Design and Synthesis of Plasmepsin I and Plasmepsin II Inhibitors with Activity in Plasmodium f alciparum-Infected Cultured Human Erythrocytes

• Published in: Journal of medicinal chemistry Vol. 46; no. 5; pp. 734 - 746
• Main Authors: Nöteberg, Daniel, Hamelink, Elizabeth, Hultén, Johan, Wahlgren, Mats, Vrang, Lotta, Samuelsson, Bertil, Hallberg, Anders
• Format: Journal Article
• Language: English
• Published: American Chemical Society 27.02.2003
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020951i

A series of protease inhibitors targeted at the malarial enzymes plasmepsin I and II, and encompassing a basic hydroxyethylamine transition state isostere scaffold, was prepared. The substituents in the P1‘ position were varied and the biological activities expressed in K i-values ranged from 60 to >2000 nM. A more than 4-fold selectivity for either of the plasmepsins could be achieved. All of the active compounds exhibited high preference for the plasmepsins over cathepsin D, the most closely related human protease. A few active compounds were shown to inhibit parasite growth in cultured infected human erythrocytes. An ED50 value as low as 1.6 μM was observed for one of the inhibitors despite K i values of 115 nM (Plm I) and 121 nM (Plm II).