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

While Plasmodium falciparum threonyl tRNA synthetase ( Pf ThrRS) 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 Pf ThrRS, 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 Pf ThrRSby biochemical assay at 100 μM concentration. These fragments were then developed into potent Pf ThrRS inhibitors ( 10a , b and 11 ) by linking them with an amino pyrimidine as a bioisostere of adenine in the enzymatic reaction intermediate.