title: Novel endoperoxide-based transmission-blocking antimalarials with liver- and blood-schizontocidal activities.
abstract: 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.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon , Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal.
authors.forename: Daniela
authors.initials: D
authors.lastname: Miranda
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon , Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Capela
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Inês S
authors.initials: IS
authors.lastname: Albuquerque
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Meireles
authors.affiliation: Centro de Malária e Outras Doenças Tropicais, IHMT, Universidade Nova de Lisboa , Rua da Junqueira No. 100, P-1349-008 Lisbon, Portugal.
authors.forename: Isa
authors.initials: I
authors.lastname: Paiva
authors.affiliation: Centro de Malária e Outras Doenças Tropicais, IHMT, Universidade Nova de Lisboa , Rua da Junqueira No. 100, P-1349-008 Lisbon, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Nogueira
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Richard
authors.initials: R
authors.lastname: Amewu
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon , Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal.
authors.forename: Rudi
authors.initials: R
authors.lastname: Oliveira
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon , Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Francesc
authors.initials: F
authors.lastname: Marti
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa , Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon , Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal.
authors.forename: Francisca
authors.initials: F
authors.lastname: Lopes
keywords: Antimalarials; P. berghei; endoperoxide; sporogonic cycle