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. Salicylic acid-based compound (LE = 0.34) was selected as a most perspective hit and was subjected to hit-to-lead optimisation. A total of 146 hit analogues were synthesised or obtained from commercial vendors and were tested. Structure-activity relationship study was supported by the crystal structure of the complex of a salicylic acid analogue with a close homologue of the plasmodium target, E. coli ThrRS (EcThrRS). Despite the availability of structural information, the hit identified via virtual screening remained one of the most potent PfThrRS inhibitors within this series. However, the compounds presented herein provide novel scaffolds for ThrRS inhibitors, which could serve as starting points for further medicinal chemistry projects targeting ThrRSs or structurally similar enzymes.

Amination of Carbenium Ions Generated by Directed Protonolysis of Cyclopropane.

Directed intramolecular protonolyis of the cyclopropane C-C bond is demonstrated as a strategy to generate carbenium ions. This intermediate can be subjected to amination with nitriles under Ritter reaction conditions. Directing groups such as carbamate, carboxamide, urea, ester, and ketone were found to be efficient for regioselective anti-Markovnikov cleavage of cyclopropane. Depending on the directing group, the amination provided orthogonally protected 1,4-diamine, ε-amino carboxylic, and ε-amino ketone derivatives.

Amide-Group-Directed Protonolysis of Cyclopropane: An Approach to 2,2-Disubstituted Pyrrolidines.

Regioselective protonolytic C-C bond cleavage of acylated aminomethyl cyclopropanes can be achieved using trifluoroacetic acid. The intermediate tertiary carbenium ion undergoes an intramolecular amination to give 2,2-substituted pyrrolidines. The strength of the acid and the amine substituent are important factors to achieve high regioselectivity, suggesting intramolecular proton transfer from the protonated amide function. Preliminary mechanistic studies revealed that cyclopropane cleavage proceeds with retention of configuration at the carbon to which the proton is attached. This observation is consistent with the "edge" protonation trajectory of the C-C bond.

Tetrahydro-1,3-oxazepines via Intramolecular Amination of Cyclopropylmethyl Cation.

An efficient synthesis of tetrahydro-1,3-oxazepines was developed involving the regioselective intramolecular amination of cyclopropylmethyl cation. The cation was generated by the abstraction of one imidate group in bis-imidate bearing a carbocation-stabilizing substituent. Using 1,1,2,3-tetrasubstituted cyclopropane substrates, highly diastereoselective intramolecular amination to trans-tetrahydro-1,3-oxazepines was achieved. The resulting tetrahydro-1,3-oxazepines were transformed to the homoallylamine derivatives in high yields.