2. Academic Validation
  3. Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action

Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action

  • ACS Infect Dis. 2019 Feb 8;5(2):303-315. doi: 10.1021/acsinfecdis.8b00272.
Malkeet Kumar 1,  John Okombo 1,  Dickson Mambwe 1,  Dale Taylor 2,  Nina Lawrence 2,  Janette Reader 3,  Mariëtte van der Watt 3,  Diana Fontinha 4,  Margarida Sanches-Vaz 4,  Belinda C Bezuidenhout 5,  Sonja B Lauterbach 5,  Dale Liebenberg 5,  Lyn-Marie Birkholtz 3,  Theresa L Coetzer 5,  Miguel Prudêncio 4,  Timothy J Egan 1 6,  Sergio Wittlin 7 8,  Kelly Chibale 1 6 9
Affiliations

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 and Microbiology, Institute for Sustainable Malaria Control , University of Pretoria , Private Bag X20 , Hatfield 0028 , South Africa.
  • 4 Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , Av. Prof. Egas Moniz , 1649-028 Lisboa , Portugal.
  • 5 Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences , University of the Witwatersrand and National Health Laboratory Service , Johannesburg 2193 , South Africa.
  • 6 Institute of Infectious Disease and Molecular Medicine , University of Cape Town , Rondebosch 7701 , South Africa.
  • 7 Swiss Tropical and Public Health Institute , Socinstrasse 57 , 4002 Basel , Switzerland.
  • 8 University of Basel , 4003 Basel , Switzerland.
  • 9 South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.
PMID: 30525439 DOI: 10.1021/acsinfecdis.8b00272
Abstract

A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the Parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC50s) of <0.1 μM against the chloroquine (CQ)-sensitive Plasmodium falciparum NF54 ( PfNF54) strain while maintaining submicromolar potency against the multidrug-resistant strain, PfK1, with most showing low likelihood of cross-resistance with CQ. Selected analogues ( PfNF54-IC50 < 0.1 μM) were tested for cytotoxicity on Chinese hamster ovarian (CHO) cells and found to be highly selective (selectivity index > 100). Screening of AST and its analogues against gametocytes revealed their moderate activity (IC50: 1-5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the Parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.

Keywords

Plasmodium falciparum; astemizole; gametocytes; repositioning; β-hematin.

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