Do Amino-Oxetanes Resemble Amides? A Matched Molecular Pairs Property and Structural Comparison

Oxetanes have been established to display properties comparable to carbonyl groups in ketone derivatives and are increasing-ly explored as bioisosteres. However, does the comparison hold for other common carbonyl derivatives: do amino-oxetanes resemble amides? Here, we present a matched molecular pair study of twelve (12) 3-aryl-3-amino-oxetane and benzamide matched molecular pairs to assess their viability as isosteric replacements. Across the surveyed physicochemical properties (pH stability, solubility, lipophilicity, clearance, permeability), amino-oxetanes exhibited comparable profiles to their amide counterparts, while displaying improved solubility. The aryl amino-oxetane motif is more basic than an amide, yet offers significant reduction of amine basicity in comparison to the benzylamine. These findings support the potential of amino-oxetanes as amide replacements. However, analysis of crystal structures of the amino-oxetane and benzamide pairs highlights the conformational difference and alternative exit vectors available through introduction of the oxetane ring. Amino-oxetanes maintain both the H-bond acceptor and H-bond donor capabilities of analogous amides. Amino-oxetanes have significantly lower barriers to rotation, allowing for the potential to flexibly accommodate binding sites of interest. However, the preferred gauche conformation makes the torsion angle and exit vectors of amino-oxetanes more similar to sulfonamides, and on this basis amino-oxetanes provide better like-for-like topological replacements for sulfonamides rather than of amides. Overall, amino-oxetanes present an attractive design option to modulate physicochemical properties and explore chemical topology.