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.     

Synthesis of a hexacationic cyclophane and formation of EDA-type host–guest complexes

A polycationic cyclophane with six cationic sites (three 4,4′-bipyridinium cation units) supported by a rigid cyclic skeleton was synthesized. It formed electron donor–acceptor complexes with electron-rich compounds, and their inclusion properties with pyrene and calixresorcin[4]arene were studied.     

Host–guest interaction of hemicucurbiturils with phenazine hydrochloride salt

The host–guest interactions between phenazine hydrochloride salt (PheH⁺) and hemicucurbit[n]uril (n = 6 or 12) (HemiQ[6 or 12]) have been studied by ¹H NMR, UV–vis, IR, mass spectrometry (MS) and quantum chemistry. In ¹H NMR spectra, the broadening of proton resonances of the hosts suggests the interactions of PheH⁺ with HemiQs. The quantitative stabilities of the host–guest systems have been obtained by UV–vis titration experiments, that is, the stoichiometric interactions of PheH⁺ with HemiQ[6] have been observed with an association constant of K_a = (2.5 ± 1.2) × 10⁶ L mol^? 1, while the 2:1 ratio complexes of PheH⁺ with HemiQ[12] are formed with stepwise association constants of K₁ = (9.2 ± 2.8) × 10⁴ L mol^? 1 and K₂ = (6.4 ± 0.9) × 10⁵ L mol^? 1, respectively, which induce a total association constant of K_a = 5.9 × 10¹⁰ L² mol^? 2. Both the 1:1 and 2:1 complexes have been detected by MS. Quantum chemistry calculations have been used to understand the static structures and thermodynamic stabilities of the supramolecular assemblies.     

Host–guest interactions of a twisted cucurbit[15]uril with paraquat derivatives and bispyridinium salts

Host–guest complexations of a twisted cucurbit[15]uril with some paraquat derivatives and bispyridinium salts in aqueous solution are investigated by nuclear magnetic resonance, UV–vis spectrometry and isothermal titration calorimetry. These complexations are mainly enthalpy-driven.     

Host–guest complexation between 5-aminoisoquinoline and β-cyclodextrin and its effect on spectral and prototropic characteristics

The effects of the addition of β-cyclodextrin (β-CDx) on the absorption and emission properties of the 5-aminoisoquinoline (5AIQ) have been investigated in aqueous media. The formation of host–guest inclusion complex with 1:1 stoichiometry was revealed by absorption, steady state and time-resolved emission spectroscopy. The complex formation has also been confirmed by FT-IR spectra and SEM image analysis of the solid inclusion complex between 5AIQ and β-CDx. No significant change was observed in the ground and excited state pKa values in β-CDx medium. Based on photophysical and prototropic characteristics of 5AIQ in β-CDx, the structure of the 1:1 inclusion complex is proposed.     

Host–guest complexation of omeprazole, pantoprazole and rabeprazole sodium salts with cyclodextrins: an NMR study on solution structures and enantiodiscrimination power

The application of different cyclodextrins (CDs) as NMR chiral solvating agents (CSAs) for the sodium salts of the proton-pump inhibitors omeprazole, pantoprazole (sesquihydrate) and rabeprazole was investigated. It was proved that the formation of diastereomeric host–guest complexes in D₂O solution between the CDs and those substrates permitted the direct ¹H NMR discrimination of the enantiomers of the sodium salts of these compounds without the need of previous working-up. Rotating frame nuclear overhauser effect spectroscopy (ROESY) was used to ascertain the solution geometries of the host–guest complexes. The results suggested a preferential binding of the benzimidazole moiety of the guest molecules within the macrocyclic cavity of α-CD, whereas the higher dimensions of β- and γ-CD also permitted the inclusion of the highly substituted pyridine moieties. Moreover, the solution stoichiometries and the binding constants of the complexes formed with pantoprazole at room temperature were determined by ¹H and ¹⁹F NMR titration. Diffusion-filtered Spectroscopy was applied to obtain clean spectra without the interference of the HOD signal.     

Toward a light-harvesting Hyperbranched Polyesteramine Host–guest Complex

A novel hyperbranched polyesteramine (PEA) architecture 1 was found to display light-harvesting properties by hosting anthracene-9-carboxylic acid guest 3. The light-harvesting ability has been studied by means of fluorescence spectroscopy. The binding behaviour has also been described by FT-IR and ¹H NMR spectroscopic methods. Hyperbranched host 1 also acts as the photon-harvesting chemosensor of the anthracenyl guest over the benzoic acid guest. Furthermore, the host loaded with the anthracenyl guest also exhibited ‘ON–OFF’ switching on protonation of amine sub-units with HCl, thereby making it of potential use as a pH-assisted photon-harvesting material.     

