Benzophenones are prevalent motifs in drugs and natural products, but suffer from chemical and metabolic instability. A common strategy in medicinal chemistry is the use of an atom or group of atoms, called isosteres, to replace problematic functionalities. We previously proposed 3,3-diaryloxetanes as new isosteres for benzophenones and developed the first synthesis of this motif using a lithium-catalyzed Friedel-Crafts reaction on oxetanols.<br/>This poster will describe a matched molecular pair (MMP) comparison of the physicochemical properties of 3,3-diaryloxetanes versus benzophenones, supporting their use as isosteres. The synthesis of 8 pairs was achieved successfully, showing the stability of the oxetane motif in a wide range of chemical transformations. The MMP study shows unprecedented high stability of the diaryloxetane motif under acidic and basic conditions. In addition, replacing benzophenones with 3,3-diaryloxetanes maintains desirable properties such as low logD and high metabolic stability, as well as enhancing the permeability, showing the viability of this motif for use in drug discovery.

3,3-Diaryloxetanes: New opportunities for drug discovery

2019 Fall National Meeting

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