de Lange Christo, Coertzen Dina, Smit Frans J, Wentzel Johannes F, Wong Ho Ning, Birkholtz Lyn-Marie, Haynes Richard K, N'Da David D
Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
Department of Biochemistry, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield 028, South Africa.
Bioorg Med Chem Lett. 2018 Feb 1;28(3):289-292. doi: 10.1016/j.bmcl.2017.12.057. Epub 2017 Dec 26.
Novel derivatives bearing a ferrocene attached via a piperazine linker to C-10 of the artemisinin nucleus were prepared from dihydroartemisinin and screened against chloroquine (CQ) sensitive NF54 and CQ resistant K1 and W2 strains of Plasmodium falciparum (Pf) parasites. The overall aim is to imprint oxidant (from the artemisinin) and redox (from the ferrocene) activities. In a preliminary assessment, these compounds were shown to possess activities in the low nM range with the most active being compound 6 with IC values of 2.79 nM against Pf K1 and 3.2 nM against Pf W2. Overall the resistance indices indicate that the compounds have a low potential for cross resistance. Cytotoxicities were determined with Hek293 human embryonic kidney cells and activities against proliferating cells were assessed against A375 human malignant melanoma cells. The selectivity indices of the amino-artemisinin ferrocene derivatives indicate there is overall an appreciably higher selectivity towards the malaria parasite than mammalian cells.
以二氢青蒿素为原料制备了新型衍生物，该衍生物通过哌嗪连接基与青蒿素核的C-10位相连的二茂铁，并针对氯喹（CQ）敏感的NF54以及CQ耐药的恶性疟原虫（Pf）K1和W2菌株进行了筛选。总体目标是赋予（来自青蒿素的）氧化剂和（来自二茂铁的）氧化还原活性。在初步评估中，这些化合物显示出在低纳摩尔范围内的活性，其中活性最高的是化合物6，其对Pf K1的IC值为2.79 nM，对Pf W2的IC值为3.2 nM。总体而言，耐药指数表明这些化合物产生交叉耐药的可能性较低。用Hek293人胚肾细胞测定细胞毒性，并针对A375人恶性黑色素瘤细胞评估其对增殖细胞的活性。氨基青蒿素二茂铁衍生物的选择性指数表明，总体而言，其对疟原虫的选择性明显高于哺乳动物细胞。
