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3-Hydroxy-propanamidines, a new class of orally active antimalarials targeting Plasmodium falciparum
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4646325
Author(s) Knaab, T. C.; Held, J.; Burckhardt, B. B.; Rubiano, K.; Okombo, J.; Yeo, T.; Mok, S.; Uhlemann, A. C.; Lungerich, B.; Fischli, C.; Pessanha de Carvalho, L.; Mordmüller, B.; Wittlin, S.; Fidock, D. A.; Kurz, T.
Author(s) at UniBasel Fischli, Christoph
Wittlin, Sergio
Year 2021
Title 3-Hydroxy-propanamidines, a new class of orally active antimalarials targeting Plasmodium falciparum
Journal Journal of medicinal chemistry
Volume 64
Number 6
Pages / Article-Number 3035-3047
Mesh terms Amidines, therapeutic use; Animals; Antimalarials, therapeutic use; Cell Line; Drug Design; Humans; Malaria, drug therapy; Malaria, Falciparum, drug therapy; Mice; Parasitic Sensitivity Tests; Plasmodium berghei, drug effects; Plasmodium falciparum, drug effects; Propane, therapeutic use
Abstract 3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains ofPlasmodium falciparum (with IC50 values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in thePlasmodium berghei mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in P. falciparum.
ISSN/ISBN 0022-2623
edoc-URL https://edoc.unibas.ch/89195/
Full Text on edoc No
Digital Object Identifier DOI 10.1021/acs.jmedchem.0c01744
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/33666415
ISI-Number WOS:000635440600012
Document type (ISI) Journal Article
 
   

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