期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 19, 页码 6624-6633出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm200463z
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资金
- South African Malaria Initiative
- South African National Research Foundation (NRF) [FA2007050-300003]
- University of Pretoria
- National Institutes of Health [7RO1-CA149095]
- TATA Africa
- EPSCoR
- Office Of The Director [919440] Funding Source: National Science Foundation
A series of alkylated (bis)urea and (bis)thiourea polyamine analogues were synthesized and screened for antimalarial activity against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. All analogues showed growth inhibitory activity against P. falciparum at less than 3 mu M, with the majority having effective IC(50) values in the 100-650 nM range. Analogues arrested parasitic growth within 24 h of exposure due to a block in nuclear division and therefore asexual development. Moreover, this effect appears to be cytotoxic and highly selective to malaria parasites (>7000-fold lower IC(50) against P. falciparum) and is not reversible by the exogenous addition of polyamines. With this first report of potent antimalarial activity of polyamine analogues containing 3-7-3 or 3-6-3 carbon backbones and substituted terminal urea- or thiourea moieties, we propose that these compounds represent a structurally novel class of antimalarial agents.
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