title: Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: an attempt to improve the activity against Mycobacterium tuberculosis.
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.
authors.affiliation: Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Center, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Mounir
authors.initials: M
authors.lastname: Andaloussi
authors.forename: Martin
authors.initials: M
authors.lastname: Lindh
authors.forename: Christofer
authors.initials: C
authors.lastname: Björkelid
authors.forename: Surisetti
authors.initials: S
authors.lastname: Suresh
authors.forename: Anna
authors.initials: A
authors.lastname: Wieckowska
authors.forename: Harini
authors.initials: H
authors.lastname: Iyer
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D063065:Organophosphonates / Q000737:chemistry; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009097:Multienzyme Complexes; D063065:Organophosphonates; D005578:Fosfomycin; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases