Plasmodium falciparum is responsible for the majority of malaria deaths globally and is the most prevalent species in sub-Saharan Africa. In 2017, 212 million new cases and 435,000 deaths were reported. Malaria is a tropical disease with the highest mortality rate in low-income countries. The findings in this paper shed light on the relationship among the speed of action, molecular target and combinatory profile and identified new hits with in vivo activity as candidates for anti-malarial combination therapy. Both compounds showed oral efficacy at 50 mg/kg in a mouse model of Plasmodium berghei malaria (64% and 40% reduction in parasitaemia on day 5 post-infection, respectively). Lastly, the in vivo activity of the thiazolopyrimidinone and benzodiazepine derivatives were assessed.
The collected data indicated that the indenopyridazinone derivative, a bc 1 complex inhibitor, had a similar association profile in combination with proguanil when compared to atovaquone combined with proguanil, thereby corroborating the correlation between the molecular target and the combination profile. The remaining compounds showed an antagonistic combinatory profile with artesunate.
Combinatory profile evaluation indicated that thiazolopyrimidinone and benzodiazepine derivatives have an additive profile, suggesting that the combination of these inhibitors with artesunate is favourable for in vitro inhibitory activity. Acridine, thiazolopyrimidine, quinoxaline, benzimidazole, thiophene, benzodiazepine, isoxazole and pyrimidoindole derivatives showed fast in vitro inhibitory activity of parasite growth, whereas hydrazinobenzimidazole, indenopyridazinone and naphthalenone derivatives were slow-acting in vitro inhibitors. Next, both the speed of action and the combination profile of each compound with artesunate was assessed. The cytotoxicity of each selected compound was evaluated and used to calculate the selectivity index (SI values ranging from 15.1 to 6100). The in vitro inhibitory activity of each compound confirmed the reported potencies (IC 50 values ranging from 0.005 to 1 µM). ResultsĪ set of 11 structurally diverse compounds from the Malaria Box with a similarity threshold of less than 0.05 was selected and compared with artesunate. berghei in vivo activity of the best compounds were assessed. Then, the speed of action, the combination profile of selected inhibitors with artesunate, and the P. falciparum 3D7 strain (SYBR Green I inhibition assay) and the cytotoxicity against HepG2 cells (MTT and neutral red assays) were evaluated. Next, the inhibitory potency against the P. The used MolPrint 2D fingerprints and the Tanimoto similarity index were used to perform a structural similarity search within the Malaria Box collection to select diverse molecular scaffolds that are different from artesunate. Evidence of resistance to ACT has been reported in Cambodia, and without new and effective anti-malarial agents, malaria burden and mortality will rise. Artemisinin-based combination therapy (ACT) is used as the first-line treatment of uncomplicated malaria caused by the Plasmodium falciparum parasite and chloroquine-resistant Plasmodium vivax parasites.
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