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- Unravelling the structure of peroxides with antiparasitic activity: the relative impact of a trioxolane or a tetraoxane pharmacophore on the overall molecular structurePublication . Amado, Patrícia; Jesus, A. J. Lopes; Paixão, José A.; Fausto, Rui; Cristiano, Maria De LurdesPlasmodium falciparum artemisinin-resistance boosted the quest for novel plasmodial "fast killers," uncovering antimalarial candidates OZ439 and E209, whose peroxide precursors are 1,2,4-trioxolane (1) and 1,2,4,5-tetraoxane (2), differing solely in the pharmacophore (trioxolane or tetraoxane). Combining X-ray crystallography and vibrational spectroscopy, along with Hirsh-feld surface analysis and calculations (CE-B3LYP/6-31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, may deepen the understanding of relative reactivity and properties of these endoperoxides classes. In the crystal, the tetraoxane ring in 2 and the trioxolane-adamantyl fragment in 1 are disordered, with molecules 1 and 2 existing as two distinct, stable conformations. Whereas the dominant C-H center dot center dot center dot O H-bonds in 1 connect an adamantyl C-H and O1 or O2 of the trioxolane ring, in 2 they involve the carbonyl oxygen, acting as a double acceptor from phenyl ring C-H groups. C-H center dot center dot center dot O and C-H center dot center dot center dot pi H-bonds define the molecular packing of 2, while C-H center dot center dot center dot H-C van der Waals interactions determine the packing of 1. The dispersive component dominates the interaction energies calculated for the most representative molecular pairs.
- Bond-breaking/Bond-forming reactions by vibrational excitation: infrared-induced bidirectional tautomerization of matrix-isolated thiotropolonePublication . Nunes, Claudio M.; Pereira, Nelson A. M.; Reva, Igor; Amado, Patrícia; Cristiano, Maria De Lurdes; Fausto, RuiInfrared vibrational excitation is a promising approach for gaining exceptional control of chemical reactions, in ways that cannot be attained via thermal or electronic excitation. Here, we report an unprecedented example of a bond-breaking/bond-forming reaction by vibrational excitation under matrix isolation conditions. Thiotropolone monomers were isolated in cryogenic argon matrices and characterized by infrared spectroscopy and vibrational computations (harmonic and anharmonic). Narrowband near-infrared irradiations tuned at frequencies of first CH stretching overtone (5940 cm(-1)) or combination modes (5980 cm(-1)) of the OH tautomer, the sole form of the compound that exists in the as-deposited matrices, led to its conversion into the SH tautomer. The tautomerization in the reverse direction was achieved by vibrational excitation of the SH tautomer with irradiation at 5947 or 5994 cm(-1), corresponding to the frequencies of its CH stretching combination and overtone modes. This pioneer demonstration of bidirectional hydroxyl. thiol tautomerization controlled by vibrational excitation creates prospects for new advances in vibrationally induced chemistry.
- Metodologias de síntese de tetraoxanos com potencial utilização em química medicinalPublication . Amado, Patrícia; Cristiano, Maria Lurdes SantosA malária é uma doença tropical infeciosa causada por parasitas do género Plasmodium, que são transmitidos pela picada de mosquitos Anopheles infetados, afetando, sobretudo, países subdesenvolvidos. Enquanto a quimioterapia continua a ser a única alternativa viável para o tratamento desta doença, existem muitos problemas associados à atual terapêutica. Para além da problemática associada aos efeitos secundários, as resistências estão a aumentar exponencialmente. Isto coloca aos químicos medicinais, o desafio premente da descoberta e desenvolvimento de novos fármacos, facilmente acessíveis, mais eficazes e seguros. Neste contexto, os tetraoxanos podem constituir potenciais candidatos. Os 1,2,4,5-tetraoxanos são compostos heterocíclicos sintéticos que possuem duas pontes endoperóxido. Estes compostos são muito relevantes em síntese, destacando-se a sua utilização na produção industrial de hidrocarbonetos macrocíclicos e de lactonas. Os tetraoxanos suscitaram especial interesse nas últimas duas décadas, devido à descoberta da sua elevada atividade antimalárica. Para além da atividade antimalárica, os tetraoxanos podem constituir potenciais candidatos para o tratamento de outras doenças negligenciadas, como a leishmaniose. O potencial farmacológico dos tetraoxanos impulsionou a otimização de estratégias de síntese de novos derivados, de forma a ampliar as bibliotecas de novos compostos para estudos de atividade farmacológica e possibilitar a identificação de novos candidatos a fármacos. Deste modo, a presente dissertação apresenta uma revisão bibliográfica relativa aos fundamentos teóricos e metodologias da síntese de 1,2,4,5-tetraoxanos, perspetivando a sua potencial utilização em química farmacêutica. A preparação relativamente económica e a estabilidade associada à função tetraoxano permitem a síntese de derivados com estruturas diversas, alargando a possibilidade de desenvolvimento de novas moléculas-alvo. No âmbito deste trabalho foram também preparados diversos tetraoxanos que demonstraram ter uma atividade antiparasitária semelhante à miltefosina, um dos fármacos utilizado atualmente no tratamento da Leishmaniose. A grande vantagem dos tetraoxanos relativamente à miltefosina reside no facto de exibirem uma toxicidade bastante inferior. De entre os compostos preparados destacaram-se os tetraoxanos LC137 e LC140. Estes compostos apresentaram valores de IC50 na região μM baixa, da mesma ordem de grandeza dos obtidos para este fármaco de referência e menor toxicidade.
