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- Structure and IR Spectra of 3(5)-Aminopyrazoles and UV-induced tautomerization in argon matrixPublication . Secrieru, Alina; Lopes, Susy; Cristiano, Maria L. S.; Fausto, RuiThe prototropic tautomerism in 3(5)-aminopyrazoles was investigated by matrix isolation infrared (IR) spectroscopy, supported by DFT(B3LYP)/6-311++G(d,p) calculations. In consonance with the experimental data, the calculations predict tautomer 3-aminopyrazole (3AP) to be more stable than the 5-aminopyrazole (5AP) tautomer (calculated energy difference: 10.7 kJ mol−1 ; Gibbs free energy difference: 9.8 kJ mol−1 ). The obtained matrix isolation IR spectra (in both argon and xenon matrices) were interpreted, and the observed bands were assigned to the tautomeric forms with help of vibrational calculations carried out at both harmonic and anharmonic levels. The matrix-isolated compound (in argon matrix) was then subjected to in situ broadband UV irradiation (λ > 235 nm), and the UV-induced transformations were followed by IR spectroscopy. Phototautomerization of the 3AP tautomer into the 5AP form was observed as the strongly prevalent reaction.
- 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.
- 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.
- Síntese e avaliação in vitro da atividade de derivados de quinolina na hiperfosforilação de proteínas tau na doença de AlzheimerPublication . Secrieru, Alina; Cristiano, Maria Lurdes Santos; Araújo, InêsA doença de Alzheimer é uma doença neurodegenerativa crónica caracterizada pela perda progressiva de memória e da cognição, e pelo aparecimento de distúrbios comportamentais e funcionais, culminando num comprometimento geral da realização de atividades diárias. Os principais traços caracterizadores desta doença são as placas senis resultantes da deposição extracelular de proteína beta-amiloide (Aβ) e as tranças neurofibrilares intracelulares resultantes de emparelhamentos entre proteínas tau (τ) hiperfosforiladas. A cinase dependente de ciclina 5, CDK5, está referenciada como uma das principais cinases envolvidas no processo de hiperfosforilação das proteínas tau e encontra-se hiperativa quando complexada com uma proteína truncada p25, em condições de neurodegenerescência. A inibição deste complexo representa uma possível abordagem para impedir a hiperfosforilação da tau. Atualmente não existe cura para a doença de Alzheimer. As terapêuticas atuais atuam meramente ao nível sintomático, não promovendo alterações significativas na progressão da doença. É, portanto, crucial o desenvolvimento de investigação que possibilite um maior conhecimento dos mecanismos da doença, por forma a identificar alvos terapêuticos que consubstanciem o desenvolvimento racional de moléculas que possam representar soluções farmacológicas para a doença de Alzheimer. As quinolinas são um grupo de compostos orgânicos caracterizados por um duplo anel resultante da fusão entre um benzeno e uma piridina, por intermédio de dois átomos de carbono adjacentes. A versatilidade do quimiótipo quinolínico tem estimulado um interesse particular nesta classe ao longo de muitas décadas, citando-se o exemplo da sua aplicação em medicina, como antibióticos e antimaláricos, entre outras aplicações terapêuticas, estando também em avaliação a sua aplicação no tratamento de doenças neurodegenerativas, nomeadamente na doença de Alzheimer. Neste sentido, a presente monografia apresenta uma revisão bibliográfica relativa aos fundamentos teóricos associados à doença de Alzheimer, debruçando-se sobre os processos que envolvem as proteínas tau e o complexo CDK5-p25, sendo este escrutinado como alvo terapêutico a considerar na concepção e síntese de compostos baseados numa estrutura química contendo um núcleo quinolínico enquanto candidatos promissores a fármacos modificadores da doença. Para além da síntese de derivados quinolínicos com atividade para o complexo CDK5-p25, é apresentado, neste âmbito, um estudo da atividade de fármacos antimaláricos derivados do quinino a nível do alvo terapêutico supramencionado, uma vez que constituem fármacos cuja estrutura se baseia igualmente num núcleo quinolínico e cujo perfil de metabolização e segurança já se encontra estabelecido. Este estudo permitiu identificar um via de síntese de quinolinas eficiente, incorporando técnicas mais recentes, e comprovar a possibilidade de indução de neurotoxicidade utilizando glutamato, para posterior avaliação da capacidade inibitória dos derivados de quinolina sintéticos farmacologicamente interessantes, no alvo selecionado.
- Antimalarial agents as therapeutic tools against toxoplasmosis: a short bridge between two distant illnessesPublication . Secrieru, Alina; Costa, Inês C. C.; O'Neill, Paul M.; Cristiano, Maria De LurdesToxoplasmosis is an infectious disease with paramount impact worldwide, affecting many vulnerable populations and representing a significant matter of concern. Current therapies used against toxoplasmosis are based essentially on old chemotypes, which fail in providing a definitive cure for the disease, placing the most sensitive populations at risk for irreversible damage in vital organs, culminating in death in the most serious cases. Antimalarial drugs have been shown to possess key features for drug repurposing, finding application in the treatment of other parasite-borne illnesses, including toxoplasmosis. Antimalarials provide the most effective therapeutic solutions against toxoplasmosis and make up for the majority of currently available antitoxoplasmic drugs. Additionally, other antiplasmodial drugs have been scrutinized and many promising candidates have emanated in recent developments. Available data demonstrate that it is worthwhile to explore the activity of classical and most recent antimalarial chemotypes, such as quinolines, endoperoxides, pyrazolo[1,5-a]pyrimidines, and nature-derived peptide-based parasiticidal agents, in the context of toxoplasmosis chemotherapy, in the quest for encountering more effective and safer tools for toxoplasmosis control or eradication.
- 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.