发现具有 II 型抑制剂药效团的强效恶性疟原虫蛋白激酶 6（PfPK6）抑制剂。
Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore.
机构信息
Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Department of Chemistry, Duke University, 124 Science Drive, Durham, NC, 27708, USA.
出版信息
Eur J Med Chem. 2023 Mar 5;249:115043. doi: 10.1016/j.ejmech.2022.115043. Epub 2022 Dec 30.
Malaria is a devastating disease that causes significant global morbidity and mortality. The rise of drug resistance against artemisinin-based combination therapy demonstrates the necessity to develop alternative antimalarials with novel mechanisms of action. We report the discovery of Ki8751 as an inhibitor of essential kinase PfPK6. 79 derivatives were designed, synthesized and evaluated for PfPK6 inhibition and antiplasmodial activity. Using group efficiency analyses, we established the importance of key groups on the scaffold consistent with a type II inhibitor pharmacophore. We highlight modifications on the tail group that contribute to antiplasmodial activity, cumulating in the discovery of compound 67, a PfPK6 inhibitor (IC = 13 nM) active against the P. falciparum blood stage (EC = 160 nM), and compound 79, a PfPK6 inhibitor (IC < 5 nM) with dual-stage antiplasmodial activity against P. falciparum blood stage (EC = 39 nM) and against P. berghei liver stage (EC = 220 nM).
疟疾是一种毁灭性疾病，在全球范围内导致了大量的发病率和死亡率。抗青蒿素联合疗法的耐药性上升表明，有必要开发具有新型作用机制的替代抗疟药物。我们报告了 Ki8751 作为 PfPK6 必需激酶抑制剂的发现。设计、合成了 79 个衍生物，并对 PfPK6 抑制作用和抗疟活性进行了评价。通过基团效率分析，我们确定了支架上关键基团的重要性，这些基团与 II 型抑制剂药效团一致。我们强调了尾部基团的修饰，这些修饰有助于抗疟活性，最终发现了化合物 67，它是一种 PfPK6 抑制剂（IC50=13 nM），对疟原虫血期具有活性（EC50=160 nM），以及化合物 79，它是一种 PfPK6 抑制剂（IC50<5 nM），对疟原虫血期（EC50=39 nM）和伯氏疟原虫肝期（EC50=220 nM）具有双重阶段抗疟活性。
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