Browsing by Author "Cristiano, Maria de Lurdes"
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- 1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of actionPublication . Mendes, Andreia; Armada, Ana; Cabral, Lília; Amado, Patrícia; Campino, Lenea; Cristiano, Maria de Lurdes; Cortes, SofiaLeishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on Leishmania parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against L. infantum and L. donovani and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2 Leishmania species, with IC50 values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on L. infantum amastigotes (IC50 13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes.
- 4-hydroxyquinolin-2(1H)-one isolated in cryogenic argon and xenon matrices: tautomers and photochemistryPublication . Secrieru, Alina; Lopes, S.; Nikitin, T.; Cristiano, Maria de Lurdes; Fausto, R.4-Hydroxyquinolin-2(1H)-one (4HQ2O) was synthesized, isolated in cryogenic matrices (argon and xenon), and studied by infrared spectroscopy. Quantum chemical calculations carried out at the DFT(B3LYP)/6-311++G (3df,3pd) level of theory were used to determine the conformational and tautomeric properties of the molecule. Two tautomeric forms were identified in the as-deposited matrices with the help of the theoretical data. To investigate the photochemistry of the compound, in situ broadband ultraviolet (lambda > 283 nm) irradiation of the asdeposited argon matrix was performed. This irradiation led to the generation of an additional tautomer, together with the products of fragmentation of the heterocyclic ring of the molecule, specifically isocyanic acid and carbon monoxide. Photoproducts such as 1,3-dihydro-2H-indol-2-one and cyclohepta-1,2,4,6-tetraene were also observed in the photolyzed argon matrix. A comprehensive assignment of the infrared spectra of all the species observed experimentally is presented.
- In vitro assessment of antimicrobial, antioxidant, and cytotoxic properties of Saccharin-Tetrazolyl and-Thiadiazolyl derivatives: the simple dependence of the pH value on antimicrobial activityPublication . Frija, Luís M. T.; Ntungwe, Epole; Sitarek, Przemysław; Andrade, Joana M.; Toma, Monika; Śliwiński, Tomasz; Cabral, Lília; Cristiano, Maria de Lurdes; Rijo, Patrícia; Pombeiro, Armando J. L.The antimicrobial, antioxidant, and cytotoxic activities of a series of saccharin-tetrazolyl and -thiadiazolyl analogs were examined. The assessment of the antimicrobial properties of the referred-to molecules was completed through an evaluation of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against Gram-positive and Gram-negative bacteria and yeasts. Scrutiny of the MIC and MBC values of the compounds at pH 4.0, 7.0, and 9.0 against four Gram-positive strains revealed high values for both the MIC and MBC at pH 4.0 (ranging from 0.98 to 125 µg/mL) and moderate values at pH 7.0 and 9.0, exposing strong antimicrobial activities in an acidic medium. An antioxidant activity analysis of the molecules was performed by using the DPPH (2,2-diphenyl-1-picrylhydrazyl) method, which showed high activity for the TSMT (N-(1-methyl-2H-tetrazol-5-yl)-N-(1,1-dioxo-1,2-benzisothiazol-3-yl) amine, 7) derivative (90.29% compared to a butylated hydroxytoluene positive control of 61.96%). Besides, the general toxicity of the saccharin analogs was evaluated in an Artemia salina model, which displayed insignificant toxicity values. In turn, upon an assessment of cell viability, all of the compounds were found to be nontoxic in range concentrations of 0-100 µg/mL in H7PX glioma cells. The tested molecules have inspiring antimicrobial and antioxidant properties that represent potential core structures in the design of new drugs for the treatment of infectious diseases.
- Methodologies for detoxifying bivalves from marine paralytic shellfish toxinsPublication . Aderogba, Adewale; Leal, Joana F.; Cristiano, Maria de LurdesThe marine environment emerges as a key provider of food and sustainable products. However, these benefits are accompanied by numerous challenges owing to harmful algal blooms (HAB) and their associated biotoxins, which accumulate in organisms, like bivalves, threatening seafood quality. Among the various biotoxins, paralytic shellfish toxins (PST), the causative agents of paralytic shellfish poisoning (PSP), are among the most potent, lethal, and frequently reported instances of human intoxication. Removing PST from marine system is particularly challenging because of their hydrophilicity, susceptibility to biotransformation and the potential influence of other substances naturally present in the environment. Although there are several methods applied to mitigate HAB, to the best of our knowledge there are no proven effective methods for removing PST in marine environments. Consequently, there is a need to develop efficient removal technologies, especially envisaging fast, environmentally safe, inexpensive, and readily available solutions. Having examined several proposed methods for removing PST (e.g., thermal and industrial procedures, adsorption using different materials, photodegradation, AOPs) and comparing their efficacy, this study aims to streamline the current knowledge on PST removal, identify knowledge gaps, and provide valuable insights for researchers, environmental managers, and policymakers engaged in mitigating the risks associated with PST.
