Drug Discovery and Development Center (H3D), University of Cape Town, Rondebosch 7701, South Africa.
Drug Discovery and Development Center (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
J Med Chem. 2021 Feb 25;64(4):2291-2309. doi: 10.1021/acs.jmedchem.1c00034. Epub 2021 Feb 12.
A novel diazaspiro[3.4]octane series was identified from a whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the cyclic amine resistance locus in the mode of resistance.
从全细胞高通量筛选活动中鉴定出了一种新型的二氮杂螺[3.4]辛烷系列。这些化合物对寄生虫生命周期的多个阶段都具有活性，再加上一种新型的富含硫的支架，为进一步优化先导化合物和进行生物学特性研究提供了有吸引力的起点。构效关系研究鉴定出了具有低纳摩尔（<50 nM）无性血阶段活性和强烈配子体杀菌作用的化合物，在标准的膜喂食试验中转化为阻断传播的活性。通过对其中一种类似物进行耐药性选择和全基因组测序的抗性研究表明，环状胺耐药基因座与耐药模式有关。
