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Comparative Hydrophobicity, Solubility, and Metabolic Stability of 4(1H)-Pyridones, 4(1H)-Quinolones, and 9(10H)-Acridones

Year: 2025

Type: article

Abstract: The relatively polar 4(1 H )-pyridone (4-pyridone) heterocycle is found in many drugs and drug candidates. In a comparison of the hydrophobicity, aqueous solubility, and metabolic stability of several matched sets of 4-pyridones, 4(1 H )-quinolones (4-quinolones), and 9(10 H )-acridones (9-acridones), measured chromatographic log D 7.4 values show that 9-acridones are more hydrophobic and less soluble than their 4-quinolone and 4-pyridone counterparts. All 4-pyridone/4-quinolone pairs had identical or very similar hydrophobicity and aqueous solubility properties. Metabolic stability increased steadily from 9-acridones to 4-quinolones to 4-pyridones, consistent with the progressive increase in Fsp 3 values and log D . The gain in metabolic stability was not as great for those 4-pyridone/4-quinolone pairs featuring additional polar functional groups/heterocycles.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.4c00618