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Cyclodextrins (CDs) are macrocycles that are well suited for forming inclusion complexes for surface-enhanced Raman scattering (SERS) detection of analytes due to their low Raman activity, which minimizes background SERS signals and enhances the detection of target molecules without interference. In this paper, we systematically investigated the synthesis of both silver (Ag) and gold (Au) nanoparticles (NPs) using CDs as reducing and capping agents in a basic environment using microwave (MW), ultrasound (US), and room temperature (RT) synthesis. We found that replacing NaOH with K2CO3 as an alkaline environment almost doubles the size (from 2CO3. All synthesized particles present SERS activity. CD capping allowed us to detect hydrophobic molecules like naphthalene and melamine. In the case of methylene blue, the CD capping prevents the changes induced in the SERS by a basic pH. We also demonstrate that the newly synthesized NPs can discriminate by SERS the propranolol enantiomers. Moreover, propranolol inclusion in CDs leads to a dramatic change in its SERS spectrum.

The study aimed to estimate the feasibility of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD) to encapsulate Mosla chinensis essential oil (EO) by ultrasonic-assisted method. The physical properties variations, stabilization mechanisms, and formation processes of the inclusion complexes (ICs) were investigated using experimental methods, molecular docking, and molecular dynamics (MD) simulation. Scanning electron microscopy, fourier transform infrared spectroscopy, thermogravimetric analysis, and gas chromatography–mass spectrometry showed that the ICs were successfully prepared, which differentially improved the thermal stability and retained the chemical composition of EO. The dissolution profile showed that the Peppas model can be used to describe the diffuse release mechanism of EO. Finally, molecular docking and MD simulation theoretically confirmed the interaction and conformational changes of carvacrol (the main active component of Mosla chinensis EO) inside the cavity of CDs. The results indicate that hydrogen bonding was the primary driving force for the carvacrol spontaneous access to the cavity. Further, a binding dynamic balance occurs between carvacrol and β-CD, whereas a bind and away dynamic balance occurs in the IC between carvacrol and α-CD, γ-CD. The comprehensive results show that the medium cavity size of β-CD is a suitable host molecule for Mosla chinensis EO of encapsulation, release, and stabilization. A combination of experimental and theoretical calculations is useful for the pinpoint targeted design and optimization of CD molecular encapsulation of small entity molecules. β-CD was rationally screened as a better candidate for stabilizing EO, which provides an option for a meaningful path to realistic EO applications.

Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/βCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/βCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/βCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice’s expression of stress-related inflammatory cytokines (IL-1β, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/βCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/βCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1β levels. The effects of the NEO/βCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.

There is an urgent need to develop safer and more effective modalities for the treatment of numerous pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Over the past decades, cyclodextrins (CDs) have gathered great attention as potential drug carriers due to their ability to enhance their bioactivities and properties. Likewise, selenium (Se) and tellurium (Te) have been extensively studied during the last decades due to their possible therapeutical applications. Although there is limited research on the relationship between Se and Te and CDs, herein, we highlight different representative examples of the advances related to this topic as well as give our view on the future directions of this emerging area of research. This review encompasses three different aspects of this relationship: (1) modification of the structure of the different CDs; (2) formation of host–guest interaction complexes of naïve CDs with Se and Te derivatives in order to overcome specific limitations of the latter; and (3) the use of CDs as catalysts to achieve novel Se and Te compounds.

α-CD:N2O “host-guest” type complexes were formed by a simple solid–gas reaction (N2O sorption into α-CD) under different gas pressures and temperatures. The new N2O inclusion method applied in the present study was compared with the already known technique based on the crystallization of clathrates from a water solution of α-CD saturated with N2O. A maximum storage capacity of 4.5 wt.% N2O was achieved when charging the cyclodextrin from a gas phase. The amount of included gas decreases to 1.3 wt.% when the complex is stored in air at 1 atm and room temperature, analogous to that achieved by the crystallization of α-CD:N2O. Furthermore, it was shown that the external coordination of N2O to either the upper or lower rim of α-CD without hydration water displacement is the preferred mode of binding, due to hydrogen bonds with neighboring -OH groups from the host macrocycle and three of the hydration water molecules nearby. The capacity of α-CD to store N2O and the thermal stability of the α-CD:N2O complex demonstrated promising applications of these types of complexes in food and beverages.

This paper presents the theoretical calculations of the inclusion complex formation between native ceftobiprole, a promising antibiotic from the cephalosporin group, and selected cyclodextrins (CDs) approved by the European Medicines Agency. Ceftobiprole was studied in three protonation states predicted from pKa calculations, along with three selected CDs in a stoichiometric ratio of 1:1. It was introduced into the CD cavity in two opposite directions, resulting in 18 possible combinations. Docking studies determined the initial structures of the complexes, which then served as starting structures for molecular dynamics simulations. The analysis of the obtained trajectories included the spatial arrangement of ceftobiprole and CD, the hydrogen bonds forming between them, and the Gibbs free energy (ΔG) of the complex formation, which was calculated using the Generalised Born Surface Area (GBSA) equation. Among them, a complex of sulfobutyl ether- (SBE-) β-CD with protonated ceftobiprole turned out to be the most stable (ΔG = −12.62 kcal/mol = −52.80 kJ/mol). Then, experimental studies showed changes in the physiochemical properties of the ceftobiprole in the presence of the CDs, thus confirming the validity of the theoretical results. High-performance liquid chromatography analysis showed that the addition of 10 mM SBE-β-CD to a 1 mg/mL solution of ceftobiprole in 0.1 M of HCl increased the solubility 1.5-fold and decreased the degradation rate constant 2.5-fold.

