Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold

In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50= 0.05 μM, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50= 0.17 μM, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of the new chemical scaffold provided more information on the binding modes and the spare volume at the binding cavity, thus can guide the design of the further potent compounds.PMID:35872393 | DOI:10.1016/j.ejmech.2022.114608

Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Sheng Han Heng Li Weixiong Chen Li Yang Xiankun Tong Jianping Zuo Youhong Hu Source Type: research