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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 (K_as) 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 (ΔE_stbs), although the complex stability orders based on K_as and ΔE_stbs 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.

SUBMITTER: Aree T

PROVIDER: S-EPMC8400697 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn this study we investigated the predictability of three thermodynamic quantities related to complex formation. As a model system we chose the host-guest complexes of beta-cyclodextrin (beta-CD) with different guest molecules. A training dataset comprised of 176 beta-CD guest molecules with experimentally determined thermodynamic quantities was taken from the literature. We compared the performance of three different statistical regression methods - principal component regression (PCR), partial least squares regression (PLSR), and support vector machine regression combined with forward feature selection (SVMR/FSS) - with respect to their ability to generate predictive quantitative structure property relationship (QSPR) models for DeltaG degrees, DeltaH degrees and DeltaS degrees on the basis of computed molecular descriptors.ResultsWe found that SVMR/FFS marginally outperforms PLSR and PCR in the prediction of DeltaG degrees, with PLSR performing slightly better than PCR. PLSR and PCR proved to be more stable in a nested cross-validation protocol. Whereas DeltaG degrees can be predicted in good agreement with experimental values, none of the methods led to comparably good predictive models for DeltaH degrees. In using the methods outlined in this study, we found that DeltaS degrees appears almost unpredictable. In order to understand the differences in the ease of predicting the quantities, we performed a detailed analysis. As a result we can show that free energies are less sensitive (than enthalpy or entropy) to the small structural variations of guest molecules. This property, as well as the lower sensitivity of DeltaG degrees to experimental conditions, are possible explanations for its greater predictability.ConclusionThis study shows that the ease of predicting DeltaG degrees cannot be explained by the predictability of either DeltaH degrees or DeltaS degrees. Our analysis suggests that the poor predictability of TDeltaS degrees and, to a lesser extent, DeltaH degrees has to do with a stronger dependence of these quantities on the structural details of the complex and only to a lesser extent on experimental error.

Project description:The study aimed to prepare inclusion complexes of 1,3-diphenylurea (DPU) with β-cyclodextrin (βCD) and 2-hydroxypropyl-β-cyclodextrin (HP-βCD) using a three-dimensional ground mixture (3DGM). Their physicochemical properties, intermolecular interactions, solubilities, and plant growth-promoting activities were investigated on broccoli sprouts. Phase-solubility diagrams indicated the stability constant (Ks) and complexation efficiency (CE) of βCD/DPU were found to be K1/1 = 250 M-1, CE = 2.48× 10-3. The Ks and CEs of HP-βCD/DPU were found to be K1/1 = 427 M-1, CE = 3.93 × 10-3 and K2/1 = 196 M-1, CE = 1.93 × 10-3 respectively. The powder X-ray diffraction results of 3DGM (βCD/DPU = 2/1, HP-βCD/DPU = 2/1) showed that the diffraction peaks originating from the DPU and βCD disappeared, indicating a halo pattern. Differential scanning calorimetry results showed an endothermic peak at 244 °C derived from the melting point of DPU, but the endothermic peak disappeared in the 3DGM (βCD/DPU = 2/1, HP-βCD/DPU = 2/1). Near-infrared absorption spectra showed peak shifts in 3DGM (βCD/DPU and HP-βCD/DPU) at the -CH and -NH groups of DPU and the -OH groups of βCDs and free water. In the dissolution test (after 5 min), the concentration of intact DPU was 0.083 μg/mL. However, the dissolution concentrations of DPU in the 3DGM (βCD/DPU = 1/1), 3DGM (βCD/DPU = 2/1), 3DGM (HP-βCD/DPU = 1/1), and 3DGM (HP-βCD/DPU = 2/1) were 3.27, 3.64, 5.70, and 7.03 μg/mL, respectively, indicating higher solubility than that of the intact DPU. Further, 1H-1H NOESY NMR spectroscopic measurements showed cross-peaks between H-A (7.32 ppm) and H-B (7.12 ppm) of DPU and H-6 (3.79 ppm) in the βCD cavity of the 3DGM (βCD/DPU = 2/1). A cross-peak was also observed among DPU H-A (7.32 ppm), H-B (7.11 ppm), and H-6 (3.78 ppm) in the βCD cavity. The results of the broccoli sprout cultivation experiment showed that 3DGM (βCD/DPU = 1/1), 3DGM (βCD/DPU = 2/1), 3DGM (HP-βCD/DPU = 1/1), and 3DGM (HP-βCD/DPU = 2/1) increased the stem thickness compared with that of the control group (DPU). These results indicated that the βCD/DPU and HP-βCD/DPU inclusion complexes were formed by the three-dimensional mixing and milling method, which enhanced the solubility and plant growth-promoting effects.

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

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