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

Abstract

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (Kas) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystallography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH2–CH2- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round β-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔEstbs), although the complex stability orders based on Kas and ΔEstbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs for efficient drug delivery.

Advancing insights on β-cyclodextrin inclusion complexes with SSRIs through lens of X-ray diffraction and DFT calculation

“…4, 5 and Table 2). Similar inclusion modes are observed for the β-CD-TCA complexes (Aree, 2020a(Aree, , 2020b(Aree, , 2020c(Aree, , 2021. The TCA aromatic A/B-rings are mostly vertically aligned in the β-CD cavity (83.7-89.7 • ) and their centroids are 0.467-1.384 Å above the CD molecular plane.…”

“…Accurately determined X-ray structures are good sources of initial atomic coordinates for DFT complete-geometry optimization of the supramolecular CD inclusion complexes, of which CDs are conformationally flexible. This has been successfully demonstrated in our previous works on the β-CD inclusion complexes with TCAs (Aree, 2020a(Aree, , 2020b(Aree, , 2020c(Aree, , 2021. As noted in Section 3.2, in the solid state the 2:2 β-CD-STL HCl (1) and 2:2 β-CD-FXT HCl (2) inclusion complexes comprised two pseudo-monomeric units of which the two drug molecules were quite different.…”

“…In the β-CD dimeric cavity of 1 and 2, the occupancy factors of two STL and two FXT sites, each was refined to unity, yielding 2:2 host-guest complexes. The protonated STL and FXT molecules were counterbalanced and indirectly coordinated by doubly disordered chlorides, which were previously observed in the crystals of eight β-CD-TCA HCl inclusion complexes (Aree, 2020a(Aree, , 2020b(Aree, , 2020c(Aree, , 2021.…”

Host–guest complexation between cucurbit[7]uril and doxepin induced supramolecular assembly

“…The host-guest complexation between tricyclic antidepressants and macrocyclic hosts has already been investigated. [52][53][54][55] For example, the binding of several tricyclic antidepressants with CDs was studied. 52 Among others, the binding affinity of DOX to α-CD and β-CD was determined as 50 and 13 000 M −1 , respectively.…”

Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular Drug Delivery Systems

“…For example, Benzalkonium chloride alters the ocular barrier, but it has a toxic effect when used for several days by accumulating in the cornea [89] and EDTA acts by altering the tight junction of superficial cells and cause paracellular transport of the drug. Cyclodextrin, by complexing with the drug, solubilizes the lipophilic molecules [90] and results in increased permeation [91]. The colloidal system provides controlled drug release and prolonged pharmacological effects.…”