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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.
Declaration of interest
The authors have declared that no competing interests exist.
This work received fundings from Conselho Nacional de Pesquisas Brasileira (CNPq), Fundação de Amparo as Pesquisas do Estado da Bahia (FAPESB), Fundação de Amparo à Pesquisa do Estado de Alagoas (FAPEAL) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). M.B.P.S., M.O.G.S., A.E.G.S., C.A.C., J.M.B.F. and R.R.S hold a CNPq fellowship. T.S.M. is holding a FAPESB doctoral scholarship, while D.R.M.M. is holding a FAPESB scholarship for visiting scholars.