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Two mixed-valence cobalt complexes, [CoIICoIII2(mpm)6](ClO4)2 (1) and [CoII2CoIII2(μ3-OMe)2(μ-mpm)4(NO3)4] (2), where mpm is the deprotonated form of R or S α-methyl-2-pyridinemethanol, have been structurally and magnetically characterized. Both complexes crystallize in chiral space groups, where 1 is a trinuclear compound with a linear Co(III)–Co(II)–Co(III) topology and 2 is a tetranuclear cluster with a defect dicubane-type structure that has two missing vertices. In both cases the mpm− ligand bridges adjacent Co ions in a η1:η2:μ manner. The molecular geometries of the complexes reveal the Co ions are octahedral, where the greatest deviation from Oh symmetry is apparent for the HS d7 Co(II) ions. The chirality of 1 and 2 were studied by circular dichroism spectroscopy where opposite Cotton effects are observed for the R- and S-enantiomers of both complexes. Magnetic susceptibility studies reveal the presence of largely quenched first order orbital angular momentum together with weak ion or intermolecular dipole exchange.

Treating Alzheimer's disease (AD) is a major challenge at the moment with no new drugs available to cure this devastating neurodegenerative disorder. In this regard, drug repurposing, which aims to determine novel therapeutic usage for drugs already approved by the regulatory agencies, is a pragmatic approach to discover novel treatment strategies. Selective serotonin reuptake inhibitors (SSRIs) are a known class of United States Food and Drug Administration approved drugs used in the treatment of depression. We investigated the ability of SSRIs fluvoxamine, fluoxetine, paroxetine, sertraline, and escitalopram on Aβ42 aggregation and fibrillogenesis. Remarkably, the aggregation kinetic experiments carried out demonstrate the anti-Aβ42 aggregation activity of SSRIs fluoxetine, paroxetine, and sertraline at all the tested concentrations (1, 10, 50, and 100 μM). Both fluoxetine and paroxetine were identified as the most promising SSRIs, showing 74.8 and 76% inhibition of Aβ42 aggregation at 100 μM. The transmission electron microscopy experiments and dot-blot study also demonstrate the ability of fluoxetine and paroxetine to prevent Aβ42 aggregation and fibrillogenesis, providing further evidence. Investigating the binding interactions of fluoxetine and paroxetine in the Aβ42 oligomer and fibril models derived from the solid-state NMR structure suggests that these SSRIs interact at a region close to the N-terminal (Lys16-Glu22) in the S-shaped cross-β-strand assembly and reduce Aβ42 fibrillogenesis. On the basis of this study, a pharmacophore model is proposed which shows that the minimum structural requirements to design novel Aβ42 aggregation inhibitors include the presence of one ionizable group, one hydrophobic group, two aromatic rings, and two hydrogen bond donor groups. These studies demonstrate that SSRIs have the potential to prevent Aβ42 aggregation by direct binding and could be beneficial to AD patients on SSRIs.

This chapter provides a summary on the recent progress in discovering small molecule therapies aimed at Alzheimer’s disease (AD). In particular, the focus is on hybrid small molecules that exhibit multifunctional properties. A summary on the design, synthetic methods utilized, in vitro and in vivo assays used, and activity data of small molecules based on diverse core templates such as quinones, selenazolones, stilbenes, hydroxyanthraquinones, indoles, coumarins, phenothiazines, phenoselenazines, pyrimidinylthioureas, quinazolines, pyrido[3,2-d]pyrimidines, thiazoles, pyridothiazoles, benzyloxyphenylpiperazines, and quinolone-indoles is described. Due to a string of recent clinical trial failures in search of anti-AD drugs, the tide is slowly shifting toward developing multifunctional small molecules as anti-AD agents. From a regulatory perspective, developing multitarget-directed ligands for treating AD would significantly increase the cost and duration in drug discovery and market launch. However, the progress to date on this front holds tremendous promise and hope to find a cure for AD.

Homometallic {NiII4} cubane-like clusters with a rare chiral core have been prepared via the employment of enantiomerically pure 2-(1-hydroxyethyl)pyridine (Hmpm). Comparison with the achiral cubanes derived from the related 2-pyridinemethanol (Hpym) ligand reveals drastic structural changes as a consequence of the transfer of chirality from the ligands to the whole structure. Their magnetic properties have been related to the structural features of their cubane-type cores.

Purpose The availability of take home naloxone (THN) was increased for Canadians in 2016, including access to kits via pharmacies. Unlike typical over-the-counter (OTC) and prescription drugs, THN kits may be stored in non-standard conditions, including in vehicles, backpacks, and out of doors. To evaluate whether these non-standard storage conditions affect stability, we investigated the impact of heat and freeze-thaw cycling on naloxone hydrochloride stability. Methods To assess the effect of heat, naloxone hydrochloride ampoules were exposed to 80 °C in a temperature-controlled oven for 8 h followed by 16 h at room temperature. To assess the effect of freeze-thaw cycles, naloxone hydrochloride ampoules were exposed to − 20 °C for 16 h followed by 8 h at 4 °C. The impact of these conditions on naloxone hydrochloride stability was evaluated each day for 1 week and after 2 and 4 weeks. The concentration of remaining naloxone hydrochloride was quantified using high-performance liquid chromatography (HPLC). Naloxone hydrochloride ampoules stored at room temperature served as the experimental control. Results Naloxone hydrochloride ampoules exhibit no changes in drug concentration following exposure to heat or freeze-thaw cycles for up to 28 days compared to ampoules maintained at room temperature (as indicated in the product monograph). Conclusions Naloxone hydrochloride remains chemically stable following exposure to heat or freeze-thaw cycles after 28 days. If THN kits are stored in non-standard conditions (for up to 28 days) the active naloxone is likely to remain stable. Despite this, pharmacists should continue to emphasize the importance of appropriate storage of THN kits to ensure optimal efficacy should naloxone administration be required in an emergency situation. Electronic supplementary material The online version of this article (10.1186/s12954-019-0288-4) contains supplementary material, which is available to authorized users.

Polyunsaturated fatty acids (PUFAs) are reported to exert beneficial effects in Alzheimer's disease. Some PUFAs are known to reduce amyloid-beta (Aβ) toxicity by promoting its degradation and clearance. Studies on the direct interactions of PUFAs with Aβ peptides are limited and contradictory. In this study, we report the interactions of fatty acids docosahexaenoic acid (DHA), eicosatetraenoic acid (EPA), α-linolenic acid (ALA), arachidonic acid (ARA), linoleic acid (LNA) and oleic acid (OA) with Aβ peptides by carrying out fluorescence based aggregation kinetic experiments, transmission electron microscopy and molecular docking studies. Our investigations demonstrate that all the fatty acids tested exhibit anti-aggregation properties by preventing both Aβ40 and Aβ42 fibrillogenesis (∼16–84% inhibition). OA and DHA were identified as excellent inhibitors of Aβ40 or Aβ42 fibrillogenesis respectively (∼84% and 81% inhibition at 25 μM). Molecular docking studies conducted, using the dimer and oligomer models of Aβ40 peptide, suggest that these fatty acids interact in the aggregation prone Phe19–Ala21 and the β-turn region (Asp23–Lys28) whereas a similar study with Aβ42 dimer and oligomer models, indicate that the fatty acids were oriented in a hydrophobic region (Gln15, Leu16, Leu17 and Leu34). These results, suggest that DHA, EPA, ALA, ARA, LNA and OA are capable of directly interacting with both Aβ40 and Aβ42 peptides. These studies will have implications in developing potential therapeutics for Alzheimer's disease.