Title |
New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum
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Published in |
Malaria Journal, April 2018
|
DOI | 10.1186/s12936-018-2281-x |
Pubmed ID | |
Authors |
Lis Lobo, Lília I. L. Cabral, Maria Inês Sena, Bruno Guerreiro, António Sebastião Rodrigues, Valter Ferreira de Andrade-Neto, Maria L. S. Cristiano, Fatima Nogueira |
Abstract |
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. 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. 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. 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. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 78 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 17 | 22% |
Student > Master | 13 | 17% |
Student > Doctoral Student | 6 | 8% |
Researcher | 6 | 8% |
Student > Bachelor | 5 | 6% |
Other | 13 | 17% |
Unknown | 18 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 14 | 18% |
Pharmacology, Toxicology and Pharmaceutical Science | 11 | 14% |
Biochemistry, Genetics and Molecular Biology | 10 | 13% |
Agricultural and Biological Sciences | 5 | 6% |
Medicine and Dentistry | 4 | 5% |
Other | 11 | 14% |
Unknown | 23 | 29% |