Incorporation of an Isohexide Subunit Improves the Drug-like Properties of Bioactive Compounds

An enhanced ability to pre-engineer favorable drug-likeness qualities into bioactive molecules would focus and streamline the drug development process. We find that phenols, carboxylic acids, and a purine react with isosorbide (“GRAS” designated) under Mitsunobu coupling conditions to deliver the isoidide conjugates selectively and efficiently. Such conjugates show improved solubility and permeability properties compared with the bare scaffold compounds themselves, and the purine adduct may have applications as a 2′-deoxyadenosine isostere. We anticipate additional benefits, implied by their structures, in metabolic stability and reduced toxicity of the isoidide conjugates as well.