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Antimicrob Agents Chemother. 2018 Dec 17. pii: AAC.01804-18. doi: 10.1128/AAC.01804-18. [Epub ahead of print]

Evaluation of 4-amino 2-anilinoquinazolines against Plasmodium and other apicomplexan parasites in vitro and in a P. falciparum humanized NOD-scid IL2Rγnull mouse model of malaria.

Author information

1
Burnet Institute, Melbourne, Victoria 3004, Australia.
2
Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
4
Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
5
Departments of Medicine, and Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont, 05405, United States of America.
6
Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Melbourne, Victoria 3052 Australia.
7
Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
8
Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
9
University of Basel, 4003 Basel, Switzerland.
10
Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva, Switzerland.
11
Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, Victoria 3000, Australia.
12
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. sleebs@wehi.edu.au.

Abstract

A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, were evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi suggesting they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available anti-malarial compounds although slightly less so than the drug sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with an EC50 generally in the low micromolar range suggesting the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound's capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg adverse effects to the humanized mice were noted and evaluation against a panel of experimental high-risk off targets indicated some potential off target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.

PMID:
30559138
DOI:
10.1128/AAC.01804-18

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