Spectroscopic study and antioxidant activity of the inclusion complexes of cyclodextrins and amlodipine besylate drug

The aim of the study was to synthesize and characterization the inclusion complexes of amlodipine besylate (AML) drug with β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) which has antioxidating activity property. The guest/host interaction of AML with β-CD and γ-CD in order to complexation drug in β-CD and γ-CD were investigated. The interaction inclusion complexes was characterized by fourier transform infrared and ultraviolet–visible spectroscopies. The formation constant was calculated by using a modified Benesi–Hildebrand equation at 25 °C. The stoichiometry of inclusion complexes was found to be 1:1 for β-CD and γ-CD with AML drug. The antioxidant activity of AML drug and its inclusion complexes were determined by the scavenging of stable radical 2,2′-diphenyl-1-picrylhydrazyl (DPPH^·). Kinetic studies of DPPH^· with AML and CDs complexes were done. The experimental results confirmed the forming of AML complexes with CDs also these indicated that the AML/β-CD and AML/γ-CD inclusion complexes was the most reactive than its free form into antioxidant activity.     

Studies on α-, β-, and γ-cyclodextrin inclusion complexes of isoquinoline alkaloids berberine, palmatine and coralyne

The complexation of three isoquinoline alkaloids berberine, palmatine and coralyne with α-, β-, and γ-CDs were studied by absorption, fluorescence, circular dichroism, NMR spectroscopy and microcalorimetric assay techniques. Their binding constant (K _BH) values were determined by Benesi–Hildebrand equation. All the alkaloids formed 1:1 stoichiometry complexes with the cyclodextrins (CDs). The binding affinity is largest in β-CD followed by γ-, and α-CD for coralyne, followed by berberine and then palmatine. The thermodynamic parameters of the complexation were determined by calorimetry. The stoichiometry of complex formation and the variation of the apparent binding constant from spectroscopic studies were confirmed by calorimetry. The formation of the inclusion complexes was entropy driven in almost all the systems. Coralyne formed the strongest complex with all the CDs, followed by berberine and palmatine in that order. Coralyne-β-CD complex was studied through NMR, indicating more than one interaction mode.     

Supramolecular Interaction of Primaquine with Native β-Cyclodextrin

The supramolecular host–guest inclusion complex of Primaquine (PQ) with the nano-hydrophobic cavity of beta-cyclodextrin (β-CD) was prepared by physical mixing, kneading and co-precipitation methods. The formation of an inclusion complex in PQ with β-CD in the solution phase has been confirmed by UV–visible and fluorescence spectroscopy. The stoichiometry of the inclusion complex is 1:1; the Primaquine molecule is deeply entrapped in the cavity of β-cyclodextrin, which was confirmed by analysis of spectral shifts and corresponding absorbance and fluorescence intensities. The Benesi–Hildebrand plot was used to calculate the binding constant of the inclusion complex of PQ with β-CD at room temperature. The Gibbs energy change of the inclusion complex process has been calculated. The \( {\text{p}}K_{\text{a}} \) and \( {\text{p}}K_{\text{a}}^{*} \) for the monocation and neutral equilibrium of PQ in aqueous and β-CD media are discussed. The thermal stability for the inclusion complex of PQ with β-CD has been analyzed using differential scanning calorimetry. The modification of the crystal structure to amorphous for the solid inclusion complex was confirmed by powder X-ray diffraction. The structure of the complex is proposed by docking studies using the Patch-Dock server. A cytotoxic analysis was also carried out for the pure PQ and its solid complex on the MDA MB 231 cell line and showed that the activity is good for both substances. The cytotoxicity neither improved nor decreased with the formation of the inclusion complex with β-CD.     

Determination of the structure of quinolone-γ-cyclodextrin complexes and their binding constants by means of UV–Vis and <Superscript>1</Superscript>H NMR

The host–guest inclusion complex structure and binding ability of two different quinolones with γ-cyclodextrin (γ-CD) were investigated in solution by means of UV–Vis and ¹H NMR spectroscopy. Competition of oxolinic and nalidixic acid molecules for the γ-CD cavity was evaluated by determination of association constants. Both quinolones form 1:1 inclusion complexes, their binding constants at room temperature (25 °C) under acidic and basic conditions were calculated using Benesi–Hildebrand equation. The stability of the complexes was dependent on the structure of the quinolone. In general, the weaker binding constants were observed for oxolinic acid-γ-CD complexes (1616 and 1765 M^?1) and the larger binding constants were obtained for nalidixic acid-γ-CD complexes (3760 and 3840 M^?1). ¹H NMR studies in D₂O were performed to elucidate the structure of each inclusion complex, nalidixic acid molecule penetrates more deeply into the γ-CD cavity and an intermolecular hydrogen bond is formed. Knowledge about structure and relative stability of quinolone-γ-CD complexes will be useful for future applications of these antimicrobial agents in medicinal chemistry.     

