Document Report Card

ID: ALA3259525

Journal: ACS Med Chem Lett

Title: Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit.

Authors: Jaudzems K, Tars K, Maurops G, Ivdra N, Otikovs M, Leitans J, Kanepe-Lapsa I, Domraceva I, Mutule I, Trapencieris P, Blackman MJ, Jirgensons A.

Abstract: Antimalarial hit 1 SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1 SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.

CiteXplore: 24900843

DOI: 10.1021/ml4004952