Hermann Theresa, Hochegger Patrick, Dolensky Johanna, Seebacher Werner, Pferschy-Wenzig Eva-Maria, Saf Robert, Kaiser Marcel, Mäser Pascal, Weis Robert
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstraße 1, A-8010 Graz, Austria.
Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Beethovenstraße 8, A-8010 Graz, Austria.
Pharmaceuticals (Basel). 2021 Oct 30;14(11):1109. doi: 10.3390/ph14111109.
The 2-phenoxybenzamide from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of . It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of . Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D. and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The -butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against NF54 (NF54 IC = 0.2690 µM) and very low cytotoxicity (L-6 cells IC = 124.0 µM) resulting in an excellent selectivity index of 460. Compared to the lead structure the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.
来自疟疾药物事业组织疟疾药盒项目的2-苯氧基苯甲酰胺对不同菌株显示出有前景的多阶段活性。它通过逆合成方法成功合成。随后，制备了21种新衍生物，并测试了它们对恶性疟原虫NF54株血液阶段的体外活性。揭示了一些关于构效关系的见解。化合物的抗疟活性和细胞毒性强烈依赖于苯胺基部分结构的取代模式以及取代基的大小。二芳基醚部分结构对活性有进一步影响。此外，计算了几个物理化学和药代动力学参数（log P、log D和配体效率）或通过实验测定（被动通透性和CYP3A4抑制）。4-{4-[2-(4-氟苯氧基)-3-(三氟甲基)苯甲酰胺基]苯基}-1-哌嗪羧酸丁酯对恶性疟原虫NF54具有高抗疟活性（NF54 IC = 0.2690 µM）和非常低的细胞毒性（L-6细胞IC = 124.0 µM），导致优异的选择性指数为460。与先导结构相比，抗疟活性以及物理化学和一些药代动力学参数都得到了改善。
