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

doi:10.1021/acsmedchemlett.3c00496

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

ACS Med Chem Lett. 2024 Mar 18;15(4):463-469. doi: 10.1021/acsmedchemlett.3c00496. eCollection 2024 Apr 11.

Authors

Dickson Mambwe¹, Dina Coertzen², Meta Leshabane², Mwila Mulubwa³, Mathew Njoroge³, Liezl Gibhard³, Gareth Girling⁴, Kathryn J Wicht¹, Marcus C S Lee^{4

5}, Sergio Wittlin^{6

7}, Diogo Rodrigo Magalhães Moreira⁸, Lyn-Marie Birkholtz², Kelly Chibale^{1

9

3

10}

Affiliations

¹ Department of Chemistry, University of Cape Town, Rondebosch, 7701 Cape Town, South Africa.
² Department of Biochemistry, Genetics & Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield, 0028 Pretoria, South Africa.
³ Drug Discovery and Development Centre (H3D), DMPK & Pharmacology, University of Cape Town, Observatory, 7925 Cape Town, South Africa.
⁴ Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, United Kingdom.
⁵ Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 4HN, Scotland, United Kingdom.
⁶ Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
⁷ University of Basel, 4003 Basel, Switzerland.
⁸ Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Instituto Gonçalo Moniz, CEP 40296-710 Salvador, Brazil.
⁹ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701 Cape Town, South Africa.
¹⁰ South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, 7701 Cape Town, South Africa.

Abstract

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 CL_int < 11 μL·min^-1·mg^-1, E_H < 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 D_7.4 = -0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.