Density functional theory (DFT) calculations based on the BLYP-D4 and PBEh-3c composite methods were performed for investigating the encapsulation mode of pentachlorophenol (PCP) inside the cavity of β-cyclodextrin (β-CD). Different quantum chemical parameters such as HOMO, LUMO, and HOMO–LUMO gap were calculated. Complexation energies were computed at the molecular level to provide insight into the inclusion of PCP inside the β-CD cavity. The Independent gradient model (IGM) approach was applied to characterize the non-covalent interactions that occurred during the complex (PCP@β-CD) formation. Two modes of inclusion were considered in this work (modes A and B). Calculated complexation energies as well as the changes in enthalpy, entropy, and free Gibbs energy exhibit negative values for both modes A and B, indicating a thermodynamically favorable process. Weak Van der Waals interactions and one strong intermolecular hydrogen bond act as the main driving forces behind the stabilization of the formed most stable complex. This study was carried out to explore the potential use of the β-CD as a host macrocycle for sensing and capturing pentachlorophenol.

Furfuryl mercaptan has the aroma characteristics of coffee. However, it is unstable during storage of coffee brew and roasted coffee. In order to enhance the stability of furfuryl mercaptan, furfuryl mercaptan-β-cyclodextrin inclusion complex was synthesized using the precipitation method in this work. Fourier transform infrared spectroscopy, x-ray diffraction, and thermogravimetric analysis (TG) were used to characterize the resulting products. The interaction of furfuryl mercaptan with β-cyclodextrin was investigated by the molecular mechanics (MM) method. These changes in FTIR and XRD gave supporting evidence for the successful formation of furfuryl mercaptan-β-cyclodextrin inclusion complex. The TG results showed that the formation of furfuryl mercaptan-β-cyclodextrin inclusion complex could improve the thermal stability of furfuryl mercaptan and provide a long-lasting effect. The structure of furfuryl mercaptan-β-cyclodextrin inclusion complex with the minimum energy was obtained by MM2 calculation, and the minimum binding energy was –77.0 kJ mol−1 at –1.96 × 10–10 m.

Fucoxanthin (Fx) possesses multiple bioactivities such as antitumor, antioxidant and anti-inflammatory activities, but its application is limited due to the poor water solubility, low bioavailability, and instability to some external harsh conditions. In this study, a stable inclusion complex of Fx and 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) was prepared with the aid of ultrasound, which was characterized by scanning electron microscope, Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry techniques. The phase solubility analysis and absorption spectroscopy results showed that Fx formed stoichiometry 1:2 inclusion complex with 2-HP-β-CD, and this could be well proved by molecular simulation. Structural analyses and molecular docking study indicated that Fx was successfully encapsulated into the cavity of 2-HP-β-CD, promoting it soluble in water and stable against heat, storage and gastrointestinal environments. In addition, Fx/2-HP-β-CD inclusion complex exhibited excellent antitumor activity against HCT116 and Caco-2 cell lines with IC50 values of 12.0 μΜ and 14.86 μΜ, respectively. Therefore, it could be a potentially promising way to promote the application of Fx in pharmaceuticals and functional foods by HP-β-CD encapsulation strategy.

The paper describes the use of native β-cyclodextrin (CD) for the modification of silver nanoparticles (AgNPs) in order to improve the determination of the anticancer drug methotrexate (MTX) using surface-enhanced Raman spectroscopy (SERS). A control experiment with unmodified AgNPs showed that the strong SERS signal of MTX can only be achieved in alkaline media. However, competitive interactions and the strong background signal of human body fluid components significantly challenge MTX determination in real samples. While previous reports propose the use of thorough sample pretreatment (e.g., solid phase extraction), the application of CD-modified AgNPs increases the SERS signal of MTX in neutral media by seven times which enables simplifying the analysis and improving its accuracy by reducing the influence of endogenous components of body fluids. A detailed study of the synthesis conditions (CD concentration and reaction time) and SERS registration conditions (pH, NaCl concentration, dilution of urine samples) was performed to maximize the analytical signal and signal-to-noise ratio. The final assay was tested for MTX determination in artificially spiked samples of real human urine. The results demonstrated that MTX can be determined within the concentration range suitable for therapeutic drug monitoring (20–300 μg mL−1) with satisfactory precision (6–15% RSD), accuracy (95–111% apparent recovery), and limit of detection (0.3 μg mL−1).

This review focuses on the methods of preparation and biological, physiochemical, and theoretical analysis of the inclusion complexes formed between estrogens and cyclodextrins (CDs). Because estrogens have a low polarity, they can interact with some cyclodextrins’ hydrophobic cavities to create inclusion complexes, if their geometric properties are compatible. For the last forty years, estrogen-CD complexes have been widely applied in several fields for various objectives. For example, CDs have been used as estrogen solubilizers and absorption boosters in pharmaceutical formulations, as well as in chromatographic and electrophoretic procedures for their separation and quantification. Other applications include the removal of the endocrine disruptors from environmental materials, the preparation of the samples for mass spectrometric analysis, or solid-phase extractions based on complex formation with CDs. The aim of this review is to gather the most important outcomes from the works related to this topic, presenting the results of synthesis, in silico, in vitro, and in vivo analysis.

