期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 5, 期 2, 页码 108-112出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml4002985
关键词
Antimalarials; endoperoxide; sporogonic cycle; P. berghei
资金
- Fundacao para a Ciencia e Tecnologia, Portugal [PTDC/SAU-FAR/118459/2010, Pest-OE/SAU/UI4013/2011, PTDC/SAU-MIC/117060/2010, SFRH/BD/63200/2009]
- Engineering and Physical Sciences Research Council [EP/K039687/1] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-MIC/117060/2010, PTDC/SAU-FAR/118459/2010, SFRH/BD/63200/2009] Funding Source: FCT
- EPSRC [EP/K039687/1] Funding Source: UKRI
In a search for effective compounds against both the blood- and liver-stages of infection by malaria parasites with the ability to block the transmission of the disease to mosquito vectors, a series of hybrid compounds combining either a 1,2,4-trioxane or 1,2,4,5-tetraoxane and 8-aminoquinoline moieties were synthesized and screened for their antimalarial activity. These hybrid compounds showed high potency against both exoerythrocytic and erythrocytic forms of malaria parasites, comparable to representative trioxane-based counterparts. Furthermore, they efficiently blocked the development of the sporogonic cycle in the mosquito vector. The tetraoxane-based hybrid 5, containing an amide linker between the two moieties, effectively cleared a patent blood-stage P. berghei infection in mice after i.p. administration. Overall, these results indicate that peroxide-8-aminoquinoline hybrids are excellent starting points to develop an agent that conveys all the desired antimalarial multistage activities in a single chemical entity and, as such, with the potential to be used in malaria elimination campaigns.
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