- On the development of selective chelators for Cadmium: Synthesis, structure and chelating properties of 3-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amino)benzo[d]isothiazole 1,1-dioxide, a novel Thiadiazolyl SaccharinatePublication . Leal, Joana F.; Guerreiro, Bruno; Amado, Patrícia; Fernandes, André L.; Barreira, Luísa; Paixão, José A.; Lurdes S. Cristiano, M.Aquatic contamination by heavy metals is a major concern for the serious negative consequences it has for plants, animals, and humans. Among the most toxic metals, Cd(II) stands out since selective and truly efficient methodologies for its removal are not known. We report a novel multidentate chelating agent comprising the heterocycles thiadiazole and benzisothiazole. 3-((5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)amino)benzo[d]isothiazole 1,1-dioxide (AL14) was synthesized from cheap saccharin and characterized by different techniques, including single crystal X-ray crystallography. Our studies revealed the efficiency and selectivity of AL14 for the chelation of dissolved Cd(II) (as compared to Cu(II) and Fe(II)). Different spectral changes were observed upon the addition of Cd(II) and Cu(II) during UV-Vis titrations, suggesting different complexation interactions with both metals.
- Recent advances of DprE1 inhibitors against mycobacterium tuberculosis: computational analysis of physicochemical and ADMET propertiesPublication . Amado, Patrícia; Woodley, Christopher; Lurdes S. Cristiano, M.; O’Neill, Paul M.D e cap renylp ho sp ho ryl-beta-D-rib os e 2 '-epimerase (DprE1) is a critical flavoenzyme in Mycobacterium tuberculosis, catalyzing a vital step in the production of lipoarabinomannan and arabinogalactan, both of which are essential for cell wall biosynthesis. Due to its periplasmic localization, DprE1 is a susceptible target, and several compounds with diverse scaffolds have been discovered that inhibit this enzyme, covalently or noncovalently. We evaluated a total of similar to 1519 DprE1 inhibitors disclosed in the literature from 2009 to April 2022 by performing an in-depth analysis of physicochemical descriptors and absorption, distribution, metabolism, excretion, and toxicity (ADMET), to gain new insights into these properties in DprE1 inhibitors. Several molecular properties that should facilitate the design and optimization of future DprE1 inhibitors are described, allowing for the development of improved analogues targeting M. tuberculosis.
- Molecular and crystal structure, spectroscopy, and photochemistry of a dispiro compound bearing the tetraoxane pharmacophorePublication . Amado, Patrícia; Lopes, Susy; Brás, Elisa M.; Paixão, José A.; Takano, Ma‐aya; Abe, Manabu; Fausto, Rui; Cristiano, Maria De LurdesThe molecular structure and photochemistry of dispiro[cyclohexane-1,3′-[1,2,4,5]tetraoxane-6′,2′′-tricyclo[3.3.1.13,7]decan]-4-one (TX), an antiparasitic 1,2,4,5-tetraoxane was investigated using matrix isolation IR and EPR spectroscopies, together with quantum chemical calculations undertaken at the DFT(B3LYP)/6-311++G(3df,3pd) level of theory, with and without Grimme's dispersion correction. Photolysis of the matrix-isolated TX, induced by in situ broadband (λ>235 nm) or narrowband (λ in the range 220–263 nm) irradiation, led to new bands in the infrared spectrum that could be ascribed to two distinct photoproducts, oxepane-2,5-dione, and 4-oxohomoadamantan-5-one. Our studies show that these photoproducts result from initial photoinduced cleavage of an O−O bond, with the formation of an oxygen-centered diradical that regioselectivity rearranges to a more stable (secondary carbon-centered)/(oxygen-centered) diradical, yielding the final products. Formation of the diradical species was confirmed by EPR measurements, upon photolysis of the compound at λ=266 nm, in acetonitrile ice (T=10–80 K). Single-crystal X-ray diffraction (XRD) studies demonstrated that the TX molecule adopts nearly the same conformation in the crystal and matrix-isolation conditions, revealing that the intermolecular interactions in the TX crystal are weak. This result is in keeping with observed similarities between the infrared spectrum of the crystalline material and that of matrix-isolated TX. The detailed structural, vibrational, and photochemical data reported here appear relevant to the practical uses of TX in medicinal chemistry, considering its efficient and broad parasiticidal properties.
