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

Oxetanes display properties comparable to ketone carbonyl
groups
and are increasingly explored as bioisosteres. However, does the comparison
hold for the most common carbonyl derivatives: do amino-oxetanes resemble
amides? Here, we present a matched molecular pair study of 12 3-aryl-3-amino-oxetane
and benzamide matched molecular pairs to assess their viability as
isosteres. Across the surveyed physicochemical properties (pH stability,
solubility, lipophilicity, clearance, permeability), amino-oxetanes
exhibited broadly comparable profiles to their amide counterparts.
Amino-oxetanes maintain both the H-bond acceptor and H-bond donor
capabilities of analogous amides. These findings support the potential
of amino-oxetanes as amide replacements. However, crystal structure
analysis highlights the conformational differences and alternative
exit vectors available through introduction of the oxetane ring. The
preferred gauche conformation makes the torsion angle
and exit vectors of amino-oxetanes more similar to sulfonamides, and
therefore better like-for-like topological replacements. Overall,
amino-oxetanes present an attractive design option to modulate physicochemical
properties and chemical topology.