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

Abstract

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 b-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 b-CD wall. Their aromatic rings are vertically aligned in the b-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 b-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 b-CD O6–H groups, and the shielding of OH groups in the b-CD wall help to stabilize these antioxidants in the b-CD cavity, as observed in our earlier studies. Moreover, PCAL and PCAC in distinct lattice environments are compared for insights into their structural flexibility.

Phenolic Thiazoles with Antioxidant and Antiradical Activity. Synthesis, In Vitro Evaluation, Toxicity, Electrochemical Behavior, Quantum Studies and Antimicrobial Screening

“…The very good activity identified for compound 8b can be structurally explained due to the lack of the methyl group on the azomethine (b series) and the presence of the catechol group, in agreement with literature reports that suggest the high activity of this type of compound is due to the internal stabilization of the resulted radicals from the catechol fragment by intramolecular hydrogen bonding [45][46][47].…”

Distinctive Supramolecular Features of β-Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline: A Comprehensive Structural Investigation

“…Note that β-CD O6–H groups do not make H-bonding with the embedded TCA aromatic ring, thus not stabilizing the β-CD–TCA inclusion complexes. On the contrary, the β-CD–polyphenol complexes are stabilized through O–H···O H-bonds between the enclosed catechol moiety and β-CD O6–H and water molecules [ 46 ]. The stabilization energies between two groups of complexes are compared in Section 2.4 .…”

“…The 4 C 1 chair conformations of seven D-glucose residues interconnected via α-1,4-glycosidic bonds are mostly intact by total or partial inclusion of various guests with different sizes and shapes in the β-CD cavity, as indicated by the small oscillations of glucose puckering parameters Q , θ [ 36 ], Table S3 . The corresponding values are: 0.552–0.571 Å, 1.4°–6.9° for 1 ; 0.537–0.569 Å, 0.0°–7.9° for 2 ; 0.559–0.583 Å, 1.4°–7.6° for uncomplexed β-CD [ 45 ]; 0.543–0.592 Å, 1.8°–9.7° for protocatechuic aldehyde (total inclusion, round β-CD) [ 46 ]; and 0.545–0.582 Å, 3.2°–8.8° for (–)-epicatechin (EC) (partial inclusion, highly distorted β-CD) [ 44 ]. β-CD hydrate is more rigid compared to other family members.…”

“…Note that the Δ E stb s in the range of –4.25 to –8.37 kcal mol −1 indicate the weak intermolecular C–H∙∙∙π interactions of the β-CD–TCA complexes. On the contrary, the β-CD–polyphenol complexes with the catechol moiety embedded in the cavity and maintained in position through H-bonding with CD rims are ~2–4 times more stable; Δ E stb = –14.38 to –32.58 kcal mol –1 [ 46 ]. This suggests that Δ E stb s and Δ E int s of the β-CD–TCA complexes are somewhat underestimated, and the approximations deserve further attention.…”

“…This suggests that Δ E stb s and Δ E int s of the β-CD–TCA complexes are somewhat underestimated, and the approximations deserve further attention. Although the DFT calculations at the B3LYP/6-31+G*/4-31G level worked quite well for the H-bonded systems of β-CD–polyphenol inclusion complexes [ 46 ], the B3LYP/6-31+G*/4-31G method seemed to insufficiently describe the dispersion interactions predominantly present in the β-CD–TCA complexes.…”