- The potential of Chitosan-Based composites for adsorption of diarrheic shellfish toxinsPublication . Leal, Joana F.; Amado, Patrícia; P. Lourenço, J.; Lurdes Santos Cristiano, MariaOkadaic acid (OA) is one of the most potent marine biotoxins, causing diarrheal shellfish poisoning (DSP). The proliferation of microalgae that produce OA and its analogues is frequent, threatening human health and socioeconomic development. Several methods have been tested to remove this biotoxin from aquatic systems, yet none has proven enough efficacy to solve the problem. In this work, we synthesized and characterized low-cost composites and tested their efficacy for OA adsorption in saltwater. For the synthesis of the composites, the following starting materials were considered: chitosan of low and medium molecular weight (CH-LW and CH-MW, respectively), activated carbon (AC), and montmorillonite (MMT). Characterization by vibrational spectroscopy (FTIR), X-ray diffraction (XRD), and microscopy revealed differences in the mode of interaction of CH-LW and CH-MW with AC and MMT, suggesting that the interaction of CH-MW with MMT has mainly occurred on the surface of the clay particles and no sufficient intercalation of CH-MW into the MMT interlayers took place. Among the composites tested (CH-LW/AC, CH-MW/AC, CH-MW/AC/MMT, and CH-MW/MMT), CH-MW/MMT was the one that revealed lower OA adsorption efficiency, given the findings evidenced by the structural characterization. On the contrary, the CH-MW/AC composite revealed the highest average percentage of OA adsorption (53 ± 11%). Although preliminary, the results obtained in this work open up good perspectives for the use of this type of composite material as an adsorbent in the removal of OA from marine environments.
- Cation-exchange resin applied to paralytic Shellfish toxins depuration from Bivalves exposed to Gymnodinium catenatumPublication . Leal, Joana F.; Bombo, Gabriel; Amado, Patrícia; Pereira, Hugo; Lurdes S. Cristiano, M.The accumulation of marine biotoxins in shellfish and their consumption causes serious food safety problems, threatening human health and compromising the availability of protein-based food. It is thus urgent to develop methodologies for the detoxification of live bivalves, avoiding their economic and nutritional devaluation. In this context, we tested an adsorption mechanism of paralytic shellfish toxins (PST) based on a cation-exchange resin. The first studies using cultures of Gymnodinium catenatum (natural producers of PST) showed a decrease of about 80% in overall toxicity after 48 h. Interestingly, we found that the toxins are adsorbed differently, with toxins’ structural features playing a part in the adsorption capacity via steric hindrance, electronic effects, or the extent of positive charge density (e.g., dcSTX). The positive effect of the resin in accelerating PST clearance from live mussels (Mytilus edulis) is not evident when compared to resin-free clearance; nevertheless, relevant information could be gathered that will facilitate further in vivo studies. Several factors appear to be at play, namely the competition of natural substances (e.g., salts, organic matter) for the same binding sites, the blocking of pores due to interactions between molecules, and/or difficulties in resin absorption by mussels. Additionally, the present work revealed the ability of mussels to neutralize pH and proposes bioconversion reactions among the PST molecules.
- Photoinduced reactivity in a Dispiro-1,2,4-trioxolane: Adamantane ring expansion and first direct observation of the long-lived triplet diradical intermediatesPublication . M Brás, Elisa; Cabral, Lília; Amado, Patrícia; Abe, Manabu; Fausto, Rui; Cristiano, Maria De LurdesDispiro-1,2,4-trioxolane, 1, an ozonide with efficient and broad antiparasitic activity, was synthesized and investigated using matrix isolation FTIR and EPR spectroscopies together with both B3LYP/6-311++G(3df, 3dp) and M06- 2X/6-311++G-(3df,3dp) theoretical methods. Irradiations (lambda >= 290 nm) of the matrix isolated 1 (Ar or N-2) afforded exclusively 4-oxahomoadamantan-5-one, 4, and 1,4-cyclohexanedione, 5. These results suggested that the reaction proceeded via a dioxygen-centered diradical intermediate, formed upon homolytic cleavage of the labile peroxide bond, which regioselectively isomerized to form the more stable (secondary carbon-centered)/oxygen-centered diradical. In situ EPR measurements during the photolysis of 1 deposited in a MeTHF-matrix led to the detection of signals corresponding to two triplet species, one of which was short-lived while the other proved to be persistent at 10 K. These observations strongly support the proposed mechanism for the photogeneration of 4 and 5, which involves intramolecular rearrangement of the intermediate diradical species 2 to afford the triplet diradical 3.
- Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybridsPublication . Amado, Patrícia S. M.; Costa, Inês C. C.; Paixão, José A.; Mendes, Ricardo F.; Cortes, Sofia; Cristiano, Maria L.Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1, OZ2) and tetraoxane–pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane–pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead.