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- Facile synthesis of oxo-/thioxopyrimidines and tetrazoles C–C linked to sugars as novel non-toxic antioxidant acetylcholinesterase inhibitorsPublication . Figueiredo, J.A.; Ismael, M.I.; Pinheiro, J.M.; Silva, A.M.S.; Justino, Jorge; Silva, Filipa V.M.; Goulart, Margarida; Mira, D.; Araújo, M.E.M.; Campoy, R.; Rauter, A.P.Microwave-assisted synthesis of oxo-/thioxopyrimidines and tetrazoles linked to furanoses with D-xylo and D-ribo configuration, and to a D-galacto pyranose is reported and compared to conventional methods. Reaction of dialdofuranoses and dialdopyranoses with a b-keto ester and urea or thiourea under micro wave irradiation at 300 W gave in 10 min the target molecules containing the 2-oxo- or 2-thioxo-pyrimidine ring in high yield. The tetrazole-derived compounds were obtained in two steps by reaction of the formyl group with hydroxylamine hydrochloride, copper sulfate, triethylamine and dicyclohexylcarbodiimide to give an intermediate nitrile, which was then treated with sodium azide. The use of microwave irradiation in the latter step also resulted in a considerably shorter reaction time (10 min) compared to hours under conventional heating to obtain a complete starting materials conversion. Acetylcholinesterase inhibition ranged from 20% to 80% for compounds concentration of 100 lg/mL, demonstrating the potential of this family of compounds for the control of Alzheimer’s disease symptoms. Most of the compounds showed antioxidant activity in the b-carotene/linoleic acid assay, some of them exhibiting IC50 values in the same order of magnitude as those of gallic acid. The bioactive compounds did not show cytotoxic effects to human lymphocytes using the MTT method adapted for non-adherent cells, nor geno toxicity determined by the short-term in vitro chromosomal aberration assay.
- Alkyl deoxy-arabino-hexopyranosides: synthesis, surface properties, and biological activitiesPublication . Silva, Filipa; Goulart, Margarida; Justino, Jorge; Neves, Ana; Santos, F.; Caio, J.; Lucas, S.; Newton, A.; Sacoto, D.; Barbosa, E.; Santos, M. S.; Rauter, A. P.Octyl and dodecyl glycosides possessing 2-deoxy-arabino-hexopyranoside moieties belonging to the D-and L-series in their alpha- and beta-forms were synthesized by reaction of an acetyl protected glycal with octanol or dodecanol, catalyzed by triphenylphosphine hydrobromide, followed by deprotection. Their surface properties were studied and discussed in terms of the adsorption and aggregation parameters, pC(20), CMC, and gamma(CMC). The antimicrobial activities were assessed using the paper disk diffusion and broth dilution methods. Both the octyl and dodecyl 2-deoxy beta-D-glycosides inhibited significantly Enterococcus faecalis, a microbe also highly susceptible to dodecyl 2,6-dideoxy-alpha-L-arabino-hexopyranoside. This compound was particularly active against Bacillus cereus and Bacillus subtilis, presenting for both Bacillus species a minimal inhibitory concentration of the same order of magnitude and a minimal lethal concentration even smaller than that obtained for chloramphenicol, a bioactivity which remained unaltered after 1 year solution storage at 4 degrees C. In addition, activity over Listeria monocytogenes was also observed. Direct cytotoxicity and genotoxicity of the glycosides were determined by proliferative index (mitotic index) evaluation in peripheral human lymphocytes of healthy donors. All compounds induced acute toxicity effects, and the response was dose dependent for the alpha-anomer of both the alkyl 2-deoxy-arabino-hexopyranosides and for the corresponding dodecyl beta-anomer, what suggests that non-toxic but still bioactive concentrations may be found for these compounds
- Bioactivity studies and chemical profile of the antidiabetic plant Genista teneraPublication . Rauter, A. P.; Martins, F.; Lopes, R.; Ferreira, J.; Serralheiro, L. M; Araújo, M. E.; Borges, C; Justino, Jorge; V.M. Silva, Filipa; Goulart, Margarida; Thomas-Oates, J.; Rodriges, J. A. P; Edwards, E; Noronha, J. P.; Pinto, R.; Mota-Filipe, H.Aim of the study: Genista tenera is a plant endemic to the island of Madeira and is used in folk medicine to control diabetes. In the present work we evaluate the antihyperglycaemic activity of its n-butanol extract and determine its chromatographic profile. In addition, this extract, the ethyl acetate and diethyl ether plant extracts were studied in order to assess the plant antioxidant and acetylcholinesterase inhibitory activities, as well as its cyto- and genotoxicities. Materials and methods: HPLC-DAD-ESI-MS was used to analyze the flavonoid profile of the n-butanol extract. The antihyperglycaemic activity of this extract was performed over streptozotocin induced diabetic Wistar rats (200mg/kg, bw/day), for 15 days. Antioxidant activity (DPPH assay) and acetylcholinesterase inhibitory effect (Ellman method) were also performed. Acute cytotoxicity and genotoxicity were assessed by proliferative index quantification and the short-term chromosomal aberration technique, after exposure of lymphocytes to the extracts. Results and conclusions: The n-butanol extract, where 21 monoglycosyl and 12 diglycosyl flavonoids were detected, significantly lowered blood glucose levels, bringing them to normal values after 15 days of treatment. The best radical scavenging activity was observed for the ethyl acetate extract (48.7% at 139.1μg/mL), which was also the most effective one at the minimal concentration tested. The highest acetylcholinesterase inhibitory activity (77.0% at 70. 0μg/mL) was also obtained with the ethyl acetate extract. In vitro toxicity studies showed no evidence for acute cytotoxicity or genotoxicity. This is the first report on antidiabetic activity of genus Genista.
