Alexidine and Pentamidine Fold Inside the Bowl-Shaped Cavity of p-Sulfonato-calix[4]arene.

Abstract

We report on the U-shaped folding of flexible guest molecules of medicinal interest upon their inclusion into macrocyclic cavity of p-sulfonato-calix[4]arene in aqueous media. Alexidine and pentamidine are FDA-approved drug compounds currently rediscovered as potent membrane-targeting antibiotic adjuvants helping restore antibiotic activity against multidrug resistant bacteria pathogens. We have adopted host-guest and crystal engineering approach to study these drugs with a view of potential supramolecular formulations and/or crystal forms. We focus on the host-guest conformational and structural behaviour of alexidine and pentamidine under macrocyclic confinement conditions benefitting from single crystal X-ray diffraction analysis, self-assembly studies in solution by NMR spectroscopy, dynamic light scattering and atomic force microscopy, and ion mobility mass spectrometry (IM-MS) analysis complemented by theoretical calculations. Our findings show that the simple bowl-shaped host promotes conformational fixing and crystallization of these guest molecules of high conformational freedom that are otherwise challenging to crystallize. The IM-MS structural studies of p-sulfonato-calix[4]arene complexes with pentamidine and alexidine revealed significant guest reorganization in the solution/gas phase, compared to the binding modes observed in the crystal structures. Despite these changes, the host-guest complexation remained consistent, with new interactions highlighting the increased role of electrostatic forces in the gas phase.