期刊
CHEMMEDCHEM
卷 9, 期 2, 页码 305-310出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201300459
关键词
N-cinnamoylation; drug resistance; dual-stage antimalarial agents; Plasmodium falciparum; quinacrine
资金
- European Regional Development Fund (FEDER), Portugal through the POFC-COMPETE program [FCOMP-01-0124-FEDER-020963]
- Portuguese Foundation for Science and Technology (FCT) [PTDC/QUI-QUI/116864/2010]
- FCT [PTDC/SAU-MII/099118/2008, SFRH/BPD/62967/2009, SFRH/BD/86166/2012]
- [PEst-C/QUI/UI0081/2011]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-MII/099118/2008, SFRH/BD/86166/2012, PEst-C/QUI/UI0081/2011, PTDC/QUI-QUI/116864/2010] Funding Source: FCT
Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N-cinnamoylated quinacrine surrogates, 9-(N-cinnamoylaminobutyl)amino-6-chloro-2-methoxyacridines, is reported. The compounds were found to be highly potent against both blood-stage P. falciparum, chloroquine-sensitive 3D7 (IC50 = 17.0-39.0 nm) and chloroquine-resistant W2 and Dd2 strains (IC50 = 3.2-41.2 and 27.1-131.0 nm, respectively), and liver-stage P. berghei (IC50 = 1.6-4.9 mm) parasites. These findings bring new hope for the possible future rise of a fallen angel in antimalarial chemotherapy, with a potential resurgence of quinacrine-related compounds as dual-stage antimalarial leads.
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