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- 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.
- Utilização de compostos com atividade antimalárica no controlo de perkinsiose em bivalvesPublication . Cabral, Lília; Dias, Catarina; Leite, Ricardo; Cristiano, Maria De LurdesOutbreaks of protozoan agents such as Perkinsus olseni represent major losses for the shellfish producers, urging the development of measures to contain and decrease these episodes. Antimalarial drugs and selective inhibitors designed to target unique metabolic features of the parasite (metabolisms that are not replicated in the host, such as the folate, and shikimate pathways), have been successfully used in the laboratory to inhibit Perkinsus proliferation. However, due to specificities in Perkinsus species and the surrounding environment, development of drug candidates requires further optimization at the molecular level, to improve pharmacologic properties, as well as development of suitable tests and administration protocols for adequate use. Recent advances and future perspectives on the use endoperoxide-type antimalarials for perkinsosis therapy are presented and discussed.
- 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 and Antileishmanial Activity of 1,2,4,5-Tetraoxanes against Leishmania donovaniPublication . Cabral, Lília; Pomel, Sébastien; Cojean, Sandrine; Amado, Patrícia; Loiseau, Philippe M.; Cristiano, Maria De LurdesA chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of Leishmania donovani. All 15 tested tetraoxanes displayed activity, with IC50 values ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC50 value of 2.52 ± 0.65 µm on L. donovani intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of L. donovani-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.