title: Bisphosphonic acids as effective inhibitors of Mycobacterium tuberculosis glutamine synthetase.
abstract: Inhibition of glutamine synthetase (GS) is one of the most promising strategies for the discovery of novel drugs against tuberculosis. Forty-three bisphosphonic and bis-H-phosphinic acids of various scaffolds, bearing aromatic substituents, were screened against recombinant GS from Mycobacterium tuberculosis. Most of the studied compounds exhibited activities in micromolar range, with N-(3,5-dichlorophenyl)-2-aminoethylidenebisphoshonic acid, N-(3,5-difluorophenyl)-2-aminoethylidene-bisphoshonic acid and N-(3,4-dichlorophenyl)-1-hydroxy-1,1-ethanebisphosphonic acid showing the highest potency with kinetic parameters similar to the reference compound - L-methionine-S-sulfoximine. Moreover, these inhibitors were found to be much more effective against pathogen enzyme than against the human ortholog. Thus, with the bone-targeting properties of the bisphosphonate compounds in mind, this activity/selectivity profile makes these compounds attractive agents for the treatment of bone tuberculosis.
authors.affiliation: a Department of Bioorganic Chemistry, Faculty of Chemistry , Wrocław University of Technology , Wrocław , Poland and.
authors.forename: Paulina
authors.initials: P
authors.lastname: Kosikowska
authors.affiliation: a Department of Bioorganic Chemistry, Faculty of Chemistry , Wrocław University of Technology , Wrocław , Poland and.
authors.forename: Marta
authors.initials: M
authors.lastname: Bochno
authors.affiliation: a Department of Bioorganic Chemistry, Faculty of Chemistry , Wrocław University of Technology , Wrocław , Poland and.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Macegoniuk
authors.affiliation: b Department of Life Science and Biotechnology , University of Ferrara , Ferrara , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Forlani
authors.affiliation: a Department of Bioorganic Chemistry, Faculty of Chemistry , Wrocław University of Technology , Wrocław , Poland and.
authors.forename: Paweł
authors.initials: P
authors.lastname: Kafarski
authors.affiliation: a Department of Bioorganic Chemistry, Faculty of Chemistry , Wrocław University of Technology , Wrocław , Poland and.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Berlicki
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D005974:Glutamate-Ammonia Ligase
keywords: Bisphosphonates; enzyme inhibitors; nitrogen metabolism; organophosphorus compounds; tuberculosis