Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University , Parkville , Victoria 3052 , Australia.
TCG Lifesciences Private Limited , Block BN, Plot 7, Salt-lake Electronics Complex, Sector V , Kolkata 700091 , West Bengal , India.
J Med Chem. 2018 Dec 13;61(23):10875-10894. doi: 10.1021/acs.jmedchem.8b01544. Epub 2018 Nov 29.
A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM.
一种多样化小分子文库的表型筛选，以抑制寄生性线虫旋毛虫幼虫的发育，导致了一种 1-甲基-1H-吡唑-5-甲酰胺衍生物的鉴定，其 IC 为 0.29 μM。为了阐明结构-活性关系（SAR），药物化学优化的目标是对支架的左侧（LHS）、中间部分和右侧（RHS）进行修饰。强烈的 SAR 允许迭代和定向组装一组 64 个类似物，其中化合物 60 被确定为最有效的化合物，对第四幼虫（L4）阶段的发育抑制的 IC 为 0.01 μM。相比之下，即使在高达 50 μM 的浓度下，也只观察到对乳腺上皮细胞系 MCF10A 活力的 18%抑制。