This study aimed to evaluate and compare the efficacy of cyclodextrans (CIs) and cyclodextrins (CDs) in improving the water solubility of a poorly water-soluble drug, clofazimine (CFZ). Among the evaluated CIs and CDs, CI-9 exhibited the highest percentage of drug inclusion and the highest solubility. Additionally, CI-9 showed the highest encapsulation efficiency, with a CFZ:CI-9 molar ratio of 0.2:1. SEM analysis indicated successful formation of inclusion complexes CFZ/CI and CFZ/CD, accounting for the rapid dissolution rate of the inclusion complex. Moreover, CFZ in CFZ/CI-9 demonstrated the highest drug release ratio, reaching up to 97%. CFZ/CI complexes were found to be an effective means of protecting the activity of CFZ against various environmental stresses, particularly UV irradiation, compared to free CFZ and CFZ/CD complexes. Overall, the findings provide valuable insights into designing novel drug delivery systems based on the inclusion complexes of CIs and CDs. However, further studies are needed to investigate the effects of these factors on the release properties and pharmacokinetics of encapsulated drugs in vivo, in order to ensure the safety and efficacy of these inclusion complexes. In conclusion, CI-9 is a promising candidate for drug delivery systems, and CFZ/CI complexes could be a potential formulation strategy for the development of stable and effective drug products.

Isoliquiritigenin (ISL) possesses a wide variety of pharmacological properties, however, its poor solubility and oral bioavailability pose a significant barrier to its application. In present studies, the ISL inclusion complex was prepared with sulfobutyl ether-β-cyclodextrin (SBE-β-CD). The physicochemical characterizations of ISL-SBE-β-CD were performed with Fourier transform infrared (FT-IR) spectroscopy and X-ray powder diffraction (XRD). Phase solubility study suggested a 1:1 formation of ISL-SBE-β-CD complexes. The water solubility of ISL rose from 13.6 μM to 4.05 mM by the inclusion of SBE-β-CD. The antioxidant activities (IC50) of ISL-SBE-β-CD reached 42.2 μg/ml, which was significantly lower than that of ISL (60.5 μg/ml). Its stability in biological environments was also enhanced.

α-tocopherol is the physiologically most active form of vitamin E, with numerous biological activities, such as significant antioxidant activity, anticancer capabilities, and anti-aging properties. However, its low water solubility has limited its potential use in the food, cosmetic, and pharmaceutical industries. One possible strategy for addressing this issue is the use of a supramolecular complex with large-ring cyclodextrins (LR-CDs). In this study, the phase solubility of the CD26/α-tocopherol complex was investigated to assess the possible ratios between host and guest in the solution phase. Next, the host–guest association of the CD26/α-tocopherol complex at different ratios of 1:2, 1:4, 1:6, 2:1, 4:1, and 6:1 was studied by all-atom molecular dynamics (MD) simulations. At 1:2 ratio, two α-tocopherol units interact spontaneously with CD26, forming an inclusion complex, as supported by the experimental data. In the 2:1 ratio, a single α-tocopherol unit was encapsulated by two CD26 molecules. In comparison, increasing the number of α-tocopherol or CD26 molecules above two led to self-aggregation and consequently limited the solubility of α-tocopherol. The computational and experimental results indicate that a 1:2 ratio could be the most suitable stoichiometry to use in the CD26/α-tocopherol complex to improve α-tocopherol solubility and stability in inclusion complex formation.

Melphalan (Mel) is an antineoplastic widely used in cancer and other diseases. Its low solubility, rapid hydrolysis, and non-specificity limit its therapeutic performance. To overcome these disadvantages, Mel was included in β-cyclodextrin (βCD), which is a macromolecule that increases its aqueous solubility and stability, among other properties. Additionally, the βCD–Mel complex has been used as a substrate to deposit silver nanoparticles (AgNPs) through magnetron sputtering, forming the βCD–Mel–AgNPs crystalline system. Different techniques showed that the complex (stoichiometric ratio 1:1) has a loading capacity of 27%, an association constant of 625 M−1, and a degree of solubilization of 0.034. Added to this, Mel is partially included, exposing the NH2 and COOH groups that stabilize AgNPs in the solid state, with an average size of 15 ± 3 nm. Its dissolution results in a colloidal solution of AgNPs covered by multiple layers of the βCD–Mel complex, with a hydrodynamic diameter of 116 nm, a PDI of 0.4, and a surface charge of 19 mV. The in vitro permeability assays show that the effective permeability of Mel increased using βCD and AgNPs. This novel nanosystem based on βCD and AgNPs is a promising candidate as a Mel nanocarrier for cancer therapy.

American trypanosomiasis or Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and is considered a neglected disease, being an important problem for public health. Benznidazole (BZN) is the drug used to treat the disease. However, it has limited efficacy and adverse side effects. Therefore, the development of new therapeutic alternatives is necessary. In this work, the trypanocidal activity and cytotoxicity of a series of catechol-containing 3-arylcoumarins, their combination with BZN, and the inclusion in β-cyclodextrins (β-CDs), were evaluated. The results obtained showed that the entire series has moderate trypanocidal activity on the trypomastigote form of the parasite, being the 3-(4′-bromophenyl)-6,7-dihydroxycoumarin (8) the most active compound (IC50 = 34 μM) and the most cytotoxic in Vero cells (IC50 = 162 μM) as well. By forming the inclusion complex 8-β-CDs, the trypanocidal activity and cytotoxicity decreased. In addition, the formation of inclusion complexes increased the solubility. The possible mechanism of action of 8 was evaluated and proved to be through the generation of oxidative stress. The combination with BZN presented a synergistic effect on the trypanocidal activity, reducing the necessary dose of BZN. The presence of a catechol in the studied scaffold seems to modulate the trypanocidal activity, and the combination of drugs proved to be a promising alternative strategy for treating the disease.

