the acidic pKa is substantially lower than the basic pKa.

Purpose of the Study:

• To investigate the conditions under which zwitterionic behavior occurs in bioactive molecules.
• To challenge the established criteria for zwitterion formation.
• To explore the physicochemical properties and medicinal chemistry implications of nonclassical zwitterions.

Main Methods:

• Concordance analysis of measured and calculated pKa values.
• Evaluation of log P (lipophilicity) measurements.
• Characterization of molecular structures, including aromatic conjugation and intramolecular hydrogen bonding.

Main Results:

• Zwitterionic behavior was observed in several drugs and natural products despite low or negative ΔpKa (difference between acidic and basic pKa).
• These nonclassical zwitterions feature weak acidic and basic pKa values and extended aromatic systems, often with pseudorings formed by intramolecular hydrogen bonds.
• Nonclassical zwitterions demonstrated excellent permeability, contrasting with typical zwitterions.

Conclusions:

• The formation of zwitterions is not strictly limited by the ΔpKa criterion.
• Nonclassical zwitterions, characterized by specific structural features, present a valuable design strategy in medicinal chemistry.
• The combination of low lipophilicity and high permeability in nonclassical zwitterions makes them attractive for developing new therapeutics.