51387-92-9Relevant articles and documents
Antiplasmodial imidazopyridazines: structure-activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles
Cheuka, Peter Mubanga,Lawrence, Nina,Taylor, Dale,Wittlin, Sergio,Chibale, Kelly
supporting information, p. 1733 - 1745 (2018/10/26)
3,6-Diarylated imidazopyridazines have recently been shown to possess good in vitro antiplasmodial and in vivo antimalarial activity. However, frontrunner compounds have been associated with poor solubility and a hERG (human ether-a-go-go-related gene) inhibition liability raising concerns for potential cardiotoxicity risks. Herein, we report the synthesis and structure-activity relationship studies of new imidazopyridazines aimed at improving aqueous solubility and countering hERG inhibition while maintaining antiplasmodial potency. While we identified new analogues with potent antiplasmodial activity (IC50 = 0.031 μM against the NF54 drug-sensitive strain, and IC50 = 0.0246 μM against the K1 multidrug resistant strain), hERG inhibition remained an issue. Excitingly, on the other hand, new analogues with a substantially improved hERG inhibition profile (IC50 = 7.83-32.3 μM) with sub-micromolar antiplasmodial activity (NF54, IC50 = 0.151-0.922 μM) were identified. Similarly, the introduced molecular features also resulted in analogues with moderate to high solubility (60-200 μM) while also displaying sub-micromolar antiplasmodial potency (NF54, IC50 = 0.136-0.99 μM).
Aromatic amino analogues of artemisinin: Synthesis and in vivo antimalarial activity
Sriram, Dharmarajan,Devakaram, Ruth Vandana,Dinakaran, Murugesan,Yogeeswari, Perumal
experimental part, p. 524 - 532 (2011/10/31)
Nine orally active novel artemisinin derivatives were prepared from artemisinin by four-step synthesis, and the compounds were evaluated in the rodent model using multidrug resistant Plasmodium yoelii nigeriensis. All of the compounds exhibited antimalarial activities with the ED50 ranging from 5.41 mg/kg-12.4 mg/kg. Among them, artemisinin derivative bearing N-(4-hydroxy-3- ((4-phenylpiperazin-1-yl)methyl)phenyl) moiety (5f) was found to be the most active compound and was found to be three times more potent than artemisinin (ED50 16.4 mg/kg). Birkhaeuser Boston 2009.
Aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)
Anderson, David R.,Hegde, Shridhar,Reinhard, Emily,Gomez, Leslie,Vernier, William F.,Lee, Len,Liu, Shuang,Sambandam, Aruna,Snider, Patricia A.,Masih, Liaqat
, p. 1587 - 1590 (2007/10/03)
A class of inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2) was discovered. These compounds have demonstrated activity against the enzyme with IC50 values as low as 130 nM and suppress the expression of TNFα in U