- Revisiting the structure and chemistry of 3(5)-Substituted PyrazolesPublication . Secrieru, Alina; O’Neill, Paul Michael; Cristiano, Maria de LurdesPyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they exhibit tautomerism. This phenomenon may influence their reactivity, with possible impact on the synthetic strategies where pyrazoles take part, as well as on the biological activities of targets bearing a pyrazole moiety, since a change in structure translates into changes in properties. Investigations of the structure of pyrazoles that unravel the tautomeric and conformational preferences are therefore of upmost relevance. 3(5)-Aminopyrazoles are largely explored as precursors in the synthesis of condensed heterocyclic systems, namely pyrazolo[1,5-a]pyrimidines. However, the information available in the literature concerning the structure and chemistry of 3(5)-aminopyrazoles is scarce and disperse. We provide a revision of data on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis. It is expected that the combined information will contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles, with a positive impact in the design of synthetic methods, where they take part.
- Substituent effects on EI-MS fragmentation patterns of 5-Allyloxy-1-aryl-tetrazoles and 4-Allyl-1-aryl-tetrazole-5-ones; Correlation with UV-induced fragmentation channelsPublication . Secrieru, Alina; Oumeddour, Rabah; Cristiano, Maria de Lurdes1,4- and 1,5-disubstituted tetrazoles possess enriched structures and versatile chemistry, representing a challenge for chemists. In the present work, we unravel the fragmentation patterns of a chemically diverse range of 5-allyloxy-1-aryl-tetrazoles and 4-allyl-1-aryl-tetrazolole-5-ones when subjected to electron impact mass spectrometry (EI-MS) and investigate the correlation with the UV-induced fragmentation channels of the matrix-isolated tetrazole derivatives. Our results indicate that the fragmentation pathways of the selected tetrazoles in EI-MS are highly influenced by the electronic effects induced by substitution. Multiple pathways can be envisaged to explain the mechanisms of fragmentation, frequently awarding common final species, namely arylisocyanate, arylazide, arylnitrene, isocyanic acid and hydrogen azide radical cations, as well as allyl/aryl cations. The identified fragments are consistent with those found in previous investigations concerning the photochemical stability of the same class of molecules. This parallelism showcases a similarity in the behaviour of tetrazoles under EI-MS and UV-irradiation in the inert environment of cryogenic matrices of noble gases, providing efficient tools for reactivity predictions, whether for analytical ends or more in-depth studies. Theoretical calculations provide complementary information to articulate predictions of resulting products.
- Synthesis and structure of novel pyrimidine‐thioethers: structural effects on reactivity along with an unpredicted dimethylamination reactionPublication . Costa, Inês; Frija, Luís M. T.; Augusto, André; Paixão, José A.; Cristiano, Maria de LurdesBuchwald–Hartwig reactions have been in the spotlight over the past years due to their usefulness in creating a wide range of chemical skeletons applied in drug discovery. Aminopyrimidines are heterocyclic structures with significant biological relevance and compounds bearing the amino- and diaminopyrimidine motifs have been associated with antiviral, antibacterial, antiparasitic, antifungal, anticancer, and anti-inflammatory properties. Given the notable status of aminopyrimidines in the design of target-specific drug candidates, the synthesis and structure of four aminopyrimidine-arylsulfide conjugates (3, 4, 5, and 6) are reported that are designed to inhibit trypanothione reductase, a key enzyme in the redox pathway of trypanosomatids. When applying the Buchwald–Hartwig synthetic approach, the formation of different products is witnessed by altering the reaction conditions, observing that regioselectivity is conditioned by reaction time and by Boc-protection of the starting 2,6-dichloropyrimidin-4-amine. The electron-withdrawing character of the protecting group appears to increase the susceptibility of the pyrimidine at C2 for further reaction with the solvent, DMF, yielding the corresponding diaminopyrimidine-based conjugates. The crystal structures of the novel aminopyrimidine-arylsulfide conjugate and their Boc-protected 2,6-dichloropyrimidin-4-amine precursors are disclosed and discussed.
