Novel Inhibitors of <i>Plasmodium</i> Phosphatidylinositol 4-kinase IIIβ with Low Propensity for Resistance: Life Cycle Stage Activity and <i>In Vivo</i> Efficacy in a Humanized Mouse Malaria Infection Model

Anticancer ATP-competitive inhibitors are a promising source of new starting points for antimalarial drug discovery. Herein, we present a novel antimalarial chemotype based on the anticancer human ataxia-telangiectasia-mutated (ATM) kinase inhibitor AZD0156. This class inhibits phosphatidylinositol 4-kinase IIIβ (PI4K) in the human malaria parasite Plasmodium, demonstrating remarkable activities against all stages of the Plasmodium falciparum life cycle. The current series exhibited a lower propensity for resistance and toxicity compared to previous Plasmodium PI4K inhibitors. The lead compound 18 was efficacious in a humanized NOD-scid IL-2Rγnull mouse model of P. falciparum malaria, with an ED90 value of 4.6 mg kg-1.抗癌ATP竞争性抑制剂是抗疟疾药物研发的极具前景的新起点。本文中，我们报道了一种基于抗癌人源共济失调毛细血管扩张症突变激酶（ataxia-telangiectasia-mutated kinase, ATM）抑制剂AZD0156的新型抗疟疾化学型。该类化合物可抑制人疟原虫（Plasmodium）中的磷脂酰肌醇4-激酶IIIβ（phosphatidylinositol 4-kinase IIIβ, PI4K），对恶性疟原虫（Plasmodium falciparum）生命周期的各个阶段均展现出优异的抑制活性。相较于此前报道的疟原虫PI4K抑制剂，本系列化合物具有更低的耐药性与毒性倾向。先导化合物18在恶性疟原虫感染的人源化NOD-scid IL-2Rγnull小鼠模型中展现出明确药效，其90%有效剂量（ED90）为4.6 mg·kg⁻¹。