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- 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.
- 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.
- Endoperóxidos com actividade antimalárica: estrutura, reactividade e actividadePublication . Guerreiro, Bruno Emanuel de Campos Guerreiro; Cristiano, Maria Lurdes SantosA Malária é uma das doenças infecciosas que mais mata a nível mundial e afecta a humanidade há milénios. É causada por parasitas unicelulares protozoários do género Plasmodium e transmitida por mosquitos fêmea do género Anopheles, sendo a Malária causada por P. falciparum de longe a forma mais grave da doença. O crescente aparecimento e disseminação de estirpes resistentes aos fármacos mais utilizados, como a cloroquina e a mefloquina, principalmente de P. falciparum, bem como a resistência do mosquito vector aos insecticidas utilizados, levaram a um aumento dos casos de Malária em todo o mundo nos últimos anos tendo recentemente a OMS considerado a Malária uma doença tropical de intervenção prioritária. Assim, com o parasita a esgotar as reservas de antimaláricos mais eficazes e seguros, a descoberta da Artemisinina na década de 1970 forneceu alguma esperança no combate à Malária e permitiu a exploração de uma nova classe de antimaláricos, os endoperóxidos antimaláricos. Estes compostos, com uma extraordinária actividade antimalárica e sem grande toxicidade associada, têm um mecanismo de actuação diferente dos fármacos tradicionalmente usados e não apresentam resistência cruzada com estes. A busca de um fármaco que conjugasse uma boa actividade antimalárica com boas propriedades farmacocinéticas e toxicológicas, e que fosse barato, levou ao desenvolvimento dos derivados sintéticos da artemisinina, sendo as classes de derivados 1,2,4-trioxolanos e 1,2,4,5-tetraoxanos as mais promissoras, estando actualmente três derivados já em ensaios clínicos: os trioxolanos OZ277 (arterolano) e OZ439 e o tetraoxano RKA 182.