Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites.
Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites.
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探讨烷基和芳烷基聚氨基（双）脲和（双）硫脲电子等排物作为针对多种生命周期形式的恶性疟原虫寄生虫的有效抗疟化学型。
DOI：
10.1016/j.bmc.2015.01.036
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发表时间：
2015
影响因子：
3.5
通讯作者：
Birkholtz,Lyn-Marie
中科院分区：
文献类型：
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作者：
Verlinden,BiancaK;deBeer,Marna;Pachaiyappan,Boobalan;Besaans,Ethan;Andayi,WarrenA;Reader,Janette;Niemand,Jandeli;vanBiljon,Riette;Guy,Kiplin;Egan,Timothy;Woster,PatrickM;Birkholtz,Lyn-Marie
合成了一系列新的有效的芳基/烷基化（双）脲和（双）硫脲多胺类似物，并在体外评价其抗疟原虫活性。改变碳骨架和末端取代基使化合物库中类似物的效力增加了3倍，其中最具活性的化合物15和16分别显示出28和30 nM的半最大抑制浓度（IC 50值），对各种恶性疟原虫寄生虫菌株没有任何交叉抗性。这些类似物的细胞毒性的体外评价显示，与哺乳动物HepG 2细胞相比，对靶向疟疾寄生虫具有显著的选择性（对寄生虫的IC 50低>5000倍）。多胺类似物抗疟原虫表型的初步生物学评价显示，（双）脲化合物靶向寄生虫无性增殖，而相同系列的（双）硫脲化合物具有阻断寄生虫的可传播配子体形式的独特能力，表明对寄生虫的增殖和非增殖形式的多药理学。在这篇手稿中，我们描述了这些结果，并假设一个完善的抗疟原虫多胺类似物的结构-活性关系（SAR）模型。具有3-5-3或3-6-3碳骨架的末端芳基/烷基化（双）脲-和（双）硫脲-多胺类似物代表了结构新颖且独特的一类潜在抗疟原虫剂，其活性在低纳摩尔范围内，并且对各种生命周期形式的P具有高选择性。恶性疟原虫
A new series of potent potent aryl/alkylated (bis)urea- and (bis)thiourea polyamine analogues were synthesized and evaluated in vitro for their antiplasmodial activity. Altering the carbon backbone and terminal substituents increased the potency of analogues in the compound library 3-fold, with the most active compounds,15and16, showing half-maximal inhibitory concentrations (IC50values) of 28 and 30 nM, respectively, against variousPlasmodium falciparumparasite strains without any cross-resistance. In vitro evaluation of the cytotoxicity of these analogues revealed marked selectivity towards targeting malaria parasites compared to mammalian HepG2 cells (>5000-fold lower IC50against the parasite). Preliminary biological evaluation of the polyamine analogue antiplasmodial phenotype revealed that (bis)urea compounds target parasite asexual proliferation, whereas (bis)thiourea compounds of the same series have the unique ability to block transmissible gametocyte forms of the parasite, indicating pluripharmacology against proliferative and non-proliferative forms of the parasite. In this manuscript, we describe these results and postulate a refined structure–activity relationship (SAR) model for antiplasmodial polyamine analogues. The terminally aryl/alkylated (bis)urea- and (bis)thiourea–polyamine analogues featuring a 3-5-3 or 3-6-3 carbon backbone represent a structurally novel and distinct class of potential antiplasmodials with activities in the low nanomolar range, and high selectivity against various lifecycle forms ofP. falciparumparasites.