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The improvement of the water solubility of lead compounds mainly involves three methods: structural modification, formulation technology, and prodrug strategy. The core is to increase the polarity of the molecule or enhance its interaction with water.
Structural modification: Introduce polar groups such as hydroxyl, amino, carboxyl, or water-soluble fragments like sulfonamide and quaternary ammonium salts (for example, replacing the hydrophobic methyl group with hydroxymethyl group); reduce hydrophobic structures such as polycyclic rings, or reduce lipophilicity through ring system modification.
Formulation technology: Prepare salts (such as hydrochloride, sulfate) to enhance solubility; use cyclodextrin to form supramolecular complexes, or prepare nano suspensions, micelles, etc., to improve dissolution behavior through formulation optimization.
Prodrug strategy: Link the poorly water-soluble parent compound with water-soluble groups such as phosphate esters, amino acids, etc., and after entering the body, the activity is restored through enzymatic hydrolysis, which can avoid the impact on drug efficacy (such as acyclovir being transformed into valacyclovir).
