Supramolecular Complexes of β-Cyclodextrin with Clomipramine and Doxepin: Effect of the Ring Substituent and Component of Drugs on Their Inclusion Topologies and Structural Flexibilities

Abstract

Depression is a global threat. Tricyclic antidepressants (TCAs) are still efficacious in treating depression, albeit with more side effects. Cyclodextrins (CDs) with a suitable nanocavity are potential drug carriers and can enhance the drug bioavailability. Aiming for an atomistic understanding of the CD encapsulation facilitating the improvement of drug stability and the reduction of side effects, a comprehensive study series of the β-CD–TCA inclusion complexes through single crystal X-ray diffraction and density functional theory (DFT) calculation was undertaken. This work reports the supramolecular complexes of β-CD with two pivotal TCAs, clomipramine (CPM; 1) and doxepin (DXP; 2). The different inclusion topologies of the β-CD–TCA complexes were notable. X-ray analysis revealed that, in 1, the CPM B-ring (without chloro group) was entrapped in the β-CD cavity, whereas, in 2, the E-DXP A-ring and the Z-DXP B-ring were disordered in the cavity, yielding energetically favorable complexes primarily maintained by intermolecular C–H⋯π interactions, as indicated by DFT calculation. Because both wings of TCAs were similar, an alternative inclusion scenario of the A-ring was evidenced crystallographically in four other TCA complexes. The enhanced TCA thermodynamic stabilities via CD inclusion complexation helped to reduce the side effects and to increase the bioavailability. Moreover, the scrutinization of six TCAs in different lattice circumstances revealed the greater TCA structural flexibilities for their optimum pharmacological activity while binding with proteins.

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

“…β-CD nomenclature is used conventionally for carbohydrates, i.e., atoms C64A(B)–O64A(B) denote the methylene C6–H 2 linked with the hydroxyl O6–H groups that are doubly disordered in sites A and B of glucose unit 4 (G4) in the β-CD–PRT HCl complex ( 1 ). As in our previous works on TCAs [ 23 , 28 , 35 ], atom numberings of PRT and MPL are used accordingly and further arbitrarily labeled with letters P and M, respectively ( Figure 1 ). We organize our comprehensive discussion as follows: the inclusion complexation of β-CD–PRT ( 1 ) and β-CD–MPL ( 2 ) driven by induced-fit is described in detail for host β-CD and guests PTR, MPL in respective Section 2.1 and Section 2.2 .…”

“…It is well known that in the less dense state (solution), the TCA side-chain is included in the β-CD cavity more thermodynamically stable than the aromatic ring; see the introduction. In the dense state of solids where the intermolecular interactions exist, the inclusion mode of an aromatic ring is exclusively observed as evidenced crystallographically [ 23 , 28 , 35 ]. Principally, the reflection symmetric A and B wings of the bending tricyclic core are equally entrapped in the β-CD cavity.…”

“…Thus far, there have been six β-CD–TCA inclusion complexes characterized crystallographically [ 23 , 28 , 34 , 35 ]; see the summary in Table 1 and Table S1 . TCAs DPM, IPM, NRT, and AMT with the reflection symmetric wings prefer the inclusion mode of the aromatic A-ring in the β-CD cavity [ 23 , 28 ] while TCAs CPM and DXP with the reflection asymmetric wings/body of the (6-7-6)-tricyclic core favor the inclusion modes of the aromatic B-ring (without Cl) and the disordered A/B-ring in the β-CD cavity, respectively [ 35 ], Scheme 1 and Table 1 . The topological inclusion structures of the six complexes crystallized in the same symmetry of the monoclinic system, space group P 2 1 have been thoroughly discussed [ 35 ].…”

“…TCAs DPM, IPM, NRT, and AMT with the reflection symmetric wings prefer the inclusion mode of the aromatic A-ring in the β-CD cavity [ 23 , 28 ] while TCAs CPM and DXP with the reflection asymmetric wings/body of the (6-7-6)-tricyclic core favor the inclusion modes of the aromatic B-ring (without Cl) and the disordered A/B-ring in the β-CD cavity, respectively [ 35 ], Scheme 1 and Table 1 . The topological inclusion structures of the six complexes crystallized in the same symmetry of the monoclinic system, space group P 2 1 have been thoroughly discussed [ 35 ]. However, after re-reviewing the literature, we found that the central C-ring could be altered for the significant changes of host–guest binding affinities of both the β-CD–PRT and β-CD–MPL complexes as described above.…”

Caffeine-Cyclodextrin Complexes as Solids: Synthesis, Biological and Physicochemical Characterization

“…Molecular modeling can be used as a tool to characterize the binding behavior between CD as hosts and small organic molecules as guests. The computational protocol used in this work was largely inspired by a number of previously reported studies [36][37][38][39][40]. In all of them, as well as in many other published works, the density functional theory (DFT) method was shown to be a powerful tool for studying CD complexes, combining high computational efficiency with the required accuracy.…”