Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121, Bonn, Germany.
Institute of Tropical Medicine, University of Tübingen, 72074, Tübingen, Germany.
Eur J Med Chem. 2024 Nov 5;277:116782. doi: 10.1016/j.ejmech.2024.116782. Epub 2024 Aug 16.
Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (ICPf3D7 = 30 nM; ICPfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (ICPbEEF = 0.25 μM), excellent microsomal stability (t > 60 min), and low cytotoxicity to HEK293 cells (IC = 136 μM).
组蛋白蛋白的乙酰化和去乙酰化等表观遗传修饰的动态变化已被证明对疟原虫生命周期的发育和存活至关重要，疟原虫是最致命的疟疾寄生虫。在这项研究中，我们提出了一系列新型基于肽的组蛋白去乙酰化酶（HDAC）抑制剂，其中包含含氮双环杂芳基残基，作为新一代抗疟基于肽的 HDAC 抑制剂。我们通过基于 Ugi 四组分反应的高效多组分方案合成了 HDAC 抑制剂。从我们的迷你文库中筛选出的 16 种化合物中，6i 是最有前途的候选物，对无性血期寄生虫具有很强的活性（ICPf3D7 = 30 nM；ICPfDd2 = 98 nM），对肝期寄生虫的活性低至亚微摩尔（ICPbEEF = 0.25 μM），对微粒体具有极好的稳定性（t > 60 分钟），对 HEK293 细胞的细胞毒性低（IC = 136 μM）。
