Rafael P. Vieira

8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation.

One of the hallmarks of Alzheimers disease (AD) in the brain are amyloid-β (Aβ) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the Aβ peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of Aβ plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8-H2QH), a thiosemicarbazone (8-H2QT), and a semicarbazone (8-H2QS) derived from 8-hydroxyquinoline. The three compounds are shown to be neutral at pH7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with Cu(II), 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the Aβ1-40 peptide showed that 8-H2QS and 8-H2QH inhibit peptide aggregation in the presence of Cu(II). Native gel electrophoresis/Western blot and TEM images were obtained to give a more detailed picture of the extent and pathways of Aβ aggregation using the more neurotoxic Aβ1-42 in the presence and absence of Cu(II), 8-H2QH, 8-H2QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of Cu(II). However, in the presence of ligands and Cu(II), the results match those for the peptide alone, suggesting that the ligands function by sequestering Cu(II) and limiting oligomer formation in this assay.

An effective anticonvulsant prepared following a host–guest strategy that uses hydroxypropyl-β-cyclodextrin and benzaldehyde semicarbazone☆

The convulsions of approximately 25% of epileptics are inadequately controlled by currently available medication; therefore the preparation of new antiepileptic drugs is of great interest. Aryl semicarbazones can be considered a new class of compounds presenting anticonvulsant activity. In addition, they can be orally administered and are more active as anticonvulsants than mephenytoin or phenobarbital. However, one disadvantage of these compounds is their low water solubility. As a strategy to circumvent this problem, a 1:1 inclusion compound of benzaldehyde semicarbazone (BS) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was prepared and characterized. The anticonvulsant activities of the free semicarbazone and of the inclusion compound were evaluated in rats using the maximum electroshock and audiogenic seizures screenings. In both tests the minimum dose of compound necessary to produce activity decreases from 100mg/kg for the free semicarbazone to 35 mg/kg for the inclusion compound, indicating a significant increase in the bio-availability of the drug.

Inclusion of Benzaldehyde Semicarbazone into β-Cyclodextrin Produces a Very Effective Anticonvulsant Formulation

Aryl semicarbazones can be considered a novel class of compounds presenting anticonvulsant activity. In order to improve the efficiency and bioavailability of benzaldehyde semicarbazone (BS) we used the host–guest strategy and β-cyclodextrin (β-CD) to prepare a BS/β-CD 1:1 inclusion compound, which was characterized by thermal analyses (TG, DTG, DSC), XRD powder pattern diffraction analyses, infrared data and 1H, 13C, 2D-ROESY NMR and 1H relaxation times. The BS/β-CD inclusion compound was tested in rats using the maximum electroshock (MES) screen. The minimum dose necessary to produce anticonvulsant activity decreased from 100 mg/Kg (ip or vo) for the free semicarbazone to 25 mg/Kg/vo (75%) and 15 mg/Kg/ip (85%), indicating that the host–guest strategy that uses β-CD and BS is very effective and could be successfully employed in the preparation of pharmaceutical formulationof anticonvulsants.

Coordination of lapachol to bismuth(III) improves its anti-inflammatory and anti-angiogenic activities

Complex [Bi(Lp)2]Cl was obtained with 4-hydroxy-3-(3-methylbut-2-enyl)naphthalene-1,2-dione, “lapachol” (HLp). Lapachol, [Bi(Lp)2]Cl and BiCl3 were evaluated in a murine model of inflammatory angiogenesis induced by subcutaneous implantation of polyether polyurethane sponge discs. Intraperitoneal (i.p.) administration of lapachol or [Bi(Lp)2]Cl reduced the hemoglobin content in the implants suggesting that reduction of neo-vascularization was caused by lapachol. In the per os treatment only [Bi(Lp)2]Cl decreased the hemoglobin content in the implants. Likewise, N-acetylglucosaminidase (NAG) activity decreased in the implants of the groups i.p. treated with lapachol and [Bi(Lp)2]Cl while in the per os treatment inhibition was observed only for [Bi(Lp)2]Cl. Histological analysis showed that the components of the fibro-vascular tissue (vascularization and inflammatory cell population) were decreased in lapachol- and complex-treated groups. Our results suggest that both lapachol and [Bi(Lp)2]Cl exhibit anti-angiogenic and anti-inflammatory activities which have been attributed to the presence of the lapachol ligand. However, coordination to bismuth(III) could be an interesting strategy for improvement of lapachol’s therapeutic properties.

