Site Discrimination and Anisotropic Growth Inhibition by Molecular Imposters on Highly Dissymmetric Crystal Surfaces

Drug-induced calculi account for 1–2% of all renal calculi, posing a threat to human health and hindering the development of effective therapies, particularly those based on drug compounds with low solubility. Recently reported compounds from a screening library of P2X3 receptor antagonists are promising candidates for non-opioid treatment of chronic pain, but they can be poorly soluble in aqueous media, as is evident from the formation of crystals in renal and infrarenal structures of rats (a.k.a. “xenostones”). This behavior prompted an investigation using real-time in situ atomic force microscopy (AFM) to elucidate the crystal growth modes and the effect of tailor-made additives chosen from structural analogues in the screening library, which serve as “molecular imposters” that inhibit crystal growth through specific binding to crystal sites on the actively growing surface. Using a readily available member (denoted as DAPSA) of the P2X3 receptor antagonist family having an aryloxydiaminopyrimidine backbone as an illustrative example, in situ AFM of the morphologically significant (011) surface revealed dislocation-actuated growth spirals with an anisotropic morphology. This behavior can be attributed to the nonuniform rate of solute attachment to eight crystallographically unique steps of the spiral, a direct consequence of the dissymmetry of this crystal surface. Eighteen molecular imposters that share the aryloxydiaminopyrimidine backbone of DAPSA were selected from the screening library to systematically investigate the roles of imposter substituent position, size, and functionality on the step velocities along the eight unique crystallographic directions. A nonuniform reduction in step velocities was observed, signaling site discrimination of imposter binding that can be attributed to stereochemical recognition of the imposters at specific crystal sites. The anisotropy of growth inhibition observed in the presence of the various imposters is consistent with binding energies calculated for the 32 crystallographically unique kink sites on steps advancing along predominant growth directions. These results provide insight into the design of growth inhibitors for molecular crystalline solids with complex and dissymmetric surfaces while also suggesting a strategy for formulations containing congeners that can prevent harmful crystal growth in human renal structures.