Design and synthesis of potent inhibitors of plasmepsin I and II: X-ray crystal structure of inhibitor in complex with plasmepsin II.
Johansson, PO; Lindberg, J; Blackman, MJ; Kvarnström, I; Vrang, L; Hamelink, E; Hallberg, A; Rosenquist, A; Samuelsson, B; (2005) Design and synthesis of potent inhibitors of plasmepsin I and II: X-ray crystal structure of inhibitor in complex with plasmepsin II. Journal of medicinal chemistry, 48 (13). pp. 4400-9. ISSN 0022-2623 DOI: https://doi.org/10.1021/jm040884n
Abstract
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 K(i) 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 microM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II.
| Item Type: | Article |
|---|---|
| Faculty and Department: | Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology |
| PubMed ID: | 15974592 |
| Web of Science ID: | 230121800025 |
| URI: | http://researchonline.lshtm.ac.uk/id/eprint/1544278 |
Statistics
Accesses by country - last 12 months | Accesses by referrer - last 12 months |
Actions (login required)
 |
Edit Item |
