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- Phytochemical profile and anticholinesterase and antimicobial activities of supercritical versus conventional extracts of Satureja montanaPublication . Silva, Filipa; Martins, A.; Salta, J.; Neng, N. R.; Nogueira, J.; Mira, Delfina; Gaspar, Natália; Justino, Jorge; Grosso, C.; Urieta, J. S.; Palavra, A. M. S.; Rauter, A. P.Winter savory Satureja montana is a medicinal herb used in traditional gastronomy for seasoning meats and salads. This study reports a comparison between conventional (hydrodistillation, HID, and Soxhlet extraction, SE) and alternative (supercritical fluid extraction, SFE) extraction methods to assess the best option to obtain bioactive compounds. Two different types of extracts were tested, the volatile (SFE-90 bar, second separator vs HID) and the nonvolatile fractions (SFE-250 bar, first and second separator vs SE). The inhibitory activity over acetyl- and butyrylcholinesterase by S. montana extracts was assessed as a potential indicator for the control of Alzheimer's disease. The supercritical nonvolatile fractions, which showed the highest content of (+)-catechin, chlorogenic, vanillic, and protocatechuic acids, also inhibited selectively and significantly butyrylcholinesterase, whereas the nonvolatile conventional extract did not affect this enzyme. Microbial susceptibility tests revealed the great potential of S. montana volatile supercritical fluid extract for the growth control and inactivation of Bacillus subtilis and Bacillus cereus, showing some activity against Botrytis spp. and Pyricularia oryzae. Although some studies were carried out on S. montana, the phytochemical analysis together with the biological properties, namely, the anticholinesterase and antimicrobial activities of the plant nonvolatile and volatile supercritical fluid extracts, are described herein for the first time.
- Synthesis and biological evaluation of sugars containing α,β-Unsaturated γ-LactonesPublication . Xavier, N. M.; Silva, S.; Madeira, P. J. A; Florêncio, M. H.; Silva, Filipa; Justino, Jorge; Thiem, J.; Rauter, A. P.The stereocontrolled synthesis of new sugar derivatives carrying the α,β-unsaturated δ-lactone (butenolide) moiety is described. Sugar-fused or sugar-linked butenolides can be constructed by an efficient reaction sequence involving Wittig olefination of 3- or 5-keto sugars and intramolecular cyclization of the intermediate γ-hydroxy α,β-unsaturated esters. The antimicrobial activities of the products and that of a known sugar-derived pyranoid α,β-unsaturated δ-lactone were investigated against six pathogenic bacteria and six fungi. The pyranoid α,β-unsaturated δ-lactone 29 proved to be the most active compound in this series towards the plant pathogenic fungi Colletotrichum coffeanum (coffee berry disease) and Pyricularia oryzae (rice blast disease).
- 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.
- 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.
- A new lupene triterpenetriol and anticholinesterase activity of Salvia sclareoidesPublication . Rauter, A. P.; Branco, I.; Lopes, R. G.; Justino, Jorge; Silva, Filipa; Noronha, J. P.; Cabrita, E. J.; Brouard, I.; Bermejo, J.A new lupene triterpenetriol was isolated from the acetone extract of the aerial parts of Salvia sclareoides and characterised as (1β,3β)-lup-20(29)-ene-1,3,30-triol (1). In addition, nepetidin (2), nepeticin (3), lupendiol (4), (1β,11α)-dihydroxy-lup-20(29)-en-3-one (5), ursolic acid (6), sumaresinolic acid (7) and hederagenin (8), were identified in this Salvia sp. To the best of our knowledge, the compounds 2 and 7 are new constituents in Salvia spp. The acetone, ethanol, butanol and water extracts of the plant were screened for the in vitro inhibitory activity of acetylcholinesterase (AChE) and butyrilcholinesterase (BChE), enzymes which play a role in the Alzheimer disease. All extracts inhibited acetylcholinesterase activity at 10 μg/ml, a remarkable activity since the standard drug rivastigmine does not inhibit acetylcholinesterase at the same concentration. Regarding the butyrilcholinesterase, the acetone extract at 1000 μg/ml was able to inhibit completely the enzyme activity and the butanol and ethanol extracts, at this concentration, produced a potent inhibition of BchE.
- 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.
- 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