An original way to manage both stereochemistry and conformational constraints in ligand candidates for bioassays is presented with reference to a group of model N,N′-tetrasubstituted o-phthalamides and thioamides. The study shows that a scale of thermal flexibility in solution can be envisaged, the divisions of which are represented by compounds sharing quite similar geometrical features. NMR spectroscopy and powder X-ray analysis were used for the physical chemical investigation. An attempt to exploit the conformational instability of a model thioamide in the medium of a bioassay was also performed.