β-Cyclodextrin Inclusion Complexes with Catechol-Containing Antioxidants Protocatechuic Aldehyde and Protocatechuic Acid-An Atomistic Perspective on Structural and Thermodynamic Stabilities

Protocatechuic aldehyde (PCAL) and protocatechuic acid (PCAC) are catechol derivatives and have broad therapeutic effects associated with their antiradical activity. Their pharmacological and physicochemical properties have been improved via the cyclodextrin (CD) encapsulation. Because the characteristics of beta-CD inclusion complexes with PCAL (1) and PCAC (2) are still equivocal, we get to the bottom of the inclusion complexation by an integrated study of single-crystal X-ray diffraction and DFT full-geometry optimization. X-ray analysis unveiled that PCAL and PCAC are nearly totally shielded in the beta-CD wall. Their aromatic rings are vertically aligned in the beta-CD cavity such that the functional groups on the opposite side of the ring (3,4-di(OH) and 1-CHO/1-COOH groups) are placed nearby the O6-H and O2-H/O3-H rims, respectively. The preferred inclusion modes in 1 and 2 help to establish crystal contacts of OH...O H-bonds with the adjacent beta-CD OH groups and water molecules. By contrast, the DFT-optimized structures of both complexes in the gas phase are thermodynamically stable via the four newly formed host-guest OH...O H-bonds. The intermolecular OH...O H-bonds between PCAL/PCAC 3,4-di(OH) and beta-CD O6-H groups, and the shielding of OH groups in the beta-CD wall help to stabilize these antioxidants in the beta-CD cavity, as observed in our earlier studies. Moreover, PCAL and PCAC in distinct lattice environments are compared for insights into their structural flexibility.

Automated summary

Protocatechuic aldehyde (PCAL) and protocatechuic acid (PCAC) are catechol derivatives with broad therapeutic effects due to their antiradical activity. Encapsulation in cyclodextrin (CD) improves their pharmacological and physicochemical properties. X-ray analysis revealed that they are shielded in the beta-CD wall and positioned in a preferred orientation for crystal contacts, contributing to their stability in the cavity.