Discovery of Malarial Threonyl tRNA Synthetase Inhibitors by Screening of a Focused Fragment Library

ACS Medicinal Chemistry Letters 2024
Jekaterina Boļšakova, Raitis Bobrovs, Larisa Varacheva, Anastasija Rudnickiha, Iveta Kaņepe, Emilio Parisini, Aigars Jirgensons

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.

Atslēgas vārdi
aminoacyl tRNA synthetase | fragment-based lead discovery | inhibitors | Malaria | threonyl tRNA synthetase
DOI
10.1021/acsmedchemlett.3c00403
Hipersaite
https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00403

Boļšakova, J., Bobrovs, R., Varacheva, L., Rudnickiha, A., Kaņepe, I., Parisini, E., Jirgensons, A. Discovery of Malarial Threonyl tRNA Synthetase Inhibitors by Screening of a Focused Fragment Library. ACS Medicinal Chemistry Letters, 2024, Vol. 15, No. 1, 76.-80.lpp. ISSN 1948-5875. Pieejams: doi:10.1021/acsmedchemlett.3c00403

Publikācijas valoda
English (en)