Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: an attempt to improve the activity against Mycobacterium tuberculosis

Mounir Andaloussi; Martin Lindh; Christofer Björkelid; Surisetti Suresh; Anna Wieckowska; Harini Iyer; Anders Karlén; Mats Larhed

doi:10.1016/j.bmcl.2011.07.005

Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: an attempt to improve the activity against Mycobacterium tuberculosis

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5403-7. doi: 10.1016/j.bmcl.2011.07.005. Epub 2011 Jul 20.

Authors

Mounir Andaloussi¹, Martin Lindh, Christofer Björkelid, Surisetti Suresh, Anna Wieckowska, Harini Iyer, Anders Karlén, Mats Larhed

Affiliation

¹ Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Center, Box 574, SE-751 23 Uppsala, Sweden.

PMID: 21824775
DOI: 10.1016/j.bmcl.2011.07.005

Abstract

Two series of FR900098/fosmidomycin analogs were synthesized and evaluated for MtDXR inhibition and Mycobacterium tuberculosis whole-cell activity. The design rationale of these compounds involved the exchange of either the phosphonic acid or the hydroxamic acid part for alternative acidic and metal-coordinating functionalities. The best inhibitors provided IC(50) values in the micromolar range, with a best value of 41 μM.

MeSH terms

Aldose-Ketose Isomerases / antagonists & inhibitors*
Aldose-Ketose Isomerases / metabolism
Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Fosfomycin / analogs & derivatives*
Fosfomycin / chemical synthesis
Fosfomycin / chemistry
Fosfomycin / pharmacology
Hydroxamic Acids / chemistry
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Multienzyme Complexes / antagonists & inhibitors*
Multienzyme Complexes / metabolism
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Organophosphonates / chemistry
Oxidoreductases / antagonists & inhibitors*
Oxidoreductases / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

Antitubercular Agents
Enzyme Inhibitors
Hydroxamic Acids
Multienzyme Complexes
Organophosphonates
Fosfomycin
fosmidomycin
3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid
Oxidoreductases
1-deoxy-D-xylulose 5-phosphate reductoisomerase
Aldose-Ketose Isomerases