Synthesis and Structure–Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4‑<i>b</i>]pyridines

Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo­[3,4-b]­pyridines targeting Plasmodium falciparum, the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar in vitro activity against the intraerythrocytic stage of the parasite as well as little to no toxicity against the human fibroblast BJ and liver HepG2 cell lines. In addition, our hit compounds show good activity against the liver stage of the parasite but little activity against the gametocyte stage. Parasitological profiles, including rate of killing, docking, and molecular dynamics studies, suggest that our compounds may target the Qo binding site of cytochrome bc1.疟疾仍是致死性最强的传染病之一，每年造成数十万人死亡，受害者主要为幼儿与孕妇。本研究报道了一系列靶向恶性疟原虫（疟原虫中致死性最强的虫种）的吡唑并[3,4-b]吡啶类化合物的发现与衍生化过程。该系列中的命中化合物对疟原虫的红细胞内期展现出亚微摩尔级体外活性，同时对人类成纤维细胞BJ株与肝脏HepG2细胞系几乎无毒性。此外，本研究中的命中化合物对疟原虫的肝脏期展现出良好活性，但对配子体期活性较弱。包括杀伤速率、分子对接与分子动力学研究在内的寄生虫学特征分析表明，本研究的化合物可能靶向细胞色素bc1复合物的Qo结合位点。