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

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.

SUBMITTER: Jaudzems K

PROVIDER: S-EPMC4027636 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Jaudzems Kristaps K Tars Kaspars K Maurops Gundars G Ivdra Natalija N Otikovs Martins M Leitans Janis J Kanepe-Lapsa Iveta I Domraceva Ilona I Mutule Ilze I Trapencieris Peteris P Blackman Michael J MJ Jirgensons Aigars A

ACS medicinal chemistry letters 20140113 4

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 sim ...[more]

PMID: 24900843

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