Host–guest inclusion complex of β-cyclodextrin and benzoic acid in water–ethanol solvents: spectroscopic and thermodynamic characterization of complex formation

Journal of Thermal Analysis and Calorimetry - In this study, an inclusion complex of benzoic acid with β-cyclodextrin (BA-βCD) was obtained from water–ethanol solvents. The yield of...     

Physicochemical characterization and molecular modeling study of host–guest systems of aripiprazole and functionalized cyclodextrins

Journal of Thermal Analysis and Calorimetry - Aripiprazole (ARP), an innovative atypical antipsychotic drug, exhibits very low aqueous solubility, affecting its dissolution and absorption and high...     

Host–guest complexes of the antituberculosis drugs pyrazinamide and isoniazid with cucurbit[7]uril

The potential use of cucurbit[7]uril (CB[7]) as an excipient in oral formulations for improved drug physical stability or for improved drug delivery was examined with the antituberculosis drugs pyrazinamide (pyrazine-2-carboxamide) and isoniazid (isonicotinohydrazide). Both drugs form 1:1 host–guest complexes with CB[7] as determined by ¹H nuclear magnetic resonance spectrometry, electrospray ionisation mass spectrometry and molecular modelling. Drug binding is stabilised by hydrophobic effects between the pyridine and pyrazine rings of isoniazid and pyrazinamide, respectively, to the inside cavity of the CB[7] macrocycle as well as hydrogen bonds between the hydrazide and amide groups of each drug to the CB[7] carbonyl portals. At pH 1.5, isoniazid binds CB[7] with a binding constant of 5.6 × 10⁵ M^?1, whilst pyrazinamide binds CB[7] at pH 7 with a much smaller binding constant (4.8 × 10³ M^?1). Finally, CB[7] prevents drug melting through encapsulation. Where previously pyrazinamide displays a typical melting point of 189 °C and isoniazid 171 °C, by differential scanning calorimetry, no melting or degradation at temperatures up to 280 °C is observed for either drug once bound by CB[7].     

HPLC study of the host–guest complexation between fluorescent glutathione derivatives and β-cyclodextrin

RP-HPLC and the van’t Hoff law were used to study the association in which β-cyclodextrin forms inclusion complexes with aminothiol–phthaldialdehyde derivatives prepared from either glutathione (GSH) or γ-glutamylcysteine (γ-glucys) and either naphthalene-2,3-dicarboxaldehyde (NDA) or o-phthaldialdehyde (OPA). Elution was carried out at pH 8.5, the derivatization pH which gave the highest fluorescence signal during batch experiments. The variation of the retention factor (k) was monitored as a function of column temperature (10–35 °C) and β-cyclodextrin concentration (0–5 mM) in the mobile phase. Apparent binding constants, enthalpy and entropy were calculated from van’t Hoff plots for the complexation reaction. These data lay the groundwork for the improvement of high throughput GSH quantification methods using fluorimetry in biological and vegetal samples.     

Host–guest complexes of cucurbit[7]uril with albendazole in solid state

The inclusion complex of cucurbit[7]uril (CB7) and albendazole (ABZ) in solid state was prepared by freeze-drying. The formation of a host–guest complex was confirmed by microanalysis, ¹H-nuclear magnetic resonance spectroscopy, and fourier transformed-infrared spectroscopy (FT-IR) techniques. The shifts in the NMR peaks supported the encapsulation from the propylthio and not the carbamate site, in agreement with the previously reported results in solution. The N₂ adsorption–desorption isotherms indicated no change in the calculated surface area or the pore size distribution for the unbound and CB7-bound ABZ solid drugs. Freeze-drying produced a system with a higher degree of amorphisation as confirmed by the X-ray powder diffraction (XRD) technique. Thermal analysis of the drug-loaded CB7 by using differential scanning calorimetry and thermogravimetry demonstrated the possibility of dehydration at temperature 100 °C beyond the melting point of unbound ABZ since no melting of the samples was observed until the CB7 itself begins to decompose around 300 °C. Putting it all together, the results supported that CB7 imparts significant thermal/physical stability on the ABZ drug in the solid state.     

