Formulation and characterization of amiodarone-methyl-beta-cyclodextrin inclusion complexes: A molecular modelling perspective.

This study aimed to develop immediate-release tablets containing amiodarone hydrochloride (AM). AM is a BCS class II compound, i.e., high permeable, and poorly soluble. The interactions between amiodarone and methyl-ß-cyclodextrin were DFT-based, theoretically measured, supporting the complexation of AM with cyclodextrin by using methyl-ß-cyclodextrin through a spray-drying process. Thus, increasing substantially the drug solubility to 93.31% and 87.14%, respectively. Solubility studies demonstrated the formation of the Drug-Methyl-ß-cyclodextrin inclusion complex with 1:1 stoichiometry. The complex formation was characterized by SBET, XRD, DSC, SEM, FTIR, and 1H NMR. Complementing, immediate-release tablets containing the inclusion complex were developed by direct compression, and in vitro dissolution studies were performed in gastrointestinal fluids using USP Pharmacopeia standard dissolution rate testing equipment. The dissolution rate of immediate-release tablets was substantially higher than the pristine drug in all mediums evaluated. These results confirm the application of methyl-ß-cyclodextrin as an effective excipient for incorporation in novel dosage forms to increase the solubility of poorly soluble drugs.

Applications of Convertible Isonitriles in the Ligation and Macrocyclization of Multicomponent Reaction-Derived Peptides and Depsipeptides.

Peptide ligation and macrocyclization are among the most relevant approaches in the field of peptide chemistry. Whereas a variety of strategies relying on coupling reagents and native chemical ligation are available, there is a continuous need for efficient peptide ligation and cyclization methods. Herein we report on the utilization of convertible isonitriles as effective synthetic tools for the ligation and macrocyclization of peptides arising from isocyanide-based multicomponent reactions. The strategy relies on the use of convertible isonitriles-derived from Fukuyama amines-and peptide carboxylic acids in Ugi and Passerini reactions to afford N-alkylated peptides and depsipeptides, respectively, followed by conversion of the C-terminal amide onto either N-peptidoacyl indoles or pyrroles. Such activated peptides proved efficient in the ligation to peptidic, lipidic and fluorescently labeled amines and in macrocyclization protocols. As a result, a wide set of N-substituted peptides (with methyl, glycosyl and amino acids as N-substituents), cyclic N-methylated peptides and a depsipeptide were produced in good yields using conditions that involve either classical heating or microwave irradiation. This report improves the repertoire of peptide covalent modification methods by exploiting the synthetic potential of multicomponent reactions and convertible isonitriles.

Protective effect of meloxicam-loaded nanocapsules against amyloid-ß peptide-induced damage in mice.

The objective of present study was to investigate the protective effect of M-NC against aß (25-35) peptide-induced damage in mice, as the first step to evaluate their potential value for the treatment of AD. Moreover, we compared the effects of M-NC with free meloxicam (M-F). Mice were divided into six groups: (I) sham, (II) aß, (III) M-NC, (IV) M-F, (V) M-NC+aß and (VI) M-F+aß. Mice were pre-treated with M-NC (5mg/kg, by gavage), M-F (5mg/kg, by gavage) or blank nanocapsules (B-NC). Thirty minutes after treatments, aß peptide (3nmol) or filtered water were i.c.v. injected. Learning and memory were assessed with the Morris water maze (MWM) (days 4-7) and step-down-type passive-avoidance (SDPA) (days 7-8) tasks. At the end of the experimental protocol (day 8), animals were euthanized and brains were removed for biochemical determinations (reactive species (RS), non-protein thiols (NPSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST)) and histological examination. Our results confirmed that aß peptide caused learning and memory deficits in mice. Histological analysis demonstrated neuronal loss, intense cellular accumulation and chromatolysis caused by aß peptide. Furthermore, this study showed that oxidative stress was increased in mice that received aß peptide. An important finding of the present study was the protective effect of M-NC in damage induced by aß peptide. However, M-F did not have protective effect. In summary, the data reported herein clearly demonstrate that meloxicam carried by polymeric nanocapsules protected against learning and memory impairments, loss neuronal and oxidative stress in a mouse model of AD induced by aß peptide.

New development of synthesis and reactivity of seleno- and tellurophenes.

Due to the many new and remarkable findings and applications that have been published in recent years in seleno- and tellurophene chemistry, this review revisits the different aspects of this chemistry, including synthesis, reactivity and applications in the field of heterocycles.

Rapid access to N-substituted diketopiperazines by one-pot Ugi-4CR/deprotection+activation/cyclization (UDAC).

The most efficient diversity generating approaches to heterocycles are combinations of a multicomponent (MCR) with a cyclization reaction, for example, by Ugi-deprotection-cylization (UDC) protocols. If the desired post-Ugi reaction requires more than one deprotection, for example of two initially protected Ugi-reactive groups, or if it requires additional activation, for example, by an Ugi-activation-cyclization (UAC), either the isolation of intermediates or a sequential process or both become necessary. A recently introduced convertible isonitrile reagent allows a mild and chemoselective in situ post-Ugi activation of the isonitrile-born carboxylate with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation. This is exemplified by the synthesis of peptide-peptoid diketopiperazines.