Roberts Bracken F, Iyamu Iredia D, Lee Sukjun, Lee Eunyoung, Ayong Lawrence, Kyle Dennis E, Yuan Yu, Manetsch Roman, Chakrabarti Debopam
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
Department of Chemistry and Chemical Biology and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
Int J Parasitol Drugs Drug Resist. 2016 Feb 12;6(1):85-92. doi: 10.1016/j.ijpddr.2016.02.004. eCollection 2016 Apr.
We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials.
我们筛选了一组由类天然产物亚结构基序组成的合成化合物，通过一种无偏向的基于细胞的测定方法，确定一种螺环色满作为一种新型抗疟药效团。活性最高的螺环化合物UCF 201对氯喹耐药的Dd2菌株表现出350 nM的50%有效浓度（EC50），并且使用人肝HepG2细胞时选择性超过50。我们对UCF 201理化性质的分析表明，它符合Lipinski参数，具有可接受的理化特征。我们对保留螺环基序的市售色满进行了有限的构效关系研究。我们对UCF 201阶段特异性的评估表明，该化合物在疟原虫发育的环状体、滋养体和裂殖体阶段以及裂殖子入侵时早期发挥作用，阻断寄生虫发育。SPC是一种有吸引力的先导候选支架，因为它能够作用于寄生虫无性生命周期的所有阶段，这与目前的抗疟药物不同。
