Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue 1 with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue 23 (PfNF54 IC₅₀ = 0.012 μM; PfK1 IC₅₀ = 0.040 μM) displaying high microsomal metabolic stability (HLM CL_int < 11.6 μL·min^–1·mg^–1) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates in vivo efficacy in Plasmodium berghei-infected mice at 4 × 50 mg·kg^–1 oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that 23 could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.

中文翻译：

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新型 3-三氟甲基-1,2,4-恶二唑类阿司咪唑具有多阶段抗疟原虫活性和在伯氏疟原虫小鼠疟疾感染模型中的体内功效

对具有相关代谢不稳定性倾向的含酯阿司咪唑 (AST) 类似物1的迭代药物化学优化导致鉴定出高效的 3-三氟甲基-1,2,4-恶二唑类似物23 ( Pf NF54 IC ₅₀ = 0.012 μM ; Pf K1 IC ₅₀ = 0.040 μM) 显示出高微粒体代谢稳定性（HLM CL _int < 11.6 μL·min ^–1 ·mg ^–1）并且与 AST 相比，hERG 的选择性高 > 1000 倍。除了无性血液阶段活性外，该化合物还显示出针对肝脏和配子体生命周期阶段的活性，并在体内展示4 × 50 mg·kg ^–1口服剂量对伯氏疟原虫感染小鼠的疗效。使用活细胞显微镜和细胞血红素形态分析对作用方式的初步调查显示，23可能影响寄生消化液泡中的多个过程，并可能在与其相关的细胞器中发挥作用的新目标。