Solid-phase extraction that utilizes selective macrocyclic receptors can serve as a useful tool for removal of chemical wastes. Hemicucurbiturils are known to form inclusion complexes with suitably sized anions; however, their use in selective binding of non-charged species is still very limited. In this study, we found that cyclohexanohemicucurbit[8]uril encapsulates five- and six-membered sulfur- and oxygen-containing unsubstituted heterocycles, which is investigated by single-crystal X-ray diffraction, NMR spectroscopy, isothermal titration calorimetry, and thermogravimetry. The macrocycle acts as a promising selective sorption material for the extraction of sulfur heterocycles, such as 1,3-dithiolane and α-lipoic acid, from water.

Cannabidiol (CBD) is one specific kind of the cannabinoid in Cannabis sativa L with a wide range of pharmacological activities. However, the poor water solubility and specificity of CBD limits its application in pharmaceutical field. For solving these problems, in this work, we successfully prepared a targeted carrier by grafting biotin (BIO) onto ethylenediamine-β-Cyclodextrin (EN-CD) in a single step to generate a functionalized supramolecule, named BIO-CD. Subsequently, an amantadine-conjugated cannabinoids (AD-CBD) was prepared and self-assembled with the BIO-CD. A series of methods were used to characterize the inclusion behavior and physicochemical properties of AD-CBD and BIO-CD. The results showed that AD-CBD entered the cavity of BIO-CD and formed a 1:1 host-guest inclusion complex. MTT assay and confocal laser scanning microscopy (CLSM) revealed that the targeting effect and anticancer activity of AD-CBD/BIO-CD inclusion complex against three human cancer cell lines were higher than BIO-CD, AD-CBD and free CBD. Moreover, the inclusion complex could release drugs under weakly acidic conditions. These results demonstrated that AD-CBD/BIO-CD inclusion complex possess excellent targeted and anticancer activity, which is hopeful to be applied in clinic as a new therapeutic approach.

An inclusion complex of praziquantel with 2-hydroxypropyl-β-cyclodextrin was designed and prepared by an optimized method and the inclusion complex was characterized by infrared absorption spectral, proton NMR spectral and scanning electron image studies. It was shown that the aqueous solubility of praziquantel has increased (~104 fold) in comparison with praziquantel alone, which is the best result so far for praziquantel solubility study. The in vivo pharmacokinetic properties of praziquantel in dogs such as Cmax, Tmax, AUC0-∞, and t1/2 have been improved significantly after complexation. The increased water solubility of the praziquantel in the complex resulted in the improved values of Cmax (4.82 μg/mL vs 0.51 μg/mL, 9.45 fold higher) and AUC0-∞ (98.06 μg h/mL vs 20.63 μg h/mL, 4.75 fold higher) in dog pharmacokinetic studies, which is useful to find a new praziquantel formulation as an anti-schistosomal agent.

Curcumin (CUR), a curcuminoid originating from turmeric root, possesses diverse pharmacological applications, including potent anticancer properties. However, the use of this efficacious agent in cancer therapy has been limited due to low water solubility and poor bioavailability. To overcome these problems, a drug delivery system was established as an excipient allowing improved dispersion in aqueous media coupled with enhanced in vitro anticancer effects. Different analyses such as UV–vis spectroscopy, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), solubility and dissolution assays were determined to monitor the successful encapsulation of CUR within the inner cavity of a β-cyclodextrin (β-CD) complex. The results indicated that water solubility was improved by 205.75-fold compared to pure CUR. Based on cytotoxicity data obtained from MTT assays, the inclusion complex exhibited a greater decrease in cancer cell viability compared to pure CUR. Moreover, cancer cell migration rates were decreased by 75.5% and 38.92%, invasion rates were decreased by 37.7% and 35.7%, while apoptosis rates were increased by 26.3% and 14.2%, and both caused caspase 3 activation toward colorectal cancer cells (SW480 and HCT116 cells). This efficacious formulation that enables improved aqueous dispersion is potentially useful and can be extended for various chemotherapeutic applications. Preliminary toxicity evaluation also indicated that its composition can be safely used in humans for cancer therapy.

This study concentrated on developing quercetin/cyclodextrin inclusion complex-loaded polyvinyl alcohol (PVA) hydrogel for enhanced stability and solubility. Quercetin was encapsulated in hydroxypropyl-β-cyclodextrin (HP-β-CD) by the solvent evaporation method. The prepared quercetin/HP-β-CD inclusion complex showed 90.50 ± 1.84% encapsulation efficiency (%EE) and 4.67 ± 0.13% loading capacity (%LC), and its successful encapsulation was confirmed by FT-IR and XRD. The quercetin/HP-β-CD inclusion complex was well dispersed in viscous solutions of PVA in various amounts (0.5, 1.0, 1.5. 2.5, and 5.0% w/v ratio), and the drug-loaded polymer solution was physically crosslinked by multiple freeze–thaw cycles to form the hydrogel. The cumulative amount of quercetin released from the prepared hydrogels increased with increasing concentrations of the inclusion complex. The introduction of the inclusion complex into the PVA hydrogels had no influence on their swelling ratio, but gelation and compressive strength reduced with increasing inclusion complex concentration. The potential cytotoxicity of quercetin/HP-β-CD inclusion complex hydrogels was evaluated by MTT assay and expressed as % cell viability. The results show biocompatibility toward NCTC 929 clone cells. The inhibitory efficacy was evaluated with 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay, and the results show a higher level of antioxidant activity for quercetin/HP-β-CD inclusion complex hydrogels compared with free quercetin. The findings of our study indicate that the developed quercetin/HP-β-CD inclusion complex hydrogels possess the required properties and can be proposed as a quercetin delivery system for wound-healing applications.