Microenvironmental effects of cyclodextrins I: Enhancement of intramolecular excimer formation of polymethylene-bisβ-naphthoate via inclusion with cyclodextrins

The effects of α-, β- and γ-cyclodextrins (CDs) on the fluorescence spectra of a series of polymethylene-bis-β-naphthoates (Bn) have been studied. It is observed that β-CD and γ-CD enhance Bn intramolecular excimer fluorescence, indicating the formation of two-to-one guest host inclusion complexes. The possible conformation of these inclusion complexes is discussed.     

Formation of nanotubes and secondary assemblies of cyclodextrins induced by BBOT

The study of cyclodextrin nanotubes is a significant topic among the self-assembly behaviors of cyclodextrins. We report herein the interaction of 2,5-bis(5′-tert-butyl-2-benzoxazoyl)thiophene (BBOT) with α-, β-, γ-cyclodextrins (CDs). It has been discovered that the reaction patterns of BBOT with CDs are remarkably different. β-CD forms a simple inclusion complex with BBOT in a stoichiometry of 1:2 (guest:host). β-CD forms a 1:1 inclusion complex with BBOT at its low concentration. At higher concentration of BBOT, the nanotube and secondary assembly of β-CD are formed. As for γ-CD, the nanotube and secondary assembly are formed within the whole concentration range of BBOT studied. The structure of γ-CD nanotubes is different from that of β-CD nanotubes to a certain extent.

     

Spectroscopic characterisation of the inclusion complexes between the antifungal drugs naftifine and terbinafine and cyclodextrins

The complexation of naftifine (NF) and terbinafine (TB) with cyclodextrins (CDs) has been investigated by UV/visible and ¹H NMR spectroscopy, ROESY techniques and also ESI-MS. Both drugs form 1:1 inclusion complexes with all the CDs tested except with α-CD, as deduced from the Benesi–Hildebrand plots and confirmed by ESI-MS and NMR spectroscopy (Job plot method). The K ₁₁ values for NF decrease in the order β-CD > methylated β-CD > 2-hydroxypropyl-β-CD >γ-CD. The determination of the enthalpy and entropy provides information about the main driving forces in the process. The stability constants of the complexes NF–β-CD, TB–β-CD and TB–γ-CD determined by ¹H NMR spectroscopy are in agreement with the values obtained by UV. For TB–β-CD, the value is higher, due to the fact that the length of the TB aliphatic chain allows a deeper inclusion of the naphthalene group inside the corresponding β-CD molecule, according to the 2D ROESY experiments.     

Host–guest association of Morin with β-CD and C-hexylpyrogallol[4]arene: Structure of the complexes and the effect of pH

The study of the host–guest association of Morin hydrate (MO) with β-cyclodextrin (β-CD) and C-hexylpyrogllol[4]arene (C-HPA) is reported in this paper. The iInclusion complexation of MO is studied by ultraviolet-visible, steady-state fluorescence, time-resolved fluorescence, ¹H nuclear magnetic resonance (NMR), and two dimentional rotating-frame nuclear overhauser effect correlation (2D ROESY) spectroscopic techniques. The stoichiometry and the binding constant for the MO–β-CD complex are derived from the linearity of the Benesi–Hildebrand equation. The binding constant for the MO–C-HPA complex is calculated from the nonlinear curve fitting of fluorescence intensities. The effects of the acid strength on the absorption and fluorescence spectra of MO are studied in the absence and the presence of β-CD/C-HPA host molecules. The pK _a values of the ground and the excited states are reported.     

