Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
Griffith Institute for Drug Discovery, 46 Don Young Road, Nathan Campus, Griffith University, QLD, 4111, Australia.
Eur J Med Chem. 2021 Feb 5;211:113065. doi: 10.1016/j.ejmech.2020.113065. Epub 2020 Dec 5.
Histone deacetylases (HDACs) have been identified as emerging antiplasmodial drug targets. In this work, we report on the synthesis, structure-activity relationships, metabolic stability and in vivo efficacy of new peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity. A mini library of HDAC inhibitors was synthesized using a one-pot, multi-component protocol or submonomer pathways. The screening of the target compounds for their activity against asexual blood stage parasites, human cell cytotoxicity, liver stage parasites, and selected human HDAC isoforms provided important structure-activity relationship data. The most promising HDAC inhibitor from this series, compound 3n, demonstrated potent activity against drug-sensitive and drug-resistant asexual stage P. falciparum parasites and was selective for the parasite versus human cells (Pf3D7 IC 0.016 μM; SI 573; PfDd2 IC 0.002 μM; SI 4580) combined with activity against P. berghei exoerythrocytic liver stages (PbEEF IC 0.48 μM). While compound 3n displayed high stability in human (Cl 5 μL/min/mg) and mouse (Cl 6 μL/min/mg) liver microsomes, only modest oral in vivo efficacy was observed in P. berghei infected mice. Together these data provide a foundation for future work to improve the properties of these dual-stage inhibitors as drug leads for malaria.
组蛋白去乙酰化酶（HDACs）已被确定为新兴的抗疟药物靶点。在这项工作中，我们报告了具有双重抗疟活性的新型肽基 HDAC 抑制剂的合成、构效关系、代谢稳定性和体内疗效。使用一锅多组分方案或亚单体途径合成了一个小型 HDAC 抑制剂文库。对目标化合物进行了抗无性血期寄生虫、人细胞细胞毒性、肝期寄生虫和选定的人 HDAC 同工型活性的筛选，提供了重要的构效关系数据。该系列中最有前途的 HDAC 抑制剂 3n 对敏感和耐药的无性期 P. falciparum 寄生虫表现出强大的活性，对寄生虫与人细胞具有选择性（Pf3D7 IC 0.016 μM；SI 573；PfDd2 IC 0.002 μM；SI 4580），同时对 P. berghei 红细胞外期肝脏阶段（PbEEF IC 0.48 μM）也具有活性。虽然化合物 3n 在人（Cl 5 μL/min/mg）和小鼠（Cl 6 μL/min/mg）肝微粒体中表现出高稳定性，但在感染 P. berghei 的小鼠中仅观察到适度的口服体内疗效。这些数据为进一步改善这些双阶段抑制剂作为疟疾药物先导的性质提供了基础。
