Exploration of Fluorinated Peptoid-Based Histone Deacetylase Inhibitors as Dual-Stage Antiplasmodial Agents

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Nina Reßing, Daniel Stopper, Thomas Martin Schäfer, Lais Pessanha de Carvalho, Elizabeth A. Winzeler, Jana Held, Finn K. Hansen
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Abstract

The antiplasmodial properties of a series of fluorinated peptoid-capped histone deacetylase inhibitors (HDACi) were investigated against asexual blood stages of the drug-sensitive 3D7 and drug-resistant Dd2 strains of Plasmodium falciparum, as well as the exo-erythrocytic liver stages and mature gametocytes. Among the series, compound 1h emerged as the most potent derivative, showing strong activity against both P. falciparum strains (Pf 3D7 and Dd2 IC50: 0.010 μM) and Plasmodium berghei liver stages (Pb EEF IC50: 0.74 μM), while lacking activity against mature gametocytes. Compound 1b was identified as a second hit compound with slightly lower activity against asexual blood and liver stages (Pf 3D7 IC50: 0.019 μM; Pf Dd2 IC50: 0.023 μM; Pb EEF IC50: 2.25 μM) but showed excellent parasite selectivity (SIHepG2/3D7: 2389; SIHepG2/Dd2: 1973) and low single-digit micromolar activity against mature gametocytes (IC50: 1.70 μM). Compared to our previous hit compound MAHA-022, both 1b and 1h exhibited improved activity against asexual blood stages and enhanced parasite selectivity, albeit with reduced activity against liver stage parasites. Taken together, compounds 1b and 1h represent promising multi-stage antiplasmodial HDACi scaffolds for further development and optimization.

Abstract Image

基于氟化肽的组蛋白去乙酰化酶抑制剂作为双期抗疟原虫药物的探索
研究了一系列含氟肽包盖组蛋白去乙酰化酶抑制剂(HDACi)对恶性疟原虫(Plasmodium falciparum)药物敏感型3D7和耐药型Dd2株的无性血期、外红细胞肝期和成熟配子体的抗疟原虫特性。其中,化合物1h是最有效的衍生物,对恶性疟原虫菌株(Pf 3D7和Dd2 IC50: 0.010 μM)和伯氏疟原虫肝期(Pb EEF IC50: 0.74 μM)均有较强的活性,但对成熟配子体缺乏活性。化合物1b被鉴定为第二hit化合物,对无性血和肝分期的活性略低(Pf 3D7 IC50: 0.019 μM;Pf Dd2 IC50: 0.023 μM;Pb EEF IC50: 2.25 μM),但具有良好的寄生虫选择性(SIHepG2/3D7: 2389;SIHepG2/Dd2: 1973)和对成熟配子体的低个位数微摩尔活性(IC50: 1.70 μM)。与我们之前的成功化合物MAHA-022相比,1b和1h对无性血阶段的活性都有所提高,对寄生虫的选择性也有所提高,尽管对肝脏阶段寄生虫的活性有所降低。综上所述,化合物1b和1h是有前景的多阶段抗疟原虫HDACi支架,值得进一步开发和优化。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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