Structure-Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II.
Structure-Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II.
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抗疟疟原虫蛋白酶体抑制剂的构效关系研究——第二部分。
DOI：
10.1021/acs.jmedchem.2c01651
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发表时间：
2023
影响因子：
7.3
通讯作者：
Sato
中科院分区：
文献类型：
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作者：
Zhang,Hao;Ginn,John;Zhan,Wenhu;Leung,Annie;Liu,YiJ;Toita,Akinori;Okamoto,Rei;Wong,Tzu-Tshin;Imaeda,Toshihiro;Hara,Ryoma;Michino,Mayako;Yukawa,Takafumi;Chelebieva,Sevil;Tumwebaze,PatrickK;Vendome,Jeremie;Beuming,Thijs;Sato
随着对青蒿素和青蒿素联合疗法耐药的报道越来越多，靶向疟原虫蛋白酶体是一种很有前途的抗疟策略。我们最近报道了一种在人源化小鼠模型中具有抗疟疾活性的高选择性恶性疟原虫蛋白酶体抑制剂。为了平衡一系列大环与其他类药物性质的通透性，我们对联苯醚系缚的大环支架进行了进一步的构效关系研究。围绕P1， P3， P5基团和肽骨架的广泛SAR研究鉴定了化合物TDI-8414。TDI-8414具有纳米摩尔抗寄生虫活性，对HepG2细胞无毒性，对疟原虫蛋白酶体的选择性优于人组成蛋白酶体和免疫蛋白酶体，提高了人与小鼠微粒体和血浆中的溶解度和PAMPA渗透性，增强了代谢稳定性。
With increasing reports of resistance to artemisinins and artemisinin-combination therapies, targeting thePlasmodiumproteasome is a promising strategy for antimalarial development. We recently reported a highly selectivePlasmodium falciparumproteasome inhibitor with anti-malarial activity in the humanized mouse model. To balance the permeability of the series of macrocycles with other drug-like properties, we conducted further structure–activity relationship studies on a biphenyl ether-tethered macrocyclic scaffold. Extensive SAR studies around the P1, P3, and P5 groups and peptide backbone identified compound TDI-8414. TDI-8414 showed nanomolar antiparasitic activity, no toxicity to HepG2 cells, high selectivity against thePlasmodiumproteasome over the human constitutive proteasome and immunoproteasome, improved solubility and PAMPA permeability, and enhanced metabolic stability in microsomes and plasma of both humans and mice.