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Proactive response to tackle the threat of emerging drugs: Synthesis and toxicity evaluation of new cathinones

Publication . Gaspar, Helena; Bronze, Soraia; Oliveira, Catarina; Victor, Bruno; Machuqueiro, Miguel; Pacheco, Rita; Caldeira, Maria João; Santos, Susana

The emergence of potentially dangerous new psychoactive substances (NPS) imposes enormous challenges on forensic laboratories regarding their rapid and unambiguous identification. Access to comprehensive databases is essential for a quick characterization of these substances, allowing them to be categorized according to national and international legislations. In this work, it is reported the synthesis and structural characterization by NMR and MS of a library encompassing 21 cathinones, 4 of which are not yet reported in the literature, but with structural characteristics that make them a target for clandestine laboratories. This in-house library will be an important tool accessible to forensic laboratories, for the quick identification of seized NPS. The in vitro cytotoxicity of all cathinones was assessed in HepG2 cells, to have a preliminary but effective indication of their human hepatotoxicity potential. The two new cathinones DMB (8) and DMP (9) were the more cytotoxic, followed by the already seized mephedrone (2), 3,4-DMMC (3), 4-MDMC (7), NEB (12) with EC50 values ranging from 0.81 mM for (3) to 1.28 mM for (2). Results suggest an increase of cytotoxicity with the increase of the chain length of the acyl moiety and with the substitution (with one or two methyl groups) in the aromatic ring. The nature of the amine moiety seems to play only a minor role in the cytotoxic effect. Molecular dynamics simulations were performed to evaluate the molecular details related with the observed cytotoxicities. Although these studies indicated that cathinones are able to cross lipid bilayers with relative ease, when in their neutral forms, it was observed only a partial correlation between lipophilicity and cytotoxicity, indicating that membrane trafficking may not be the only key factor influencing the bioactivity of these compounds. This work is a valuable contribution to the forensic science field since a quick identification of novel cathinones is urgent to match their rapid increase in the market.

2018-09Journal article

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Ordinal sums of impartial games

Publication . Carvalho, Alda; Neto, João; Santos, Carlos

In an ordinal sum of two combinatorial games G and H, denoted by G : H, a player may move in either G (base) or H (subordinate), with the additional constraint that any move on G completely annihilates the component H. It is well-known that the ordinal sum does not depend on the form of its subordinate, but depends on the form of its base. In this work, we analyze g(G : H) where G and H are impartial forms, observing that the g-values are related to the concept of minimum excluded value of order k. As a case study, we introduce the ruleset OAK, a generalization of GREEN HACKENBUSH. By defining the operation gin sum, it is possible to determine the literal forms of the bases in polynomial time. (C) 2017 Elsevier B.V. All rights reserved.

2018-07-10Journal article

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Bioactivities of decoctions from Plectranthus species related to their traditional use on the treatment of digestive problems and alcohol intoxication

Publication . Brito, Elsa; Gomes, Emma; Fale, Pedro; Borges, Carlos; Pacheco, Rita; Teixeira, Vítor; Machuqueiro, Miguel; Ascensão, Lia; Serralheiro, Maria Luisa

Ethnopharmacological relevance Decoctions of Plectranthus species are traditionally ingested after large meals for treatment of food digestion and alcohol abuse. Aim of the study This study aims at associating the digestion-related ethno-uses of Plectranthus species decoctions to molecular mechanism that might explain them: easing digestion (AChE inhibition) and treating hangover (ADH inhibition) Material and methods Decoctions from Plectranthus species were analysed for their alcohol dehydrogenase (ADH) inhibition and acetylcholinesterase (AChE) inhibition, related with alcohol metabolism and intestinal motility, respectively. Identification of the active components was carried out by LC-MS/MS and the docking studies were performed with AChE and the bioactive molecules detected. Results All decoctions inhibited ADH activity. This inhibition was correlated with their rosmarinic acid (RA) content, which showed an IC50 value of 19 μg/mL, similar to the reference inhibitor CuCl2. The presence of RA also leads to most decoctions showing AChE inhibiting capacity. P. zuluensis decoction with an IC50 of 80 μg/mL presented also medioresinol, an even better inhibitor of AChE, as indicated by molecular docking studies. Furthermore, all decoctions tested showed no toxicity towards two human cell lines, and a high capacity to quench free radicals (DPPH), which also play a helpful in the digestive process, related with their RA content. Conclusions All activities presented by the RA-rich Plectranthus decoctions support their use in treating digestion disorders and P. barbatus could explain its use also for alleviating hangover symptoms. Medioresinol, which is present in P. zuluensis, exhibited a significant AChE inhibition and may provide, in the future, a new lead for bioactive compounds.

2018-06-28Journal article

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Serum albumin modulates the bioactivity of rosmarinic acid

Publication . Brito, Elsa; Silva, André; Fale, Pedro; Pacheco, Rita; Serralheiro, António; Haris, Parvez I.; Ascensão, Lia; Serralheiro, Maria Luisa

Rosmarinic acid (RA) is a phenolic compound with biological activity. The objective of the present study was to investigate whether this compound kept its biological activity in the presence of proteins. For this purpose, bovine serum albumin (BSA) was used as a model protein, and the capacity of the RA to inhibit acetylcholinesterase (AChE) and affect antioxidant activity was evaluated in the absence and presence of BSA. A mixture of phenolic compounds containing RA, obtained from a medicinal plant was added to this study. The AChE inhibitory activity of RA was reduced by *57% in the presence of BSA, while the antioxidant activity increased. These results lead to the investigation of the effect of RA on the BSA structure using Fourier transform infrared spectroscopy (FTIR). At 37 C and higher temperatures, RA caused a decrease in the temperature modiﬁcations onthe proteinstructure. Furthermore, FTIR and native-gel analysis revealed that protein aggregation/ precipitation, induced bytemperature, wasreduced in thepresence of RA. The novelty of the present work resides in thestudy of the enzyme inhibitory activity and antioxidant capacity of polyphenols, such as RA, in the presence of a protein. The ﬁndings highlight the need to consider the presence of proteins when assessing biological activities of polyphenols in vitro and that enzyme inhibitory activity may be decreased, while the antioxidant capacity remains or even increases.

2018-08Journal article

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BioMol4Health_Biological chemistry: longevity in a cup of tea

Publication . RESSAISSI, Asma; Fale, Pedro; Pacheco, Rita; Serralheiro, Maria Luisa

Infusions have been studied on what concerns Alzheimer Disease, digestive process, diet cholesterol absorption and its biosynthesis inhibition. In the first two cases the inhibition of acetylcholinesterase (AChE) has been addressed. In the last two situations, an in vitro intestinal barrier has been simulated and the inhibition of the regulator enzyme (HMGR) in cholesterol biosysnthesis pathway has been studied. AChE has been the target of infusions inhibitory activity as its inhibition has been seen to improve cognition and global functioning1 in AD suffering people and to improve the gastrointestinal motility2. Given to lab animals the compounds presente in the infusions were able to reach the brain and inhibit the enzyme3. The effect of infusions on cholesterol bioavailability pointed out that some infusions were able to reduce cholesterol permeation4 and also to have some inhibitory activity5. Studies have indicated that phenolics are able to modify the cell proteome6. The infusions have also been shown to modify the amount of cholesterol transporter proteins in cell membrane and this maybe one of possible explanations for the reduction in cholesterol transport detected under the effect of infusions, on some people ando n simulated intestinal barrier.

2018-10Conference object

Open access