Aurisin A (AA), an aristolane dimer sesquiterpene isolated from the luminescent mushroom Neonothopanus nambi, exhibits various biological and pharmacological effects. However, its poor solubility limits its use for further medicinal applications. This study aimed to improve the water solubility of AA via complexation with β-cyclodextrin (βCD) and its derivatives (2,6-di-O-methyl-βCD (DMβCD) and 2-hydroxypropyl-βCD (HPβCD). A phase solubility analysis demonstrated that the solubility of AA linearly enhanced with increasing concentrations of βCDs (ranked in the order of AA/DMβCD > AA/HPβCD > AA/βCD). Notably, βCDs, especially DMβCD, increased the thermal stability of the inclusion complexes. The thermodynamic study indicated that the complexation between AA and βCD(s) was a spontaneous endothermic reaction, and AA/DMβCD possesses the highest binding strength. The complex formation between AA and DMβCD was confirmed by means of FT-IR, DSC, and SEM. Molecular dynamics simulations revealed that the stability and compactness of the AA/DMβCD complex were higher than those of the DMβCD alone. The encapsulation of AA led to increased intramolecular H-bond formations on the wider rim of DMβCD, enhancing the complex stability. The antiproliferative activity of AA against A549 and H1975 lung cancer cells was significantly improved by complexation with DMβCD. Altogether, the satisfactory water solubility, high thermal stability, and enhanced antitumor potential of the AA/DMβCD inclusion complex would be useful for its application as healthcare products or herbal medicines.

Cyclodextrins (CDs) and their derivatives have good prospects in soil remediation application due to their ability to enhance the stability and solubility of low water-soluble compounds by inclusion performance. To investigate the effect of different structural properties of cyclodextrin and its derivatives on the inclusion complexation, molecular dynamic (MD) simulations were performed on the inclusion complexes formed by three kinds of CDs with polycyclic aromatic hydrocarbons (PAHs). Based on neutral β-CD, the other two CDs were modified by introducing substitutional groups, including 2-hydroxypropyl and sulfonated butyl (SBE) functional groups in the ring structure, called HP-CD and SBE-CD. MD results show that PAH can merely enter into the cavity of SBE–β-CD from its wide rim. The substitutional groups significantly affect the structure of CDs, which may also cause the flipping of the glucose units. However, the substitutional groups can also enlarge the volume of the hydrophobic cavity, resulting in a tight combination with the guest molecules.

Anthocyanidins, the aglycons of anthocyanins, are known, beyond their function in plants, also as compounds with a wide range of biological and pharmacological activities, including cytostatic effect against various cancer cells. The nature and position of the substituents in the flavylium cation is essential for such biological properties, as well as the equilibrium between the multistate of the different chemical species that are generated by the flavylium cation, including quinoidal base, hemiketal, and cis- and trans-chalcones. In this work, eight new flavylium derivatives were synthesized, characterized for confirmation of the structure by FT-IR and 2D-NMR, and investigated in vitro as possible cytostatic compounds against HCT116 and HepG2 cancer cells. The most active two compounds were explored for their halochromic properties that can influence the biological activity and subjected to molecular encapsulation in β-cyclodextrin derivatives in order to increase their solubility in water and bioavailability. The anticancer effect was influenced by the position (6-, 7-, or 8-) of the methoxy group in the β-ring of the methoxy-4′-hydroxy-3′-methoxyflavylium cation, while the study of the halochromic properties revealed the important role played by the chalcone species of the pH-dependent multistate in both the uncomplexed and inclusion complex forms of these anthocyanidins.

Sulfur mustard (SM) is a harmful warfare agent that poses a serious threat to human health and the environment. Thus, the design of porous materials capable of sensing and/or capturing SM is of utmost importance. In this paper, the interactions of SM and its derivatives with ethylpillar[5]arene (EtP[5]) and the interactions between SM and a variety of host macrocycles were investigated through molecular docking calculations and non-covalent interaction (NCI) analysis. The electronic quantum parameters were computed to assess the chemical sensing properties of the studied hosts toward SM. It was found that dispersion interactions contributed significantly to the overall complexation energy, leading to the stabilization of the investigated systems. DFT energy computations showed that SM was more efficiently complexed with DCMP[5] than the other hosts studied here. Furthermore, the studied macrocyclic containers could be used as host-based chemical sensors or receptors for SM. These findings could motivate experimenters to design efficient sensing and capturing materials for the detection of SM and its derivatives.