Effect of pH and α-, β- and γ-cyclodextrin on the spectral properties of etoricoxib: spectroscopic and molecular dynamics study

The spectral properties of etoricoxib (ETR) at pH 2.0, 6.0 and 10.0 in the presence of cyclodextrins (CDs) were investigated. The absorption spectrum of ETR in acidic medium exhibited two bands centered at 236 and 273 nm, while in basic medium it exhibited two bands centered at 236 and 285 nm. No change in the spectrum was observed in the presence of CDs. The fluorescence emission spectra of ETR in acidic and basic media exhibited one band at 380 nm and another one at 484 nm. The emission band at 484 nm was enhanced when ETR was complexed with β-CD and γ-CD at pH 2.0, 6.0 and 10.0, while the band at 380 nm was enhanced selectively when ETR was complexed with α-CD at pH 2.0. Molecular dynamics simulations computations revealed that at pH 2.0, the sulfonyl moiety of H₂ETR²⁺ is preferentially included within the α-CD cavity, which is believed to cause the enhancement of the band at 380 nm. Moreover, at pH 6.0 and 10.0, the enhancement of the band at 484 nm was related to the inclusion of the chloropyridinyl and methylpyridinyl groups of the bipyridine moiety of HETR⁺ and ETR within β-CD and γ-CD cavities. Benesi–Hildebrand analysis showed that the ETR/β-CD complex adopts a 1:1 stoichiometry with association constant of K ₁₁?=?64.8 at pH 2.0, K ₁₁?=?105.4 at pH 6.0 and K ₁₁?=?520.5 at pH 10.0.     

Spectral modulation of charge transfer fluorescence probe encapsulated inside aqueous and non-aqueous β-cyclodextrin nanocavities

In this work, we report the spectral modulations of a intramolecular charge transfer (ICT) molecule ethyl ester of N,N-dimethylaminonaphthyl-(acrylic)-acid (EDMANA) when encapsulated in the water and N,N-dimethylformamide (DMF) solution of β-CD nanocavities. From the nature of the Benesi-Hildebrand (B-H) plots, the stoichiometry of the host guest inclusion complexes are found to be 1:1 in water β-CD solution and both 1:1 and 1:2 in DMF β-CD solution. The preferential location and difference in orientation of EDMANA molecule inside the β-CD cavity has been accessed by analysis of the effect of acid and metal cation Ni²⁺ on the spectral characteristics in both the media. In case of 1:1 complex, the polar donor group prefers to expose to bulk aqueous phase capable of binding with H⁺ and Ni²⁺ ions and the acceptor to the hydrophobic interior. On the other hand, the acceptor group remains exposed to the non-polar bulk phase and the donor group is orientated preferentially inside the non-polar core in 1:2 inclusion complexes.     

Diarylethylene guest anchored into a cyclodextrin molecular host: optical,quantum chemical studies and biological activity

The host–guest complexation between a novel guest namely; 2-(4-pyridinylbenzothiazolyl) ethane, PBE and β-cyclodextrin was studied using steady-state absorption and emission techniques. The fluorescence maximum is strongly blue-shifted with a great enhancement in the fluorescence intensity upon addition of β-CD, confirming the formation of inclusion complexes. The solid inclusion complex between PBE and β-CD has been prepared, characterised using FT-IR, X-ray diffraction and scanning electron microscope techniques. PBE is encapsulated with β-CD nanocavity and 1:1 PBE–β-CD host–guest interaction is identified. This is confirmed using semi-empirical quantum chemical calculations. PBE guest entered into the less polar cavity through the benzothiazole moiety. The negative values of enthalpy and free energy changes suggest that the encapsulation process is thermodynamically favourable. Additionally, the fluorescence is more sensitive to the micellar medium, whether it was cationic, anionic or neutral as well as metal ions like, Li⁺, Cu²⁺ and Fe³⁺. Finally, the antimicrobial activities of PBE guest and its inclusion complex with β-CD host are studied.     

Investigation of the complexation of essential oil components with cyclodextrins

The formation of inclusion complexes of six essential oil (EO) components (β-caryophyllene, cis-ocimene, trans-ocimene, sabinene hydrate (thujanol), γ-terpinene and α-terpineol) with six cyclodextrins (CDs) (α-CD, β-CD, γ-CD, HP-β-CD, RAMEB and CRYSMEB) was investigated by using static headspace-gas chromatography and UV–visible spectroscopy. Retention studies showed that CDs could efficiently reduce the volatility of EO components except for β-caryophyllene with α-CD. In this case, no inclusion complex was detected while for other compounds the formation of 1:1 inclusion complexes was observed. Results revealed that the inclusion stability mainly depends on geometric complementarity between encapsulated molecule and CD's cavity. Molecular modelling was used to investigate the complementarities between host and guest. Thus, CDs could efficiently be regarded as promising encapsulants for EO components leading to improve their application in cosmetic, pharmaceutical and agriculture fields.     

