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 ?M against the NF54 drug-sensitive strain, and IC₅₀ = 0.0246 ?M 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 ?M) with sub-micromolar antiplasmodial activity (NF54, IC₅₀ = 0.151-0.922 ?M) were identified. Similarly, the introduced molecular features also resulted in analogues with moderate to high solubility (60-200 ?M) while also displaying sub-micromolar antiplasmodial potency (NF54, IC₅₀ = 0.136-0.99 ?M).

SUBMITTER: Cheuka PM 

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

REPOSITORIES: biostudies-literature