- Tuning the bioactivity of tensioactive deoxy glycosides to structure: antibacterial activity versus selective cholinesterase inhibition rationalized by molecular dockingPublication . Martins, A.; Santos, M.S.; Dias, C.; Serra, P.; Cachatra, V.; Pais, J.; Caio, J.; Teixeira, V.H.; Machuqueiro, M.; Silva, M.S.; Pelerito, A.; Justino, Jorge; Goulart, Margarida; Silva, Filipa; Rauter, A.P.New octyl/dodecyl 2,6-dideoxy-D-arabino-hexopyranosides have been synthesized by a simple but efficient methodology based on the reaction of glycals with alcohols catalysed by triphenylphosphane hydrobromide, deprotection, regioselective tosylation and reduction. Their surface-active properties were evaluated in terms of adsorption and aggregation parameters and compared with those of 2-deoxy-D-glycosides and 2,6-dideoxy-L-glycosides. Deoxygenation at the 6-position led to a decrease in the critical micelle concentration, and an increase in the adsorption efficiency (pC20) promoting aggregation more efficiently than adsorption. With regard to the antibacterial activity, dodecyl 2,6-dideoxy-α-L-arabino-hexopyranoside was the most active compound towards Bacillus anthracis (MIC 25 μM), whereas its enantiomer exhibited a MIC value of 50 μM. Both 2,6-dideoxy glycosides were active towards Bacillus cereus, Bacillus subtilis, Enterococcus faecalis and Listeria monocytogenes. In contrast, none of the 2-deoxy glycosides was significantly active. These results and the data on surface activity suggest that aggregation is a key issue for antimicrobial activity. Beyond infection, Alzheimer’s disease also threatens elderly populations. In the search for butyrylcholinesterase (BChE) selective inhibition, 2- deoxy glycosides were screened in vitro by using Ellman’s assay. Octyl 2-deoxy-α-D-glycoside was found to be a BChE selective inhibitor promoting competitive inhibition. Docking studies supported these results as they pinpoint the importance of the primary OH group in stabilizing the BChE inhibitor complex. A size-exclusion mechanism for inhibition has been proposed based on the fact that acetylcholinesterase (AChE) exhibits several bulky residues that hinder access to the active-site cavity. This work shows how the deoxygenation pattern, configuration and functionality of the anomeric centre can tune physical and surface properties as well as the bioactivity of these multifunctional and stereochemically rich molecules.
- Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholinesterasePublication . Marcelo, F.; Silva, Filipa; Goulart, Margarida; Justino, Jorge; Sinay, P.; Blériot, Y.; Rauter, A. P.The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N 7-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 oC, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N 7 nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N 7 nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N 7-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.
- Non-toxic Salvia sclareoides Brot. extracts as a source of functional food ingredients: Phenolic profile, antioxidant activity and prion binding propertiesPublication . Justino, Jorge; Rauter, Amélia; Dias, Catarina; Martins, Alice; Branco, Isabel; Goulart, Margarida; Nogueira, José; Neng, Nuno; Silva, Filipa; Trevitt, Clare; Waltho, JonSalvia sclareoides is an aromatic herb native to Portugal, of which phenolic content (Folin–Ciocalteau method), chemical profile (HPLC/DAD), antioxidant activity (DPPH, β-carotene/linoleic acid assays), acute toxicity (MTT method, adapted for non-adherent cells), genotoxicity (short-term chromosomal aberration assay) and prion binding properties were evaluated in the acetone, water, ethanol, methanol and n-butanol extracts. The latter presented the highest phenolic content and antioxidant activity (DPPH assay), and was the single one with the flavonoids (+)-catechin, kaempferol O-glucoside and quercetin. Vanillic acid was the major component of all extracts but gallic, gentisic, caffeic, syringic, coumaric and ferulic acids were also found in some extracts. Only the n-butanol extract had components binding to the cellular form of human prion protein detected by NMR which showed specificity for two regions of the folded domain and for the unstructured N-terminal region. Extracts were not cytotoxic nor genotoxic, reinforcing the potential of S. sclareoides for nutraceutical purposes.