Investigation of the inclusion of the herbicide cycluron in native cyclodextrins by X-ray diffraction,nuclear magnetic resonance spectroscopy and isothermal titration calorimetry

The formation of inclusion complexes between the native cyclodextrins (CDs) and the urea herbicide cycluron has been investigated both in solution and in the solid state. Single-crystal X-ray structures of both the uncomplexed guest and the β-CD·cycluron complex were determined while powder X-ray diffraction was used to confirm complexation between γ-CD and cycluron in the solid state. Solution-state complexation between the herbicide and α-, β- and γ-CD was established using ¹H NMR spectroscopy and isothermal titration calorimetry (ITC). From the ¹H NMR spectroscopic studies 1:1 complex stoichiometry was indicated in all cases and association constant values (K) were determined as 228, 3254 and 155 for the complexes α-CD·cycluron, β-CD·cycluron and γ-CD·cycluron, respectively. Assigning a 1:1 host–guest ratio, the ITC technique produced K values of the same order as those determined using the spectroscopic method. The thermodynamic parameters ΔH, ΔS and ΔG obtained using ITC provide insights into the driving forces involved during complex formation.     

Spectral study on the inclusion complex of cryptophane-E and CHCl3

Cryptophane-E was synthesized from vanillin by a three-step method, and its absorption and fluorescence spectroscopic properties were determined. Two absorption bands at about 245–260 and 280–290 nm were observed for cryptophane-E and the fluorescence emission maxima were at 320–330 nm depending on the solvent used. The interaction of cryptophane-E with CHCl₃ was studied in detail by absorption and fluorescence spectroscopies. The results showed that cryptophane-E and CHCl₃ can easily form a stable 1:1 host–guest inclusion complex. Their binding constant (K) was determined by Benesi–Hildebrand equation and the nonlinear least squares fit method. The binding constant is largest in ethyl acetate, followed by dioxane and with acetonitrile as the smallest. In addition, the effect of guest volume on the host–guest inclusion complex was investigated. Guest molecules including CH₂Cl₂ and CCl₄ were unable to form inclusion complex with cryptophane-E because of sizes mismatching with the host cavity.     

Host–guest complexation of a nitroheterocyclic compound with cyclodextrins: a spectrofluorimetric and molecular modeling study

Nitroheterocyclic compounds (NC) were candidate drugs proposed for Chagas disease chemotherapy. In this study, we investigated the complexation of hydroxymethylnitrofurazone (NFOH), a potential antichagasic compound, with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), Hydroxypropyl-β-cyclodextrin (HP-β-CD), Dimethyl-β-cyclodextrin (DM-β-CD) and γ-cyclodextrin (γ-CD) by fluorescence spectroscopy and molecular modeling studies. Hildebrand–Benesi equation was used to calculate the formation constants of NFOH with cyclodextrins based on the fluorescence differences in the CDs solution. The complexing capacity of NFOH with different CDs was compared through the results of association constant according to the following order: DM-β-CD > β-CD > α-CD > HP-β-CD > γ-CD. Molecular modeling studies give support for the experimental assignments, in favor of the formation of an inclusion complex between cyclodextrins with NFOH. This is an important study to investigate the effects of different kinds of cyclodextrins on the inclusion complex formation with NFOH and to better characterize a potential formulations to be used as therapeutic options for the oral treatment of Chagas disease.     

Enantioseparation of 1-(p-bromophenyl)ethanol by crystallization of host–guest complexes with permethylated β-cyclodextrin: crystal structures and mechanisms of chiral recognition

It is shown that racemic 1-(p-bromophenyl)ethanol (p-Br-PE) can be quantitatively resolved by successive recrystallizations of (1:1) supramolecular complexes formed with permethylated β-cyclodextrin (TMβ-CD). The two enantiomerically pure complexes were characterized by physical methods and their crystal structures were determined. The comparison of both inclusion geometries and packing modes in these structures revealed distinct structural features allowing the enantioseparation of the guest to be understood. Chiral discrimination mechanisms are discussed in terms of the capability of TMβ-CD to induce the formation of stereospecific host–guest complexes by simple crystallization in aqueous medium.     

Chiral discrimination of ethyl and phenyl N-benzyloxycarbonylaminophosphonates by cyclodextrins

Enantiodifferentiation of N-protected ethyl and phenyl α-aminophosphonates with application of commercially available cyclodextrins as chiral solvating agent was studied by means of nuclear magnetic resonance spectroscopy. Four cyclodextrins (α-CD, β-CD, γ-CD and HP-γ-CD) were chosen due to the differences in the size of their inner cavities and substitution of the rim, which in turn might change the affinity of the compounds analyzed to these chiral selectors. The influence of solution pD and host concentration on the enantiodiscrimination efficiency was also studied. As a result, a methodology for the simple and rapid assessment of the enantiomeric composition of various N-benzyloxycarbonyl-α-aminophosphonates has been elaborated upon. 2D Rotating frame nuclear Overhauser and exchange spectrometry experiments and continuous variation methods were applied for establishing the molecular recognition mechanism and structure of the guest–host assemblies.     