(1) Background: When the body is exposed to microwave radiation, the brain is more susceptible to damage than other organs. However, few effective drugs are available for the treatment of microwave-induced brain injury (MIBI) because most drugs are difficult to cross the blood–brain barrier (BBB) to reach the brain. (2) Methods: Nasal cinnarizine inclusion complexes with thermo-and ion-sensitive hydrogels (cinnarizine ISGs) were prepared to treat MIBI and the characteristics of the inclusion complexes and their thermo-and ion-sensitive hydrogels were evaluated. (3) Results: Due to high viscosity, cinnarizine ISGs can achieve long-term retention in the nasal cavity to achieve a sustained release effect. Compared with the model, the intranasal thermo-and ion-sensitive cinnarizine ISGs significantly improved the microwave-induced spatial memory and spontaneous exploration behavior with Morris water maze and open field tests. Cinnarizine ISGs inhibited the expression of calcineurin and calpain 1 in the brain, which may be related to the inhibition of calcium overload by cinnarizine. (4) Conclusion: Intranasal thermo- and ion-sensitive cinnarizine ISGs are a promising brain-targeted pharmaceutical preparation against MIBI.

The complexes formed by β-cyclodextrin and some amino acids (alanine, valine, leucine, and isoleucine) in vacuo are studied by molecular mechanics and dynamics simulations. These methods have been improved with respect to our previous studies with amino acids, regarding the determination of molecular structures or initial enantiomer dispositions in the molecular dynamics trajectories. The greatest contribution to the interaction energy is from the van der Waals term, although the discrimination between enantiomers is due mainly to the electrostatic contribution. The lowest energy structures of the complexes obtained from molecular mechanics are inclusion complexes in which the carboxylic end of amino acids is pointing toward the narrow (D-) or wide rim (L-) of β-cyclodextrin. The position probability density provided by molecular dynamics also confirms inclusion complex formation, because the guests spend most time inside the cavity of β-cyclodextrin along its axis, with the carboxylic end pointing toward the narrow rim. The L-amino acids are the first eluted enantiomers in all cases and chiral discrimination increases with the size of guests, except leucine, which has the lowest capacity to discriminate. During the simulation, Ala and Val remain in weakly enantioselective regions, while Leu and Ile stay in zones with great chiral selectivity.

Abstract Background Flunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state. Results The structural assignments of FLN and β-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, β-CD and their mixtures confirmed the formation of β-CD-FLN inclusion complex in solution. 1H NMR titration data for β-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of K a = 157 M−1 and change in Gibbs free energy of ∆G = − 12.65 kJ mol−1. The binding constant of the β-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the β-CD cavity. The possible geometrical structures of the β-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the β-CD truncated cone. Conclusion NMR spectroscopic studies of FLN, β-CD and FLN:β-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into β-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of β-CD. The splitting of aromatic signals of FLN in the presence of β-CD suggests chiral differentiation of the guest FLN by β-CD.

The interactions of two conformers of newly synthesized photoswitchable azobenzene analogue of methotrexate, called Phototrexate, with two cavitand derivatives, have been investigated in dimethyl sulfoxide medium. Photoluminescence methods have been applied to determine the complex stabilities and the related enthalpy and entropy changes associated to the complex formation around room temperature. Results show opposite temperature dependence of complex stabilities. The structure of the upper rims of the host molecules and the reordered solvent structure were identified as the background of the opposite tendencies of temperature dependence at molecular level. These results can support the therapeutic application of the photoswitchable phototrexate, because the formation of inclusion complexes is a promising method to regulate the pharmacokinetics of drug molecules.

The nature and mechanisms of interaction between two selected methyl benzoate derivatives (methyl o-methoxy p-methylaminobenzoate–I and methyl o-hydroxy p-methylaminobenzoate–II) and model transport protein bovine serum albumin (BSA) was studied using steady-state and time-resolved spectroscopic techniques. In order to understand the role of Trp residue of BSA in the I-BSA and II-BSA interaction, the effect of free Trp amino acid on the both emission modes (LE–locally excited (I and II) and ESIPT–excited state intramolecular proton transfer (II)) was investigated as well. Experimental results show that the investigated interactions (with both BSA and Trp) are mostly conditioned by the ground and excited state complex formation processes. Both molecules form stable complexes with BSA and Trp (with 1:1 stoichiometry) in the ground and excited states. The binding constants were in the order of 104 M−1. The absorption- and fluorescence-titration experiments along with the time-resolved fluorescence measurements show that the binding of the I and II causes fluorescence quenching of BSA through the static mechanism, revealing a 1:1 interaction. The magnitude and the sign of the thermodynamic parameters, ΔH, ΔS, and ΔG, determined from van’t Hoff relationship, confirm the predominance of the hydrogen-bonding interactions for the binding phenomenon. To improve and complete knowledge of methyl benzoate derivative-protein interactions in relation to supramolecular solvation dynamics, the time-dependent fluorescence Stokes’ shifts, represented by the normalized spectral response function c(t), was studied. Our studies reveal that the solvation dynamics that occurs in subpicosecond time scale in neat solvents of different polarities is slowed down significantly when the organic molecule is transferred to BSA cavity.