NMR Studies of Host–guest Complexes Between Monocarboxylic Acids and Amide-based Cyclophanes in Chloroform

Formation of host–guest complexes with acetic acid and benzoic acid was studied by NMR for amide-based octaazacyclophanes having pendant methyl ester arms; the cyclophanes were tetramethyl 2,9,18,25-tetraoxo-1,4,7,10,17,20,23,26-octaaza[10.10]paracyclophane-4,7,20,23-tetraacetate, its meta-isomer and analogues. Amide NH proton and CH₂ proton adjacent to amide C = O in every cyclophane host showed down-field NMR shifts in the presence of the guest acids in CHCl₃-d, suggesting the formation of 1:1 complexes in which the carboxyl group of an acid molecule formed two hydrogen bonds with the amide NH and C = O moieties of a host molecule. Since the complex formation competed with the dimerization of the guest acids, the monomer–dimer equilibrium was restudied by NMR and the equilibrium constant was determined to be 330 M^? 1 for acetic acid and 518 M^? 1 for benzoic acid. By using these values, the formation constants of the host–guest complexes were determined to be 8–51 M^? 1. The close contact between the host and guest molecules via hydrogen bonding was consistently confirmed by NMR shifts due to the ring current of aromatic group.     

Synthesis and host–guest complexation,photophysical and electrochemical studies on novel thiophenophanes

Synthesis of thiophene-based cyclophanes called thiophenophanes is described. The photophysical and electrochemical properties of thiophenophanes synthesised reveal that they show permanent fluorescence-sensing property, and the cyclic voltammogram reflects the ease with which the electron on the sulphur atom can be removed. Complexation studies of the thiophenophanes with TCNQ reveal the formation of 1:1 complex.     

Host–guest system of etodolac in native and modified β-cyclodextrins: preparation and physicochemical characterization

Etodolac, being a practically insoluble candidate, exhibits certain toxic effects and a limited bioavailability. Upon chronic use, it causes gastro-intestinal injury and increases the risk of ulcer complications. The approach of this study was to improve the physicochemical properties of the drug utilizing complexation phenomenon with β-, methyl-β- and hydroxypropyl-β-cyclodextrins, which may enhance the aqueous solubility and dissolution rate of etodolac, in an effort to increase oral bioavailability. In certain instances, this approach can be used to increase drug solubility, improve organoleptic properties and maximize the gastrointestinal tolerance by reducing drug irritation after oral administration. Differential UV measurements as well as continuous variation plots revealed the formation of equimolar complex with hydroxypropyl-β-cyclodextrin and 1:2 complexes with β-cyclodextrin and its methyl derivative. Differential scanning calorimetry (DSC), X-ray and FT-IR measurements were applied to prove inclusion complex formation and characterize the complexes. These results lend support to the idea that solubilization of etodolac is mainly related to inclusion complex formation and to a lesser extent to cyclodextrin aggregates. Understanding the factors that influence the performance of etodolac, will allow us to state that molecular encapsulation of the drug and other modifications with appropriate hydroxylation or methylation of parent β-cyclodextrin is able to overcome its problems and facilitate safe and efficient delivery of the drug.     

Host–guest complexes of various cucurbit[n]urils with the hydrochloride salt of 2,4-diaminoazobenzene

The interaction products of normal cucurbit[n]urils (n = 7, 8; Q[7] Q[8]) and a sym- tetramethyl-substituted cucurbit[6]uril derivative (TMeQ[6]) with the hydrochloride salts of 2,4-diaminoazobenzene (g·HCl) were investigated in aqueous solution using ¹H NMR spectroscopy, electronic absorption spectroscopy, as well as single crystal X-ray diffraction. The ¹H NMR spectra analysis established a basic interaction model in which inclusion complexes with a host:guest ratio of 1:1 form for the TMeQ[6] and Q[7] cases, while they form with a host:guest ratio of 1:2 for the Q[8] case. Commonly, the hosts selectively bound to the phenyl moieties of the guests. Absorption spectrophotometric analysis in aqueous solution defined the stability of the host–guest inclusion complexes at pH 3.2. Quantitatively, at this pH, complexes with a host:guest ratio of 1:1—those with smaller hosts TMeQ[6] and Q[7]—formed with logK values between 6 and 7. That with host Q[8] and a host:guest ratio of 1:2 formed with a logK value of 10.8. Single crystal X-ray structures of the inclusion complexes TMeQ[6]–g·HCl and Q[8]–g·HCl showed the phenyl moiety of the guest inserted into the host cavity. This result supports the solution-based ¹H NMR spectroscopic study.