Institute of Medical Chemistry, Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria.
Wien Klin Wochenschr. 2007;119(19-20 Suppl 3):83-7. doi: 10.1007/s00508-007-0864-6.
Candidate drugs related to the lead compound propafenone are highly effective inhibitors of P. falciparum growth with 50% inhibitory concentrations (IC(50)s) in the sub-micromolar range. The parental compound propafenone is a cardiac sodium channel blocker which is in clinical use for the treatment of ventricular arrhythmia. An in house library of more than 400 compounds with systematically varied structures is available for 2D and 3D quantitative structure activity relationship studies. In a first step selected compounds were evaluated for their antimalarial activity using the histidine-rich protein 2 drug sensitivity assay. Propafenone analogues contain an inherently photoactive aryl-carbonyl substructure, which allows their use in photolabeling studies. Labelling efficiency is increased for compounds in which the phenylpropiophenone core structure is replaced by a benzophenone substructure. However, the phenylpropiophenone substructure represents part of the pharmacophore of the compounds. Benzophenone-type analogues show IC(50) values that are higher than their congeneric phenylpropiophenones. Nevertheless, one of the photoligands shows an IC(50) value in the low micro-molar range. Use of this photoligand is thus expected to allow identification of candidate targets by mass spectrometry following two dimensional separation of the plasmodial proteome. The Malaria Genome Project has advanced our understanding of parasite biology and development of novel drugs can mount on data made available by the recently completed sequencing effort of P. falciparum. The lead compound propafenone is a registered drug and this compound class might therefore have a major potential as an antimalarial drug, either alone, or in combination with conventional antimalarials.
候选药物与先导化合物普罗帕酮相关，是高度有效的疟原虫生长抑制剂，半数抑制浓度（IC50）在亚微米范围内。母体化合物普罗帕酮是一种心脏钠离子通道阻滞剂，用于治疗室性心律失常。内部拥有 400 多种具有系统变化结构的化合物库，可用于二维和三维定量构效关系研究。在第一步中，使用组氨酸丰富蛋白 2 药物敏感性测定法评估了选定的化合物的抗疟活性。普罗帕酮类似物含有内在光活性的芳基-羰基亚结构，允许在光标记研究中使用。当苯丙基苯并酮核心结构被苯并酮亚结构取代时，化合物的标记效率会增加。然而，苯丙基苯并酮亚结构是化合物药效团的一部分。苯并酮型类似物的 IC50 值高于其同类的苯丙基苯并酮。然而，其中一种光配体的 IC50 值在低微摩尔范围内。使用这种光配体有望通过二维分离疟原虫蛋白质组后，通过质谱鉴定候选靶标。疟疾基因组计划提高了我们对寄生虫生物学的理解，新型药物的开发可以利用最近完成的疟原虫测序工作提供的数据。先导化合物普罗帕酮是一种注册药物，因此这种化合物类别可能具有作为抗疟药物的主要潜力，无论是单独使用还是与传统抗疟药物联合使用。
