Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure–activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.
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机译:在这里,我们描述了由面向多样性的合成(DOS)途径加速的药物化学,以及我们先前报道的源自合成途径的大环抗疟剂的体内研究。集中于附肢和骨骼特征的构效关系产生了纳摩尔的恶性疟原虫无性血液阶段生长抑制剂,具有改善的溶解度和微粒体稳定性,并减少了hERG结合。建立/配对/配对(B / C / P)合成策略(用于最初的筛选文库)有助于简化抗疟疾药物的药物化学优化。
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