Cheuka, P.MLawrence, NTaylor, DWittlin, SChibale, K2024-08-032024-08-032018-10-01Cheuka PM, Lawrence N, Taylor D, Wittlin S, Chibale K . Antiplasmodial imidazopyridazines: structure-activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles. MedChemComm. 2018 Sep 6;9(10):1733-1745. DOI: 10.1039/c8md00382chttps://doi.org/10.1039/C8MD00382Chttps://pubs.rsc.org/en/content/articlelanding/2018/md/c8md00382chttps://hdl.handle.net/11288/5970973,6-Diarylated imidazopyridazines have recently been shown to possess good antiplasmodial and antimalarial activity. However, frontrunner compounds have been associated with poor solubility and a hERG (human -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 (IC = 0.031 μM against the NF54 drug-sensitive strain, and IC = 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 (IC = 7.83-32.3 μM) with sub-micromolar antiplasmodial activity (NF54, IC = 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, IC = 0.136-0.99 μM).enArticle