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- Structural investigation of nitrogen-linked saccharinate–tetrazolePublication . Gómez-Zavaglia, A.; Ismael, Amin; Cabral, Lília; Kaczor, A.; Paixão, J. A.; Fausto, R.; Cristiano, Maria Lurdes SantosThe molecular structure of nitrogen-linked saccharinate–tetrazole, N-(1,1-dioxo-1,2-benzisothiazol-3-yl)-amine-1H-tetrazole (BAT), was investigated in the crystalline state using X-ray crystallography and infrared and Raman spectroscopies, and isolated in argon matrix by infrared spectroscopy. Interpretation of the experimental results was supported by quantum chemical calculations undertaken at the DFT(B3LYP)/6-311++G(3df,3pd) level of theory. In the neat crystalline solid (space group C2/c, a = 21.7493(3) Å, b = 8.85940(10) Å, c = 10.76900(10) Å, b = 103.3300(10) deg; Z = 8), BAT units exist in the (1H)-tetrazole aminosaccharin tautomeric form, with the NH spacer establishing a hydrogen bond to the nitrogen in position-4 of the tetrazole group of a neighbour molecule, and the NH group of the tetrazole fragment forming a bifurcated H-bond to the saccharyl nitrogen of the same molecule and to one of the oxygen atoms of a second neighbour molecule. On the other hand, according to both the matrix isolation infrared studies and the theoretical calculations, the isolated BAT molecule exists preferentially as the (1H)-tetrazole iminosaccharin tautomer, where the main stabilizing interaction is the intramolecular H-bond established between the NH group of the saccharyl ring and the tetrazole nitrogen atom in position 4. A detailed conformational analysis of the studied molecule and full assignment of the vibrational spectra for both the matrix-isolated compound and crystalline sample were undertaken.
- 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.
- Synthesis and structure of 2-substituted pyrene-derived scaffoldsPublication . Cabral, Lília; Henriques, Marta Sofia; Paixão, José António; Lurdes S. Cristiano, M.Pyrenes bear a propensity to form fluorescent excimers, and thus this chromophore is often found in sensors and fluorescent probes. 2-FunctionaIized pyrenes are of particular interest, however the preparation of these scaffolds is not trivial, involving synthetic routes that require 4,5,9,10-tetrahydropyrene as a key intermediate. Herein, the development and optimization of routes for the synthesis of 2-functionalized pyrene-derived building blocks, with potential to be used as tags in the preparation of fluorescent probes, is described. Additionally, the crystal structures of ethyl 4,5,9,10-tetrahydro-2-pyrene-5-oxopentanoate and 2-acetyl-4,5,9,10-tetrahydropyrene revealed distinct conformations of the saturated tetrahydropyrene rings. (C) 2017 Elsevier Ltd. All rights reserved.
- The thermal sigmatropic isomerization of pseudosaccharyl crotyl etherPublication . Cabral, Lília; Maria, T. M. R.; Martelo, L.; Eusébio, M. E. S.; Cristiano, Maria Lurdes Santos; Fausto, R.The thermally induced sigmatropic isomerization of the pseudosaccharyl crotyl ether, 3-(E)-but-2-enoxy)-1,2-benzisothiazole 1,1-dioxide (CBID), has been investigated by using temperature dependent infrared spectroscopy, differential scanning calorimetry (DSC), and polarized light thermomicroscopy. The reaction can take place in both melted and crystalline phases, affording the product resulting from the [3,30] migration of the allylic system from O to N, 2-(E)-1-methylprop-2-en-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (CBIOD). In the melt, the activation energy of the process was determined as being 49.1 5.3 kJ mol 1, with k¼(22.2 0.6) 104 s 1 at 140 C. In the solid state, at 110 C, the rate constant drops by one order of magnitude [k¼(1.46 0.07) 104 s 1]. The enthalpy of reaction, determined by DSC, is DrxH¼ 27.0 0.8 kJ mol 1. Assignments were proposed for the infrared spectra of the observed neat condensed phases of the two compounds.
- Highly active ozonides selected against drug resistant malariaPublication . Lobo, Lis; Sousa, Bruno de; Cabral, Lília; Cristiano, Maria Lurdes Santos; Nogueira, FátimaEver increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites.
- In vitro susceptibility of Leishmania infantum to Artemisinin derivatives and selected trioxolanesPublication . Cortes, Sofia; Albuquerque, Andreia; Cabral, Lília; Lopes, Liliana; Campino, Lenea; Cristiano, Maria L. S.Leishmaniasis is among the world's most neglected diseases. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. A small library of artemisinin-derived trioxanes and synthetic trioxolanes was tested against promastigote and intramacrophage amastigote forms of Leishmania infantum. The trioxolanes LC50 and LC95 presented the best activity and safety profiles, showing potential for further studies in the context of leishmanial therapy. Our results indicate that the compounds tested exhibit peroxide-dependent activity.
- 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.
- New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparumPublication . Lobo, Lis; Cabral, Lília; Sena, Maria I.; Guerreiro, Bruno; Rodrigues, António S.; de Andrade-Neto, Valter F.; Cristiano, Maria Lurdes Santos; Nogueira, FatimaBackground: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. Methods: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. Results: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3–71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. Conclusion: The investigated, trioxolane–tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.
- 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.
- Organocatalyzed oxidation of benzyl alcohols by a tetrazole-amino-saccharin: A combined experimental and theoretical (DFT) studyPublication . Frija, Luis M. T.; Kuznetsov, Maxim L.; Rocha, Bruno G. M.; Cabral, Lília; Cristiano, Maria Lurdes Santos; Kopylovich, Maximilian N.; Pombeiro, Armando J. L.A new catalytic system for the anaerobic oxidation of benzyl alcohols using a tetrazole-amino-saccharin organocatalyst has been established. In a solvent-free and microwave assisted process comprising aqueous tert-butyl hydroperoxide (TBHP) as oxidant, a variety of benzyl alcohols has been efficiently converted to aldehydes under mild conditions. Most reactions are complete within 30 min and the catalyst exhibits varied functional group compatibility. A catalytic cycle for the oxidation of the alcohols promoted by the tetrazole-amino-saccharin derivative is outlined involving radical species. DFT calculations performed for the oxidation of benzyl alcohol with and without organocatalyst show that the rate limiting step of the whole reaction is the cleavage of the O-O bond in TBHP with the subsequent hydrogen abstraction from the alcohol. The tetrazole-amino-saccharin organocatalyst assists the H-abstraction from benzyl alcohol by the bound HO center dot radical. The simplicity, selectivity and softness of reaction conditions of the studied organocatalytic protocol suggest a great potential for extensive use in synthetic chemistry. (C) 2017 Elsevier B.V. All rights reserved.