Complexation of N-methyl-4-(p-methyl benzoyl)-pyridinium methyl cation and its neutral analogue by cucurbit[7]uril and β-cyclodextrin: a computational study

In this work, molecular dynamics (MD) simulations have been conducted to study the inclusion complexes between cucurbit[7]uril (CB7) and β-cyclodextrin (β-CD) with N-methyl-4-(p-methyl benzoyl)-pyridinium methyl cation, and N-methyl-4-(p-methyl benzoyl)-pyridine in aqueous solutions to gain detailed information about the dynamics and mechanism of the inclusion complexes. The obtained MD trajectories were used to estimate the binding free energy of the studied complexes using the molecular mechanics/Poisson Bolzmann surface area (MM–PBSA) method. Results indicate preference of CB7 to bind to the cationic guest more than the neutral guest, whereas β-CD exhibits more or less the same affinity to complex with either species. Furthermore it was interesting to note that β-CD forms more stable complexes with both guests than CB7. Average structure of each complex and the distances between the center of masses of the guest and the host were also discussed.     

Inclusion complexes of cyclodextrins with 4-amino-1,8-naphthalimides (part 2)

Fluorescence spectroscopy was used to characterize inclusion compounds between 4-amino-1,8-naphthalimides (ANI) derivatives and different cyclodextrins (CDs). The ANI derivatives employed were N-(12-aminododecyl)-4-amino-1,8-naphthalimide (mono-C₁₂ANI) and N,N′-(1,12-dodecanediyl)bis-4-amino-1,8-naphthalimide (bis-C₁₂ANI). The CDs used here were α-CD, β-CD, γ-CD, HP-α-CD, HP-β-CD and HP-γ-CD. The presence of CDs resulted in pronounced blue-shifts in the emission spectra of the ANI derivatives, with increases in emission intensity. This behavior was parallel to that observed for the dyes in apolar solvents, indicating that inclusion complexes were formed between the ANI and the CDs. Mono-C₁₂ANI formed inclusion complexes of 1:1 stoichiometry with all the CDs studied. Complexes with the larger CDs (HP-β-CD, HP-γ-CD and γ-CD) were formed by inclusion of the chromophoric ANI ring system, whereas the smaller CDs (α-CD, HP-α-CD and β-CD) formed complexes with mono-C₁₂ANI by inclusion of the dodecyl chain. Bis-C₁₂ANI formed inclusion complexes of 1:2 stoichiometry with HP-β-CD, HP-γ-CD and γ-CD, but did not form inclusion complexes with α-CD, HP-α-CD and β-CD. The data were treated in the case of the large CDs using a Benesi-Hildebrand like equation, giving the following equilibrium constants: mono-C₁₂ANI:HP-β-CD (K ₁₁ = 50 M^?1), mono-C₁₂ANI:HP-γ-CD (K ₁₁ = 180 M^?1), bis-C₁₂ANI:HP-β-CD (K ₁₂ = 146 M^?2), bis-C₁₂ANI:HP-γ-CD (K ₁₂ = 280 M^?2).     

Inclusion complexes between cyclic siloxanes and cyclodextrins: synthesis and characterization

Molecular inclusion complexes between cyclodextrins and cyclic siloxanes were prepared and characterized via a combination of liquid and solid state NMR, FT-IR, TGA, powder X-ray diffraction, SEM–EDS and elemental analyses. The crystalline complexes adopted the channel-type conformation. Depending from the size of both the cyclic sugar cavity and the silicon guest, various yields (between 0 and 41%) and host–guest molar ratios (between 1:1 and 4:1) were obtained. α-cyclodextrin (α-CD) and β-cyclodextrin (β-CD) were observed to form crystalline inclusion complexes only with D₃ (cyclic dimethyltrisiloxane) due to steric effects, whereas the larger γ-cyclodextrin (γ-CD) formed inclusion complexes both with D₃, D₄ (cyclic dimethyltetrasiloxane) and D₅ (cyclic dimethylpentasiloxane). This study is believed to be the first step towards the selective removal of cyclic siloxanes impurities from commercial PDMS preparations.