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

Peter Mubanga Cheuka; Nina Lawrence; Dale Taylor; Sergio Wittlin; Kelly Chibale

doi:10.1039/c8md00382c

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/c8md00382c. eCollection 2018 Oct 1.

Authors

Peter Mubanga Cheuka¹, Nina Lawrence², Dale Taylor², Sergio Wittlin^{3

4}, Kelly Chibale^{1

2

5

6}

Affiliations

¹ Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa . Email: Kelly.Chibale@uct.ac.za ; ; Tel: +27 21 6502553.
² Drug Discovery and Development Centre (H3D) , Division of Clinical Pharmacology , Department of Medicine , University of Cape Town , Observatory , Cape Town 7925 , South Africa.
³ Swiss Tropical and Public Health Institute , Socinstrasse 57 , 4002 Basel , Switzerland.
⁴ University of Basel , 4003 Basel , Switzerland.
⁵ Institute of Infectious Disease and Molecular Medicine , University of Cape Town , Rondebosch 7701 , South Africa.
⁶ South African Medical Research Council Drug Discovery and Development Research Unit , University of Cape Town , Rondebosch 7701 , South Africa.

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 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).