Antiplasmodial imidazopyridazines: structure–activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles

Abstract

3,6-Diarylated imidazopyridazines have recently been shown to possess good <i>in vitro</i> antiplasmodial and <i>in vivo</i> antimalarial activity. However, frontrunner compounds have been associated with poor solubility and a hERG (human <i>ether-a-go-go</i>-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).