多阶段活性疟疾盒式化合物MMV030666的新衍生物及其抗疟效力
New Derivatives of the Multi-Stage Active Malaria Box Compound MMV030666 and Their Antiplasmodial Potencies.
作者信息
Hermann Theresa, Wallner Robin, Dolensky Johanna, Seebacher Werner, Pferschy-Wenzig Eva-Maria, Kaiser Marcel, Mäser Pascal, Weis Robert
机构信息
Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Schubertstraße 1, 8010 Graz, Austria.
Pharmacognosy, Institute of Pharmaceutical Sciences, University of Graz, Beethovenstraße 8, 8010 Graz, Austria.
出版信息
Pharmaceuticals (Basel). 2022 Dec 2;15(12):1503. doi: 10.3390/ph15121503.
MMV's Malaria Box compound MMV030666 shows multi-stage activity against various strains of and lacks resistance development. To evaluate the importance of its diarylether partial structure, diarylthioethers and diphenylamines with varying substitution patterns were prepared. A number of evident structure-activity relationships were revealed. Physicochemical and pharmacokinetic parameters were determined experimentally (passive permeability) or calculated. Compared to the lead compound a diarylthioether was more active and less cytotoxic resulting in an excellent selectivity index of 850. In addition, pharmacokinetic and physicochemical parameters were improved.
MMV的疟疾盒化合物MMV030666对多种疟原虫菌株显示出多阶段活性，且不会产生耐药性。为了评估其二芳基醚部分结构的重要性，制备了具有不同取代模式的二芳基硫醚和二苯胺。揭示了许多明显的构效关系。通过实验（被动通透性）或计算确定了物理化学和药代动力学参数。与先导化合物相比，一种二芳基硫醚活性更高，细胞毒性更小，选择性指数高达850，表现优异。此外，药代动力学和物理化学参数也得到了改善。
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