Synthesis and Evaluation of an Agrocin 84 Toxic Moiety (TM84) Analogue as a Malarial Threonyl tRNA Synthetase Inhibitor

Organic and Biomolecular Chemistry 2023
Jhon Alexander Rodriguez Buitrago, Gundars Leitis, Iveta Kaņepe-Lapsa, Anastasija Rudnickiha, Emilio Parisini, Aigars Jirgensons

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 Plasmodium falciparum threonyl t-RNA synthetase (PfThrRS) inhibitor. This TM84 analogue features submicromolar inhibitory potency (IC50 = 440 nM) comparable to that of borrelidin (IC50 = 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 E. coli homologue enzyme (EcThrRS) was obtained, revealing crucial ligand-protein interactions that will pave the way for the design of novel ThrRS inhibitors.

DOI
10.1039/d3ob00670k
Hipersaite
https://pubs.rsc.org/en/content/articlelanding/2023/ob/d3ob00670k

Buitrago, J., Leitis, G., Kaņepe-Lapsa, I., Rudnickiha, A., Parisini, E., Jirgensons, A. Synthesis and Evaluation of an Agrocin 84 Toxic Moiety (TM84) Analogue as a Malarial Threonyl tRNA Synthetase Inhibitor. Organic and Biomolecular Chemistry, 2023, Vol. 21, No. 26, 5433.-5439.lpp. ISSN 1477-0520. Pieejams: doi:10.1039/d3ob00670k

Publikācijas valoda
English (en)