While threonyl tRNA synthetase (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 ThrRS, a set of fragments were designed which incorporated bioisosteres of the -acylphosphate moiety of the aminoacyladenylate as an intermediate of an enzymatic reaction. -Acyl sulfamate- and -acyl benzenethiazolsulfonamide-based fragments and were identified as inhibitors of the ThrRSby biochemical assay at 100 μM concentration. These fragments were then developed into potent ThrRS inhibitors (, and ) by linking them with an amino pyrimidine as a bioisostere of adenine in the enzymatic reaction intermediate.
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| http://dx.doi.org/10.1021/acsmedchemlett.3c00403 | DOI Listing |
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