- Targeting trypanothione synthetase and Trypanothione reductase: development of common inhibitors to tackle Trypanosomatid diseasePublication . Augusto, André; Costa, Inês; Conceição, Jaime; Cristiano, Maria de LurdesNeglected Tropical Diseases (NTDs) encompass a range of disorders, including infectious diseases caused by viruses, bacteria, parasites, fungi, and toxins, mainly affecting underprivileged individuals in developing countries. Among the NTDs, those caused by parasites belonging to the Trypanosomatidae family are particularly impacting and require attention, since the lack of financial incentives has led to constraints on the development of novel drugs to tackle them effectively. To circumvent the minor advances in drug discovery in this area, academic research emerges as a crucial player, namely through the identification and validation of new drug targets, thereby contributing to the development of more efficient, safe, and less expensive therapies against Trypanosomatidae infections. Noteworthy, this is a matter of utmost urgency since these diseases are endemic in countries with low socioeconomic standards. This review provides a comprehensive understanding of the current paradigm of NTDs caused by parasites belonging to the Trypanosomatidae family, addressing the ongoing limitations and challenges associated to the current chemotherapy solutions for these diseases and discussing the opportunities unravelled by recent research that led to the identification of new biomolecular targets that are common to Trypanosomatidae parasites. Among these, the unique properties of Trypanothione Synthetase (TryS) and Trypanothione Reductase (TryR), two key protozoan enzymes that are essential for the survival of Trypanosoma and Leishmania parasites, will be emphasised. In addition to a critical analysis of the latest advances in the discovery of novel molecules capable of inhibiting TryS and TryR, the possibility of dual targeting through a combination of TryS and TryR inhibitors will be addressed.
- Unanticipated reactivity toward nucleophilic attack in the synthesis of saccharyl-1,3,4-thiadiazolyl conjugates: structure and mechanistic insightsPublication . Guerreiro, Bruno; Carvalho, Daniel F.; Coelho, Jaime A. S.; Frija, Luís M. T.; Paixão, José A.; Cristiano, Maria de LurdesAlong with the synthetic process optimization of 3- [(5-methyl-1,3,4-thiadiazole-2-yl)sulfanyl]-1,2-benzothiazole 1,1- dioxide (MTSB), a selective copper chelator with potential interest in cancer chemotherapy, the unprecedented isolation of a novel compound, 3-(1,1-dioxidobenzo[d]isothiazol-3-yl)-5-methyl-1,3,4- thiadiazole-2(3H)-thione (BMTT), evidenced an unexpected reactivity of the starting 5-methyl-1,3,4-thiadiazole-2-thiol. To shed light into the reaction mechanisms, quantum chemical calculations were conducted at the M06-2X/def2-TZVPP/PCM- (THF)//M06-2X/6-31++G(d,p) level of theory. The results conjecture the formation of BMTT from nucleophilic attack of the nitrogen at position 3 of the thiadiazole ring, involved in an Sto-N delocalized thiadiazole-2-thiolate structure, which is thermodynamically more favorable in the presence of Na+ . Experimental assays refute a plausible concerted 1,3-sigmatropic S- to Nrearrangement of MTSB that would lead to BMTT. Hence, contradicting the nucleophilicity indices of sulfur (from thiol) and nitrogen atoms of 5-methyl-1,3,4-thiadiazole-2-thiol, it is believed that an exotic nucleophilic attack by the nitrogen at 3-position of this reagent to the sp2 carbon in position 3 of pseudo-saccharyl chloride should take place. Besides, the crystal structures of the MTSB and BMTT hybrids were investigated in detail by X-ray crystallography.
- Why are bivalves not detoxified?Publication . Leal, Joana F.; Cristiano, Maria de LurdesParalytic (PSP), diarrheic (DSP), and amnesic shellfish poisonings are among the most prominent foodborne diseases threatening the food security. Because of the absence of legal methods capable of eliminating these biotoxins, the option is to rely on natural detoxification, compromising the availability of protein-based food and imposing severe socioeconomic impacts. In vivo detoxification methodologies have focused on the use of adsorbents (mainly applied to PSP), some of which are combined with nontoxic algae. Alternative methodologies for DSP have emerged, but they are based on absorption inhibition, which may be unfeasible in real situations. It is thus imperative to optimize existing proposals or develop novel, safe, and cost-effective methods so that the solution is seen as an attractive financial investment.