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.
Highlights
Glutamine synthetase (GS, glutamate-ammonia ligase, E.C. 6.3.1.2), one of the key enzymes in nitrogen metabolism[1], catalyses the formation of glutamine from glutamate and ammonia in the presence of adenosine triphosphate (ATP) (Figure 1)
Most of the studied compounds exhibited activities in micromolar range, with N-(3,5-dichlorophenyl)-2-aminoethylidenebisphoshonic acid, N-(3,5difluorophenyl)-2-aminoethylidene-bisphoshonic acid and N-(3,4-dichlorophenyl)-1-hydroxy1,1-ethanebisphosphonic acid showing the highest potency with kinetic parameters similar to the reference compound – L-methionine-S-sulfoximine
We have previously shown aminomethylenebisphosphonic acids to be effective inhibitors of plant GS15
Summary
Glutamine synthetase (GS, glutamate-ammonia ligase, E.C. 6.3.1.2), one of the key enzymes in nitrogen metabolism[1], catalyses the formation of glutamine from glutamate and ammonia in the presence of adenosine triphosphate (ATP) (Figure 1). This enzyme, together with glutamate synthase (GOGAT, E.C. 1.4.1.13), is a component of a metabolic cycle that enables the incorporation of inorganic nitrogen (in the form of ammonium ions) into the organic molecules present in living cells. GS2 is primarily found in eukaryotes, but its expression has later been confirmed in some actinomycetes and rhizobia[6,7] This form of the enzyme is composed of 10 subunits forming two pentameric rings.
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