title: Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent.
abstract: This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the β-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol.
authors.affiliation: Fundação Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz , Salvador, BA , Brazil .
authors.forename: Diogo R M
authors.initials: DR
authors.lastname: Moreira
authors.forename: Matheus S
authors.initials: MS
authors.lastname: de Sá
authors.forename: Taís S
authors.initials: TS
authors.lastname: Macedo
authors.forename: Maria N
authors.initials: MN
authors.lastname: Menezes
authors.forename: José Rui M
authors.initials: JR
authors.lastname: Reys
authors.forename: Antônio E G
authors.initials: AE
authors.lastname: Santana
authors.forename: Thaissa L
authors.initials: TL
authors.lastname: Silva
authors.forename: Gabriela L A
authors.initials: GL
authors.lastname: Maia
authors.forename: José M
authors.initials: JM
authors.lastname: Barbosa-Filho
authors.forename: Celso A
authors.initials: CA
authors.lastname: Camara
authors.forename: Tania M S
authors.initials: TM
authors.lastname: da Silva
authors.forename: Katia N
authors.initials: KN
authors.lastname: da Silva
authors.forename: Elisalva T
authors.initials: ET
authors.lastname: Guimaraes
authors.forename: Ricardo R
authors.initials: RR
authors.lastname: dos Santos
authors.forename: Marília O F
authors.initials: MO
authors.lastname: Goulart
authors.forename: Milena B P
authors.initials: MB
authors.lastname: Soares
mesh_terms: D000107:Acetylation; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015162:Micronucleus Tests; D009285:Naphthoquinones / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D009285:Naphthoquinones; C008252:lapachol
keywords: Antiparasitic agents; Plasmodium falciparum; hemozoin; malaria; mitochondria; naphthoquinones