Towards New Antimalarial Drugs: Synthesis of Non-Hydrolyzable Phosphate Mimics as Feed for a Predictive QSAR Study on 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Inhibitors
| Autor: | Hassan Jomaa, Andreas Link, Claus Weidemeyer, Dirk Gießmann, Silke Sanderbrand, Serge Van Calenbergh, Philipp Heidler, Timothy Haemers, Armin Reichenberg, Jochen Wiesner |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Quantitative structure–activity relationship
Stereochemistry Plasmodium falciparum Organophosphonates Quantitative Structure-Activity Relationship Bioengineering Biochemistry Antimalarials chemistry.chemical_compound 1-deoxy-D-xylulose 5-phosphate reductoisomerase Fosfomycin Multienzyme Complexes Escherichia coli medicine Animals Moiety Enzyme Inhibitors Molecular Biology Aldose-Ketose Isomerases Binding affinities Chemistry Drugs synthesis General Chemistry General Medicine Phosphate Affinities Fosmidomycin Drug Design Molecular Medicine Oxidoreductases medicine.drug |
| Zdroj: | Chemistry & Biodiversity. 5:643-656 |
| ISSN: | 1612-1880 1612-1872 |
| DOI: | 10.1002/cbdv.200890060 |
| Popis: | The conversion of 1-deoxy-D-xylulose-5-phosphate (DOXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP) is effectively blocked by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitors such as the natural antibiotic fosmidomycin. Prediction of binding affinities for closely related Dxr ligands as well as estimation of the affinities of structurally more distinct inhibitors within this class of non-hydrolyzable phosphate mimics relies on the synthesis of fosmidomycin derivatives with a broad range of target affinity. Maintaining the phosphonic acid moiety, linear modifications of the lead structure were carried out in an effort to expand the SAR of this physicochemically challenging class of compounds. Synthetic access to a set of phosphonic acids with inhibitory activity (IC(50)) in the range from 1 to >30 microM vs. E. coli Dxr and 0.4 to 20 microM against P. falciparum Dxr is reported. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text