Department of Biochemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, PO Box x20, Pretoria, 0028, South Africa.
J Med Chem. 2011 Oct 13;54(19):6624-33. doi: 10.1021/jm200463z. Epub 2011 Sep 14.
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 μM, 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.
一系列烷基化（双）脲和（双）硫脲多胺类似物被合成并筛选其抗疟活性，针对体外氯喹敏感和耐药的恶性疟原虫株。所有类似物均显示对恶性疟原虫的生长抑制活性，低于 3 μM，其中大多数具有在 100-650 nM 范围内的有效 IC 50 值。由于核分裂和无性发育的阻断，类似物在暴露后 24 小时内阻止寄生虫生长。此外，这种作用似乎是细胞毒性的，并且对疟原虫具有高度选择性（对恶性疟原虫的 IC 50 低 7000 倍以上），并且不能通过外源性添加多胺来逆转。由于首次报道了含有 3-7-3 或 3-6-3 碳骨架和取代末端脲基或硫脲基团的多胺类似物具有很强的抗疟活性，我们提出这些化合物代表了一类结构新颖的抗疟药物。
