Design and Synthesis of Plasmepsin I and Plasmepsin II Inhibitors with Activity in Plasmodium f alciparum-Infected Cultured Human Erythrocytes
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...
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| Published in | Journal of medicinal chemistry Vol. 46; no. 5; pp. 734 - 746 |
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| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
American Chemical Society
27.02.2003
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| Online Access | Get full text |
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| Abstract | 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). |
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| AbstractList | 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). |
| Author | Samuelsson, Bertil Nöteberg, Daniel Hamelink, Elizabeth Vrang, Lotta Hultén, Johan Hallberg, Anders Wahlgren, Mats |
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| Title | Design and Synthesis of Plasmepsin I and Plasmepsin II Inhibitors with Activity in Plasmodium f alciparum-Infected Cultured Human Erythrocytes |
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