Ionic liquids (ILs) are promising electrolyte materials for developing next-generation rechargeable batteries. In order to improve their properties, several kinds of additives have been investigated. In this study, β-cyclodextrin (β-CD) was chosen as a new additive in IL electrolytes because it can form an inclusion complex with bis(trifluoromethylsulfonyl)amide (TFSA) anions. We prepared the composites by mixing N-methyl-N-propylpyrrolidinium bis(trifluoromethylsulfonyl)amide/LiTFSA and a given amount of triacetyl-β-cyclodextrin (Acβ-CD). The thermal behaviors and electrochemical properties of the composites were analyzed by several techniques. In addition, pulse field gradient NMR measurements were conducted to determine the self-diffusion coefficients of the component ions. The addition of Acβ-CD to the IL electrolytes results in the decrease in the conductivity value and the increase in the viscosity value. In contrast, the addition of Acβ-CD to the IL electrolytes induced an improvement in the anodic stability because of the formation of an inclusion complex between the Acβ-CD and TFSA anions. CDs are potential candidates as additives in IL electrolytes for electrochemical applications.

l-menthol has been widely used in flavour, food and pharmaceuticals. Because of its high volatility and whisker growth, l-menthol-hydroxypropyl-β-cyclodextrin inclusion complex was produced to improve shelf-life, provide protection, and enhance the stability of l-menthol. The inclusion complex was characterized by Fourier transform infrared spectroscopy, X-ray diffraction. The results show that l-menthol was successfully encapsulated in hydroxypropyl-β-cyclodextrin. l-menthol loading capacity is about 8.44%. Geometries and binding energies of l-menthol-hydroxypropyl-β-cyclodextrin inclusion complexes were investigated using molecular mechanics calculations. The shape and orientation of the most stable complex, and the minimum binding energy were determined. L-menthol release from complex was determined by thermogravimetric analysis. Two l-menthol release rate peaks were observed at 69.3 and 279.1°C. The l-menthol release reaction order, release activation energy and the preexponential factor were obtained.

Formation of inclusion complexes involving a cavitand derivative (as host) and an antimetabolite drug, methotrexate (as guest) was investigated by photoluminescence measurements in dimethyl sulfoxide solvent. Molecular modeling performed in gas phase reflects that, due to the structural reasons, the cavitand can include the methotrexate in two forms: either by its opened structure with free androsta-4-en-3-one-17α-ethinyl arms or by the closed form when all the androsta-4-en-3-one-17α-ethinyl arms play role in the complex formation. Experiments reflect enthalpy driven complex formation in higher temperature range while at lower temperature the complexes are stabilized by the entropy gain.

Ascorbic acid (AA) is a general antioxidant used in aqueous pharmaceutical formulations. However, in aqueous solutions, AA is unstable and easily oxidized when exposed to air, light and/or heat. Cyclodextrins are well known for their ability to form inclusion complexes with various compounds to improve their solubility and stability. Previous studies demonstrate that cyclodextrins preserve the antioxidant capacity of AA but data for γ-cyclodextrin (γCD) have not been reported. Poly(vinyl alcohol) (PVA) is a hydrophilic polymer widely used as a drug matrix in various pharmaceutical fields, but its application for drug stabilization is limited. This study aimed to investigate the protective ability of γCD on AA through the formation of ternary complexes with PVA. Binary (i.e., AA/γCD, AA/PVA and γCD/PVA) and ternary (i.e., AA/γCD/PVA) complexes were first confirmed. It was reported that those complexes were formed through interactions between the heterocyclic ring of AA, hydroxyl group of PVA and hydrophobic cavity of γCD. The hydrodynamic diameter of complexes was then studied. It was found that the diameter of γCD/PVA complexes increased with respect to the concentration of γCD. Higher γCD concentrations also resulted in increasing hydrodynamic diameters of the ternary complex. The presence of AA in ternary complexes interfered with the aggregation tendency of γCD/PVA binary complexes. Furthermore, the antioxidant capacity of AA in binary and ternary complexes was investigated. It was found that the presence of γCD preserved the antioxidant activity of AA, whereas PVA showed a contrasting effect. The influence of γCD and PVA concentration on antioxidant capacity was then studied through central composite design (CCD). Even though the concentration of γCD significantly affected the inhibition efficiency of the ternary complex, the insignificant influence of PVA could not be ignored. A promising protective ternary complex should consist of an optimized concentration of PVA and a high concentration of γCD.

Isoliquiritigenin (ILTG) possesses many pharmacological properties. However, its poor solubility and stability in water hinders its wide applications. The solubility of bioactive compounds can often be enhanced through preparation and delivery of various cyclodextrin (CD) inclusion complexes. The 6-O-α-D-maltosyl-β-CD (G2-β-CD), as one of the newest developments of CDs, has high aqueous solubility and low toxicity, especially stable inclusion characteristics with bioactive compounds. In this work, we for the first time construct and characterize the supermolecular structure of ILTG/G2-β-CD by scanning electron microscopy (SEM), ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffractometry (XRD). The solubility of ILTG in water at 25 °C rises from 0.003 to 0.717 mg/mL by the encapsulation with G2-β-CD. Our experimental observations on the presence of the ILTG/G2-β-CD inclusion complex are further supported by the ONIOM(our Own N-layer Integrated Orbital molecular Mechanics)-based QM/MM (Quantum Mechanics/Molecular Mechanics) calculations, typically substantiating these supermolecular characteristics, such as detailed structural assignments, preferred binding orientations, selectivity, solvent effects, interaction energies and forces of the ILTG/G2-β-CD inclusion complex. Our results have elucidated how ILTG interacts with G2-β-CD, demonstrating the primary host-guest interactions between ILTG and G2-β-CD, characterized by hydrogen bonds, hydrophobic interactions, electrostatic forces, and conformational effects, are favored for the formation of the ILTG/G2-β-CD inclusion.

