Design and synthesis of potent inhibitors of plasmepsin I and II: x-ray crystal structure of inhibitor in complex with plasmepsin II
2005 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 13, 4400-4409 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2005. Vol. 48, no 13, 4400-4409 p.
National CategoryEngineering and Technology
IdentifiersURN: urn:nbn:se:liu:diva-50477DOI: 10.1021/jm040884nOAI: oai:DiVA.org:liu-50477DiVA: diva2:271373