Design and Synthesis of Metabolically Stable tRNA Synthetase Inhibitors Derived from Cladosporin.
Chembiochem
; 20(5): 644-649, 2019 03 01.
Article
em En
| MEDLINE
| ID: mdl-30462880
ABSTRACT
Selective and specific inhibitors of Plasmodium falciparum lysyl-tRNA synthetase represent promising therapeutic antimalarial avenues. Cladosporin was identified as a potent P.â
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.
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Base de dados:
MEDLINE
Assunto principal:
Malária Falciparum
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Inibidores Enzimáticos
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Isocumarinas
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Descoberta de Drogas
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Lisina-tRNA Ligase
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Antimaláricos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article