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

Animals Antimalarials / chemistry Astemizole / analogs & derivatives CHO Cells Chloroquine / pharmacology Cricetulus Drug Repositioning Drug Resistance, Multiple Hemeproteins / antagonists & inhibitors Inhibitory Concentration 50 Life Cycle Stages Plasmodium falciparum / drug effects
Plasmodium falciparum astemizole gametocytes repositioning β-hematin

Journal

ACS infectious diseases
ISSN: 2373-8227
Titre abrégé: ACS Infect Dis
Pays: United States
ID NLM: 101654580

Informations de publication

Date de publication:
08 02 2019
Historique:
pubmed: 12 12 2018
medline: 18 12 2019
entrez: 12 12 2018
Statut: ppublish

Résumé

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 (IC

Identifiants

DOI: 10.1021/acsinfecdis.8b00272 PMID: 30525439
pubmed: 30525439
doi: 10.1021/acsinfecdis.8b00272
doi:

Substances chimiques

Antimalarials 0
Hemeproteins 0
hemozoin 39404-00-7
Astemizole 7HU6337315
Chloroquine 886U3H6UFF

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

303-315

Auteurs

Malkeet Kumar (M)

Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.

John Okombo (J)

Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.

Dickson Mambwe (D)

Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.

Dale Taylor (D)

Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine , University of Cape Town , Observatory 7925 , South Africa.

Nina Lawrence (N)

Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine , University of Cape Town , Observatory 7925 , South Africa.

Janette Reader (J)

Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control , University of Pretoria , Private Bag X20 , Hatfield 0028 , South Africa.

Mariëtte van der Watt (M)

Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control , University of Pretoria , Private Bag X20 , Hatfield 0028 , South Africa.

Diana Fontinha (D)

Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , Av. Prof. Egas Moniz , 1649-028 Lisboa , Portugal.

Margarida Sanches-Vaz (M)

Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , Av. Prof. Egas Moniz , 1649-028 Lisboa , Portugal.

Belinda C Bezuidenhout (BC)

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.

Sonja B Lauterbach (SB)

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.

Dale Liebenberg (D)

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.

Lyn-Marie Birkholtz (LM)

Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control , University of Pretoria , Private Bag X20 , Hatfield 0028 , South Africa.

Theresa L Coetzer (TL)

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.

Miguel Prudêncio (M)

Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , Av. Prof. Egas Moniz , 1649-028 Lisboa , Portugal.

Timothy J Egan (TJ)

Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.
Institute of Infectious Disease and Molecular Medicine , University of Cape Town , Rondebosch 7701 , South Africa.
ORCID: 0000-0001-7720-8473

Sergio Wittlin (S)

Swiss Tropical and Public Health Institute , Socinstrasse 57 , 4002 Basel , Switzerland.
University of Basel , 4003 Basel , Switzerland.

Kelly Chibale (K)

Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.
Institute of Infectious Disease and Molecular Medicine , University of Cape Town , Rondebosch 7701 , South Africa.
South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.
ORCID: 0000-0002-1327-4727

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiparasitaires › Antiprotozoaires › Antipaludiques › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzimidazoles › Astémizole › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules CHO › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinoléines › Aminoquinoléines › Chloroquine › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Arvicolinae › Cricetinae › Cricetulus › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Repositionnement des médicaments › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Multirésistance aux médicaments › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Concentration inhibitrice 50 › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Morphogenèse › Métamorphose biologique › Étapes du cycle de vie › Multistage Antiplasmodium Activity of...
questionsmedicales.fr › Eucaryotes › Alveolata › Apicomplexa › Haemosporida › Plasmodium › Plasmodium falciparum › Multistage Antiplasmodium Activity of...