hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole

Dickson Mambwe, Dina Coertzen, Meta Leshabane, Mwila Mulubwa, Mathew Njoroge, Liezl Gibhard, Gareth Girling, Kathryn J. Wicht, Marcus C.S. Lee, Sergio Wittlin, Diogo Rodrigo Magalhães Moreira, Lyn Marie Birkholtz, Kelly Chibale (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Downloads (Pure)


Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 μM; hERG IC50 = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 μM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 μM, and liver-stage PbHepG2 IC50 = 2.30 μM), good microsomal metabolic stability (MLM CLint < 11 μL·min-1·mg-1, EH < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg-1 resulting from poor permeability (log D7.4 = −0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.

Original languageEnglish
Pages (from-to)463-469
Number of pages7
JournalACS Medicinal Chemistry Letters
Issue number4
Early online date18 Mar 2024
Publication statusPublished - 11 Apr 2024


  • Astemizole
  • gametocytocidal
  • human ether-á-go-go-related gene (hERG)
  • liver-stage activity
  • Plasmodium berghei
  • Plasmodium falciparum
  • repositioning
  • resistance phenotypes

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


Dive into the research topics of 'hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole'. Together they form a unique fingerprint.

Cite this