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.

Cobalt-Catalyzed, Directed C-H Functionalization/Annulation of Phenylglycinol Derivatives with Alkynes.

A new method for cobalt-catalyzed C(sp)-H functionalization of phenylglycinol derivatives with terminal and internal alkynes directed by picolinamide auxiliary has been developed. This method offers an efficient and highly regioselective route for the synthesis of 1-hydroxymethyltetrahydroisoquinolines. The reaction employs commercially available Co(II) catalyst in the presence of Mn(III) cooxidant and oxygen as a terminal oxidant and proceeds with full preservation of original stereochemistry.