Browsing by Author "Cristiano, Maria De Lurdes"
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- 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.
- Artemisinin inspired synthetic endoperoxide drug candidates: Design, synthesis, and mechanism of action studiesPublication . Woodley, Christopher M.; Amado, Patrícia; Cristiano, Maria De Lurdes; O'Neill, Paul M.Artemisinin combination therapies (ACTs) have been used as the first-line treatments against Plasmodium falciparum malaria for decades. Recent advances in chemical proteomics have shed light on the complex mechanism of action of semi-synthetic artemisinin (ARTs), particularly their promiscuous alkylation of parasite proteins via previous heme-mediated bioactivation of the endoperoxide bond. Alarmingly, the rise of resistance to ART in South East Asia and the synthetic limitations of the ART scaffold have pushed the course for the necessity of fully synthetic endoperoxide-based antimalarials. Several classes of synthetic endoperoxide antimalarials have been described in literature utilizing various endoperoxide warheads including 1,2-dioxanes, 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes. Two of these classes, the 1,2,4-trioxolanes (arterolane and artefenomel) and the 1,2,4,5-tetraoxanes (N205 and E209) based antimalarials, have been explored extensively and are still in active development. In contrast, the most recent publication pertaining to the development of the 1,2-dioxane, Arteflene, and 1,2,4-trioxanes fenozan-50F, DU1301, and PA1103/SAR116242 was published in 2008. This review summarizes the synthesis, biological and clinical evaluation, and mechanistic studies of the most developed synthetic endoperoxide antimalarials, providing an update on those classes still in active development.
- 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.
- Copper(II) and cobalt(II) tetrazole-saccharinate complexes as effective catalysts for oxidation of secondary alcoholsPublication . Frija, Luis M. T.; Alegria, Elisabete C. B. A.; Sutradhar, Manas; Cristiano, Maria De Lurdes; Ismael, Amin; Kopylovich, Maximilian N.; Pombeiro, Armando J. L.Mononuclear Cu(II) and Co(II) complexes comprising 2-methyltetrazole-saccharinate bidentate N,N-chelating ligand have been synthesized for the first time and tested as homogeneous catalysts for oxidation of secondary alcohols in a solvent-free and microwave assisted protocol using aqueous tertbutyl hydroperoxide (TBHP) as oxidant. The developed catalytic system exhibits broad functional group compatibility, allowing efficient and selective conversion of a variety of secondary alcohols, including allylic ones, into the corresponding ketones. With typical 0.2 mol% content of the catalyst and under 20-50 W microwave irradiation, most reactions are complete within 10 min, presenting TONs up to 5.5 x 10(2) and TOFs up to 1.1 x 10(4)h(-1). No additives and co-oxidants have been used, while TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) acts as inhibitor in most cases. A plausible reaction mechanism involving the new catalytic systems is outlined. (C) 2016 Elsevier B.V. All rights reserved.
- Insights into the photochemistry of 5-aminotetrazole derivatives with applications in coordination chemistry. Effect of the saccharyl moiety on the photostabilityPublication . Ismael, Amin; Abe, Manabu; Fausto, Rui; Cristiano, Maria De LurdesThe properties and applications of 2-methyl-(211)-tetrazole-5-amino-saccharinate (2MTS) in catalysis and chelant-based chemotherapy stimulated investigations on its photostability. The photochemistry of monomeric 2MTS in solid argon (15 K) was compared with those of 2-methyl-(2H)-tetrazole-5-amine (2MT) and 1-methyl-(2H)-tetrazole-5-amine (1MT). Compounds were subjected to in situ narrowband UV-irradiation at different wavelengths. Reactions were followed by infrared spectroscopy, supported by B3LYP/6-311++G(d,p) calculations. Photochemical pathways for 2MT and 2MTS proved similar but photodegradation of 2MTS was 20x slower, unraveling the photostabilizing effect of the saccharyl moiety that extends into the nitrilimine formed from 2MTS and its antiaromatic 1H-diazirene isomer, which proved photostable at 290 nm, unlike the 1H-diazirene formed from 2MT. Analysis of the photochemistries of 2MTS/2MT (250 nm) and 1MT (222 nm), including energy trends calculated for the isomeric C2H5N3 species postulated/observed from photolysis and EPR results, enabled a deeper insight into the photodegradation mechanisms of 1,5-substituted and 2,5-substituted tetrazoles. We postulate a pivotal singlet state imidoylnitrene species, (s)N1, as common intermediate, which undergoes a Wolff-type isomerization to a stable carbodiimide. Photo-extrusion of N-2 from 1,5-substituted tetrazoles generates (s)N1 directly but from 2,5-substituted tetrazoles it originates a nitrilimine, then a diazirene, which finally leads to (s)N1. Selective formation of cyanamide from 1MT requires photoisomerization between (s)N1 and (s)N2, accessible at 222 nm. EPR studies enabled the detection of methyl nitrene, arising from photolysis of 1H-diazirene intermediate.
