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
- Author
- D Giessmann, P Heidler, Timothy Haemers, Serge Van Calenbergh (UGent) , A Reichenberg, H Jomaa, C Weidemeyer, S Sanderbrand, J Wiesner and A Link
- Organization
- Abstract
- 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 (IC50) in the range from 1 to >30 mu M vs. E. coli Dxr and 0.4 to 20 mu M against P. falciparum Dxr is reported.
- Keywords
- 5-PHOSPHATE REDUCTOISOMERASE, REDUCTO-ISOMERASE, ISOPRENOID BIOSYNTHESIS, SUBSTITUTED FOSMIDOMYCIN ANALOGS, N-6-SUBSTITUTED ADENOSINE DERIVATIVES, PLASMODIUM-FALCIPARUM MALARIA, GROWTH-INHIBITORS, CLINDAMYCIN, PATHWAY, ACID
Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-526399
- MLA
- Giessmann, D., et al. “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.” CHEMISTRY & BIODIVERSITY, vol. 5, no. 4, Wiley, 2008, pp. 653–56.
- APA
- Giessmann, D., Heidler, P., Haemers, T., Van Calenbergh, S., Reichenberg, A., Jomaa, H., … Link, A. (2008). 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. CHEMISTRY & BIODIVERSITY, 5(4), 653–656.
- Chicago author-date
- Giessmann, D, P Heidler, Timothy Haemers, Serge Van Calenbergh, A Reichenberg, H Jomaa, C Weidemeyer, S Sanderbrand, J Wiesner, and A Link. 2008. “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.” CHEMISTRY & BIODIVERSITY 5 (4): 653–56.
- Chicago author-date (all authors)
- Giessmann, D, P Heidler, Timothy Haemers, Serge Van Calenbergh, A Reichenberg, H Jomaa, C Weidemeyer, S Sanderbrand, J Wiesner, and A Link. 2008. “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.” CHEMISTRY & BIODIVERSITY 5 (4): 653–656.
- Vancouver
- 1.Giessmann D, Heidler P, Haemers T, Van Calenbergh S, Reichenberg A, Jomaa H, et al. 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. CHEMISTRY & BIODIVERSITY. 2008;5(4):653–6.
- IEEE
- [1]D. Giessmann et al., “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,” CHEMISTRY & BIODIVERSITY, vol. 5, no. 4, pp. 653–656, 2008.
@article{526399,
abstract = {{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 (IC50) in the range from 1 to >30 mu M vs. E. coli Dxr and 0.4 to 20 mu M against P. falciparum Dxr is reported.}},
author = {{Giessmann, D and Heidler, P and Haemers, Timothy and Van Calenbergh, Serge and Reichenberg, A and Jomaa, H and Weidemeyer, C and Sanderbrand, S and Wiesner, J and Link, A}},
issn = {{1612-1872}},
journal = {{CHEMISTRY & BIODIVERSITY}},
keywords = {{5-PHOSPHATE REDUCTOISOMERASE,REDUCTO-ISOMERASE,ISOPRENOID BIOSYNTHESIS,SUBSTITUTED FOSMIDOMYCIN ANALOGS,N-6-SUBSTITUTED ADENOSINE DERIVATIVES,PLASMODIUM-FALCIPARUM MALARIA,GROWTH-INHIBITORS,CLINDAMYCIN,PATHWAY,ACID}},
language = {{eng}},
number = {{4}},
pages = {{653--656}},
publisher = {{Wiley}},
title = {{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}},
volume = {{5}},
year = {{2008}},
}