Design and Synthesis of Metabolically Stable tRNA Synthetase Inhibitors Derived from Cladosporin.
antimalarial agents
drug discovery
inhibitors
natural products
structure-activity relationships
Journal
Chembiochem : a European journal of chemical biology
ISSN: 1439-7633
Titre abrégé: Chembiochem
Pays: Germany
ID NLM: 100937360
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
01
10
2018
pubmed:
22
11
2018
medline:
31
12
2019
entrez:
22
11
2018
Statut:
ppublish
Résumé
Selective and specific inhibitors of Plasmodium falciparum lysyl-tRNA synthetase represent promising therapeutic antimalarial avenues. Cladosporin was identified as a potent P. falciparum lysyl-tRNA synthetase inhibitor, with an activity against parasite lysyl-tRNA synthetase >100-fold more potent than that of the activity registered against the human enzyme. Despite its compelling activity, cladosporin exhibits poor oral bioavailability; a critical requirement for antimalarial drugs. Thus, the quest to develop metabolically stable cladosporin-derived analogues, while retaining similar selectivity and potency to that of the natural compound, has begun. Chemogenomic profiling of a designed library allowed an entirely innovative structure-activity relationship study to be initiated; this shed light on structural evidence of a privileged scaffold with a unique activity against tRNA synthetases.
Identifiants
pubmed: 30462880
doi: 10.1002/cbic.201800587
doi:
Substances chimiques
Antimalarials
0
Enzyme Inhibitors
0
Isocoumarins
0
cladosporin
81PR0D5FI4
Lysine-tRNA Ligase
EC 6.1.1.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
644-649Informations de copyright
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.