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.