期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 30, 期 4, 页码 615-621出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/14756366.2014.958083
关键词
Antiparasitic agents; hemozoin; malaria; mitochondria; naphthoquinones; Plasmodium falciparum
资金
- Conselho Nacional de Pesquisas Brasileira (CNPq)
- Fundacao de Amparo as Pesquisas do Estado da Bahia (FAPESB)
- Fundacao de Amparo a Pesquisa do Estado de Alagoas (FAPEAL)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- CNPq fellowship
- FAPESB doctoral scholarship
- FAPESB scholarship
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 beta-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.
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