- Investigations into the Mechanism of Solvolysis of 3-aryloxybenzisothiazolesPublication . Ismael, Amin; Gago, David J. P.; Cabral, Lília; Fausto, Rui; Cristiano, Maria De LurdesThe solvolysis of selected 3-aryloxybenzisothiazoles (6a-c; Figure 1) in alcohols has been theoretically investigated. The geometries of ethers 6a-c were fully optimized at the DFT(O3LYP) level, with the 6-31++G(d,p) and 6-311++G(3df,3pd) basis sets. Calculations including solvation effects were performed with the 6-31++G(d,p) basis set. Overall, theoretical values for bond lengths and angles around the central ether linkage in ethers 6a-c are very close, for the isolated molecule and in methanol, and are also very close to those obtained by X-ray crystallography, revealing that the nature of the substituent on the aryl system has a negligible effect on geometric parameters around the ether linkage. The same applies to charge distributions, predicted using the NPA approach. However, measured rate constants for the solvolysis of the same compounds in alcohols show that the rate is affected by the electron-withdrawing/-donating characteristics of the substituent on the aryl ring and by the polarity of solvent. Two general pathways were considered for the solvolysis of ethers 6: associative (addition-elimination) or dissociative (fragmentation-recombination) mechanisms. Molecular orbital calculations by means of polarized continuum model (PCM) reaction field predicted that solvolysis of ethers 6 prefers an addition-elimination mechanism. Calculations show also that a dissociative mechanism for the solvolysis of ethers 6a-c is energetically much more demanding than its addition-elimination counterpart and is therefore a highly improbable pathway for the solvolysis. In addition, it was found that the putative cation intermediate formed during a dissociative process should easily convert into its 2-cyanobenzenesulfone cation isomer, via cleavage of the S-N bond.
- Marine paralytic shellfish toxins: chemical properties, mode of action, newer analogues, and structure–toxicity relationshipPublication . Leal, Joana F.; Cristiano, Maria De LurdesUp to the end of 2020 Every year, the appearance of marine biotoxins causes enormous socio-economic damage worldwide. Among the major groups of biotoxins, paralytic shellfish toxins, comprising saxitoxin and its analogues (STXs), are the ones that cause the most severe effects on humans, including death. However, the knowledge that currently exists on their chemistry, properties and mode of toxicological action is disperse and partially outdated. This review intends to systematically compile the dispersed information, updating and complementing it. With this purpose, it addresses several aspects related to the molecular structure of these toxins. Special focus is given to the bioconversion reactions that may occur in the different organisms (dinoflagellates, bivalves, and humans) and the possible mediators involved. A critical review of the most recently discovered analogues, the M-series toxins, is presented. Finally, a deep discussion about the relationship between the molecular structure (e.g., effect of the substituting groups and the net charge of the molecules) and the toxic activity of these molecules is performed, proposing the concept of "toxicological traffic light" based on the toxicity equivalency factors (TEFs).
- 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.
- On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylatePublication . Horta, Pedro; Henriques, Marta S. C.; Bras, Elisa M.; Murtinheira, Fernanda; Nogueira, Fatima; O'Neill, Paul M.; Paixao, Jose A.; Fausto, Rui; Cristiano, Maria De LurdesRecent studies directed to the design of compounds targeting the bc(1) protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc(1) inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol(-1), are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.
- 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.