hERG, plasmodium life cycle, and cross resistance profiling of new azabenzimidazole analogues of astemizole

Department of Chemistry. University of Cape Town, Rondebosch. Cape Town, South Africa.
Department of Biochemistry. Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
epartment of Biochemistry. Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town, Observatory. Cape Town, South Africa.
Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town, Observatory. Cape Town, South Africa.
Drug Discovery and Development Centre (H3D). DMPK & Pharmacology. University of Cape Town, Observatory. Cape Town, South Africa.
Wellcome Sanger Institute. Wellcome Trust Genome Campus. Hinxton, United Kingdom.
Department of Chemistry. University of Cape Town. Rondebosch. Cape Town, South Africa.
Wellcome Sanger Institute, Wellcome Trust Genome Campus. Hinxton, United Kingdom / Biological Chemistry and Drug Discovery. School of Life Sciences. University of Dundee. Dundee, Scotland, United Kingdom.
Swiss Tropical and Public Health Institute, Socinstrasse. Basel, Switzerland / University of Basel. Basel, Switzerland.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Department of Biochemistry. Genetics & Microbiology. Institute for Sustainable Malaria Control. University of Pretoria. Private Bag X20. Hatfield, Pretoria, South Africa.
Department of Chemistry. Institute of Infectious Disease and Molecular Medicine. South African Medical Research Council Drug Discovery. Development Research Unit. University of Cape Town. Cape Town, South Africa / Centre (H3D), DMPK & Pharmacology. University of Cape Town. 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 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.

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American Chemical Society

Citation

MAMBWE, Dickson et al. hERG, plasmodium life cycle, and cross resistance profiling of new azabenzimidazole analogues of astemizole. ACS Medicinal Chemistry Letters, v. 15, n. 4, p. 1-7, 2024.

DOI

10.1021/acsmedchemlett.3c00496

ISSN

1948-5875

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/64128

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