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 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

SUBMITTER: Cheuka PM 

PROVIDER: S-EPMC6194489 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature