Structure-based identification of salicylic acid derivatives as malarial threonyl tRNA-synthetase inhibitors.

Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Threonyl t-RNA synthetase (ThrRS) is one of the enzymes involved in this pathway, and it has been validated as an anti-malarial drug target. Here, we present 9 structurally diverse low micromolar Plasmodium falciparum ThrRS inhibitors that were identified using high-throughput virtual screening (HTVS) and were verified in a FRET enzymatic assay.

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

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.

Synthesis and evaluation of an agrocin 84 toxic moiety (TM84) analogue as a malarial threonyl tRNA synthetase inhibitor.

An analogue of a toxic moiety (TM84) of natural product agrocin 84 containing threonine amide instead of 2,3-dihydroxy-4-methylpentanamide was prepared and evaluated as a putative threonyl t-RNA synthetase (PfThrRS) inhibitor. This TM84 analogue features submicromolar inhibitory potency (IC = 440 nM) comparable to that of borrelidin (IC = 43 nM) and therefore complements chemotypes known to inhibit malarial PfThrRS, which are currently limited to borrelidin and its analogues. The crystal structure of the inhibitor in complex with the homologue enzyme (EcThrRS) was obtained, revealing crucial ligand-protein interactions that will pave the way for the design of novel ThrRS inhibitors.