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ACS Med Chem Lett. 2013 Dec 20;5(2):108-12. doi: 10.1021/ml4002985. eCollection 2014 Feb 13.

Novel endoperoxide-based transmission-blocking antimalarials with liver- and blood-schizontocidal activities.

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Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon , Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal.
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
Centro de Malária e Outras Doenças Tropicais, IHMT, Universidade Nova de Lisboa , Rua da Junqueira No. 100, P-1349-008 Lisbon, Portugal.
Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
Department of Medicine, San Francisco General Hospital, University of California, San Francisco , San Francisco, California 94143, United States.


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.


Antimalarials; P. berghei; endoperoxide; sporogonic cycle

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