학술논문
Evaluation of 4-Amino 2-Anilinoquinazolines against Plasmodium and Other Apicomplexan Parasites In Vitro and in a P. falciparum Humanized NOD- scid IL2Rγ null Mouse Model of Malaria.
Document Type
Academic Journal
Author
Gilson PR; Burnet Institute, Melbourne, Victoria, Australia.; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Nguyen W; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Poole WA; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Teixeira JE; Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA.; Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont, USA.; Thompson JK; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Guo K; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Stewart RJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Ashton TD; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; White KL; Centre for Drug Candidate Optimisation, Monash University, Parkville, Melbourne, Victoria, Australia.; Sanz LM; Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.; Gamo FJ; Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.; Charman SA; Centre for Drug Candidate Optimisation, Monash University, Parkville, Melbourne, Victoria, Australia.; Wittlin S; Swiss Tropical and Public Health Institute, Basel, Switzerland.; University of Basel, Basel, Switzerland.; Duffy J; Medicines for Malaria Venture, ICC, Geneva, Switzerland.; Tonkin CJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Tham WH; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Crabb BS; Burnet Institute, Melbourne, Victoria, Australia.; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Parkville, Victoria, Australia.; Cooke BM; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Huston CD; Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA.; Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont, USA.; Cowman AF; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Sleebs BE; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia sleebs@wehi.edu.au.; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
Source
Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE
Subject
Language
English
Abstract
A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum , was 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 that 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 antimalarial compounds, although slightly less so than against 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 a 50% effective concentration generally in the low micromolar range, suggesting that 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 of body weight, 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.
(Copyright © 2019 American Society for Microbiology.)
(Copyright © 2019 American Society for Microbiology.)