Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum In Vitro

Dickson Mambwe; Malkeet Kumar; Richard Ferger; Dale Taylor; Mathew Njoroge; Dina Coertzen; Janette Reader; Mariëtte van der Watt; Lyn-Marie Birkholtz; Kelly Chibale

doi:10.1021/acsmedchemlett.1c00328

Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum In Vitro

ACS Med Chem Lett. 2021 Aug 2;12(8):1333-1341. doi: 10.1021/acsmedchemlett.1c00328. eCollection 2021 Aug 12.

Authors

Affiliations

¹ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
² Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
³ Department of Biochemistry, Genetics & Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag X20, Hatfield, Pretoria 0028, South Africa.
⁴ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
⁵ South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.

Abstract

In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (PfNF54 IC₅₀ = 0.025-0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; PfLG IC₅₀ = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.