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

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.
Peter Mubanga Cheuka 1,  Nina Lawrence 2,  Dale Taylor 2,  Sergio Wittlin 3 4,  Kelly Chibale 1 2 5 6
Affiliations

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.
PMID: 30429978 DOI: 10.1039/c8md00382c
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).

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