Intraneural dexamethasone applied simultaneously to rat sciatic nerve constriction delays the development of hyperalgesia and allodynia

Although neuroimmune interactions associated with the development of pain sensitization in models of neuropathic pain have been widely studied, there are some aspects that require further investigation. Thus, we aimed to evaluate whether the local intraneural or perineural injections of dexamethasone, an efficacious anti-inflammatory and immunosuppressant drug, delays the development of both thermal hyperalgesia and mechanical allodynia in an experimental model of neuropathic pain in rats. Hargreaves and electronic von Frey tests were applied. The chronic constriction injury (CCI) of right sciatic nerve was performed. Single intraneural dexamethasone administration at the moment of constriction delayed the development of sensitization for thermal hyperalgesia and mechanical allodynia. However, perineural administration of dexamethasone, at the highest dose, did not delay experimental pain development. These results show that inflammation/immune response at the site of nerve lesion is an essential trigger for the pathological changes that lead to both hyperalgesia and allodynia. In conclusion, this approach opens new opportunities to study cellular and molecular neuroimmune interactions associated with the development of pain derived from peripheral neuropathies.

Influence of susceptibility to hydrolysis and hydrophobicity of arylsemicarbazones on their anti-nociceptive and anti-inflammatory activities.

Benzaldehyde semicarbazone (BS) inhibited zymosan writhing response, carrageenan paw edema and both phases of formaldehyde nociceptive response. 2-hydroxybenzaldehyde semicarbazone (2-OHBS) and semicarbazide inhibited carrageenan paw edema and the second phase of formaldehyde nociceptive response. 2-OHBS inhibited zymosan writhing response. 3- and 4-OHBS did not show such activities. 2-OHBS showed the lowest LUMO energy, the highest contribution of the iminic carbon to LUMO energy, the highest positive charge on the iminic carbon, the highest negative charge on the iminic nitrogen and the highest susceptibility to hydrolysis. Hence semicarbazide may play important roles in 2-OHBSs activities. Inhibition of the first phase of formaldehyde response by BS could be attributed to its higher hydrophobicity and lower susceptibility to hydrolysis in comparison to 2-OHBS.

Synthesis and evaluation of benzothiazole-triazole and benzothiadiazole-triazole scaffolds as potential molecular probes for amyloid-β aggregation

Small-molecule ligands that bind to misfolded protein aggregates are essential tools for the study and detection of pathological hallmarks in neurodegenerative disorders, such as Alzheimers disease (AD). In the present study, three compounds (one benzothiazole-triazole, L1, and two benzothiadiazole-triazoles, L2 and L3) were synthesized via a modular approach (azide–alkyne cycloaddition) and evaluated as potential ligands for amyloid-β (Aβ) aggregates. The binding to amyloid-like fibrils, generated from recombinant Aβ1–42, were studied and the binding specificity to amyloid deposits was evaluated in brain sections from transgenic mice with AD pathology. All three derivatives showed significant reduced emission in the presence of recombinant Aβ1–42 amyloid fibrils. In addition, the observed binding to Aβ deposits in tissue sections suggests that the benzothiazole-triazole and benzothiadiazole-triazole structures are promising molecular scaffolds that can be modified for binding to specific protein aggregates.

Benzaldeído Semicarbazona: Um Candidato a Fármaco que Alia Simplicidade Estrutural a um Amplo Perfil de Atividades

Since the efficacy and safety of many currently available analgesic, anti-inflammatory and anticonvulsant drugs are not adequate, there is a continuing search for new drug candidates. Benzaldehyde semicarbazone (BS) inhibits convulsions in experimental models of epilepsy. Upon inclusion of BS into cyclodextrins (CDs) a 75-85% reduction of the dose necessary to induce the anticonvulsant effect is observed. BS also inhibits the nociceptive response and edema induced by different stimuli, and angiogenesis in experimental animals, suggesting that the compound, like many anticonvulsant drugs, presents antiinflammatory and analgesic properties. The wide variety of bioactivities indicates that BS and related compounds, either free or included into CDs, represent a promising group of drug candidates that may be useful in the treatment of human or veterinary diseases.