R-α-lipoic acid (RLA) is an endogenous organic acid, and works as a cofactor for mitochondrial enzymes and as a kind of antioxidant. Inclusion complexes of RLA with α-, β- or γ-cyclodextrins (CD) were prepared and orally administered as a suspension to rats. Among them, RLA/γ-CD showed the highest plasma exposure, and its area under the plasma concentration-time curve (AUC) of RLA was 2.2 times higher than that after oral administration of non-inclusion RLA. On the other hand, the AUC after oral administration of non-inclusion RLA and RLA/γ-CD to pylorus-ligated rats did not differ. However, the AUC after intraduodenal administration of RLA/γ-CD was 5.1 times higher than that of non-inclusion RLA, and was almost comparable to the AUC after intraduodenal administration of RLA-Na solution. Furthermore, the AUC after intraduodenal administration of RLA/γ-CD was not affected by biliary ligation or co-administration of an amylase inhibitor. These findings demonstrated that RLA was absorbed from the small intestine effectively when orally administered as a γ-CD inclusion complex, which could be easily dissolved in the lumen of the intestine. In conclusion, γ-CD inclusion complex is an appropriate formulation for supplying RLA as a drug or nutritional supplement with respect to absorption.

Pipemidic acid (HPPA) is a quinolone antibacterial agent used mostly to treat gram-negative infections of the urinary tract, but its therapeutic use is limited because of its low solubility. Thus, to improve drug solubility, natural cyclodextrins (CDs) are used for their ability of including guest molecules within their cavities. The aim of this work was to evaluate the antibacterial activity and the preliminary anticancer activity of HPPA included into Heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB) as a possible approach for a new innovative formulation. The inclusion complex of HPPA with TRIMEB was prepared in solid state by the kneading method and confirmed by FT-IR and powered X-ray diffraction. The association in aqueous solutions of pipemidic acid with TRIMEB was investigated by UV-Vis spectroscopy. Job’s plots have been drawn by UV-visible spectroscopy to confirm the 1:1 stoichiometry of the host–guest assembly. The antibacterial activity of HPPA, TRIMEB and of their complex was tested on Escherichia coli, Pseudomonas aeruginosa, and Staphilococcus aureus. The complex was able to increase 47.36% of the median antibacterial activity of the free HPPA against E. coli (IC50 = 249 µM vs. 473 µM). Furthermore, these samples were tested on HepG-2 and MCF-7. After 72 h, the median tumoral cytotoxicity exerted by the complex was increased by 78.08% and 94.27% for HepG-2 and MCF-7 respectively, showing a stronger bioactivity of the complex than the single HAPPA.

A well-designed and synthesized water-soluble class of β-cyclodextrin supported palladium complex PdLn@Et-β-CD could efficiently validate high catalytic activity and act as a supramolecular platform for phosphine-free Suzuki–Miyaura cross‐coupling reactions between arylboronic acid/ arylboronic ester and aryl halides in water under mild conditions. The presented novel PdLn@Pr-β-CD complex catalyst was characterized by NMR, XRD, FT-IR, and DSC analysis. Furthermore, the role of the PdLn@Et-β-CD fragment in the reaction mechanism studied by molecular complexation was proposed based on FT-IR, 2D NMR (ROESY) spectroscopy, FE-SEM, and DSC spectroscopic analysis. The important benefits of this technique comprise simple phosphine-free preparation of the palladium catalyst, a wide range of functional-group tolerance, and easy recyclability; this method, furthermore, eschews hazardous reagents or solvents.

The aptitude of cyclodextrins (CDs) to form host-guest complexes has prompted an increase in the development of new drug formulations. In this study, the inclusion complexes of pipemidic acid (HPPA), a therapeutic agent for urinary tract infections, with native β-CD were prepared in solid state by kneading method and confirmed by FT-IR and 1H NMR. The inclusion complex formation was also characterized in aqueous solution at different pH via UV-Vis titration and phase solubility studies obtaining the stability constant. The 1:1 stoichiometry was established by a Job plot and the inclusion mechanism was clarified using docking experiments. Finally, the antibacterial activity of HPPA and its inclusion complex was tested on P. aeruginosa, E. coli and S. aureus to determine the respective EC50s and EC90s. The results showed that the antibacterial activity of HPPA:β-CD against E. coli and S. aureus is higher than that of HPPA. Furthermore, HPPA and HPPA:β-CD, tested on human hepatoblastoma HepG2 and MCF-7 cell lines by MTT assay, exhibited, for the first time, antitumor activities, and the complex revealed a higher activity than that of HPPA. The use of β-CD allows an increase in the aqueous solubility of the drug, its bioavailability and then its bioactivity.

In the present paper, the effect of β-cyclodextrin (β-CD) inclusion complexation on the solubility and enzymatic hydrolysis of naringin was investigated. The inclusion complex of naringin/β-CD at the molar ratio of 1:1 was obtained by the dropping method and was characterized by differential scanning calorimetry. The solubility of naringin complexes in water at 37 ± 0.1 °C was 15 times greater than that of free naringin. Snailase-involved hydrolysis conditions were tested for the bioconversion of naringin into naringenin using the univariate experimental design. Naringin can be transformed into naringenin by snailase-involved hydrolysis. The optimum conditions for enzymatic hydrolysis were determined as follows: pH 5.0, temperature 37 °C, ratio of snailase/substrate 0.8, substrate concentration 20 mg·mL−1, and reaction time 12 h. Under the optimum conditions, the transforming rate of naringenin from naringin for inclusion complexes and free naringin was 98.7% and 56.2% respectively, suggesting that β-CD complexation can improve the aqueous solubility and consequently the enzymatic hydrolysis rate of naringin.