Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites
Structurally simple, potent, Plasmodium selective farnesyltransferase inhibitors that arrest the growth of malaria parasites
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DOI：
10.1021/jm060081v
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发表时间：
2006-09-21
影响因子：
7.3
通讯作者：
Hamilton, Andrew D.
中科院分区：
文献类型：
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作者：
Glenn, Matthew P.;Chang, Sung-Youn;Hamilton, Andrew D.
第三世界国家需要立即获得廉价的治疗方法，以对抗疟疾造成的高死亡率。在这里，我们报告了一类新的抗疟疾蛋白法尼基转移酶(PFT)抑制剂，特别强调简单的分子结构，以便于获得基于最近验证的抗疟疾靶点的治疗。这一新的系列化合物代表了第一个报道的恶性疟原虫选择性PFT抑制剂(高达145倍的选择性)，铅抑制剂显示出良好的体外活性(IC50和lt；1 NM)和在低浓度(ED50和lt；100 NM)对培养的寄生虫的毒性。报告了吸收、代谢和口服生物利用度的初步研究。
Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC50 < 1 nM) and toxicity to cultured parasites at low concentrations (ED50 < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.