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Design and synthesi...
Design and synthesis of potent inhibitors of plasmepsin I and II : x-ray crystal structure of inhibitor in complex with plasmepsin II
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- Johansson, Per-Ola (författare)
- Linköpings universitet,Kemi,Tekniska högskolan
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- Lindberg, Jimmy (författare)
- Department of Cell and Molecular Biology, BMC, Uppsala University, Uppsala, Sweden
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- Blackman, Michael J. (författare)
- Division of Parasitology, National Institute for Medical Research, United Kingdom
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- Kvarnström, Ingemar (författare)
- Linköpings universitet,Kemi,Tekniska högskolan
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- Vrang, Lotta (författare)
- Medivir AB, Huddinge, Sweden
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- Hamelink, Elizabeth (författare)
- Medivir AB, Huddinge, Sweden
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- Hallberg, Anders (författare)
- Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
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- Rosenquist, Åsa (författare)
- Linköpings universitet,Kemi,Tekniska högskolan
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- Samuelsson, Bertil (författare)
- Medivir AB, Huddinge, Sweden and Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden
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(creator_code:org_t)
- 2005-06-02
- 2005
- Engelska.
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:13, s. 4400-4409
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.
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- TEKNIKVETENSKAP
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