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
Dirk GiessmannAndreas Link

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 (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.

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Citations

Jul 9, 2013·Bioscience, Biotechnology, and Biochemistry·Kazuya NakagawaNobutaka Imamura
Feb 26, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·René ChoforSerge Van Calenbergh
Jul 12, 2011·Cellular and Molecular Life Sciences : CMLS·Tobias GräwertWolfgang Eisenreich
Feb 23, 2012·Scientific Reports·Tomonobu UmedaKazuo T Nakamura

Related Concepts

Fosmidomycin sodium salt
YaeM protein, E coli
Antimalarials
Enzyme Inhibitors
Alkalescens-Dispar Group
Monuril
Multienzyme Complexes
Oxidase
Plasmodium falciparum
Drug Modeling

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