| Title |
New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum
|
|---|---|
| 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. |
Mendeley readers
The data shown below were compiled from readership statistics for 79 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 79 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 17 | 22% |
| Student > Master | 12 | 15% |
| Researcher | 6 | 8% |
| Student > Doctoral Student | 6 | 8% |
| Student > Bachelor | 5 | 6% |
| Other | 15 | 19% |
| Unknown | 18 | 23% |
| Readers by discipline | Count | As % |
|---|---|---|
| Chemistry | 14 | 18% |
| Pharmacology, Toxicology and Pharmaceutical Science | 12 | 15% |
| Biochemistry, Genetics and Molecular Biology | 10 | 13% |
| Agricultural and Biological Sciences | 5 | 6% |
| Medicine and Dentistry | 4 | 5% |
| Other | 11 | 14% |
| Unknown | 23 | 29% |
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 24 April 2018.
All research outputs
#8,135,862
of 24,400,706 outputs
Outputs from Malaria Journal
#2,585
of 5,827 outputs
Outputs of similar age
#134,129
of 332,864 outputs
Outputs of similar age from Malaria Journal
#59
of 124 outputs
Altmetric has tracked 24,400,706 research outputs across all sources so far. This one is in the 44th percentile – i.e., 44% of other outputs scored the same or lower than it.
So far Altmetric has tracked 5,827 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 7.0. This one is in the 47th percentile – i.e., 47% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 332,864 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 52% of its contemporaries.
We're also able to compare this research output to 124 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 50% of its contemporaries.