Discovery of Malarial Threonyl tRNA Synthetase Inhibitors by Screening of a Focused Fragment Library.
ACS Med Chem Lett
; 15(1): 76-80, 2024 Jan 11.
Article
em En
| MEDLINE
| ID: mdl-38229753
ABSTRACT
While Plasmodium falciparum threonyl tRNA synthetase (PfThrRS) has clearly been validated as a prospective antimalarial drug target, the number of known inhbitors of this enzyme is still limited. In order to expand the chemotypes acting as inhibitors of PfThrRS, a set of fragments were designed which incorporated bioisosteres of the N-acylphosphate moiety of the aminoacyladenylate as an intermediate of an enzymatic reaction. N-Acyl sulfamate- and N-acyl benzenethiazolsulfonamide-based fragments 9a and 9k were identified as inhibitors of the PfThrRSby biochemical assay at 100 µM concentration. These fragments were then developed into potent PfThrRS inhibitors (10a,b and 11) by linking them with an amino pyrimidine as a bioisostere of adenine in the enzymatic reaction intermediate.
Texto completo:
1
Base de dados:
MEDLINE
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
ACS Med Chem Lett
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Letônia