Bisphosphonic acids as effective inhibitors of <i>Mycobacterium tuberculosis</i> glutamine synthetase

<p>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-<i>H</i>-phosphinic acids of various scaffolds, bearing aromatic substituents, were screened against recombinant GS from <i>Mycobacterium tuberculosis.</i> Most of the studied compounds exhibited activities in micromolar range, with <i>N</i>-(3,5-dichlorophenyl)-2-aminoethylidenebisphoshonic acid, <i>N</i>-(3,5-difluorophenyl)-2-aminoethylidene-bisphoshonic acid and <i>N</i>-(3,4-dichlorophenyl)-1-hydroxy-1,1-ethanebisphosphonic acid showing the highest potency with kinetic parameters similar to the reference compound – <i>L</i>-methionine-<i>S</i>-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.</p>