Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 82

Fig. 5.22 MbtI-catalyzed synthesis of salicylate from chorismate [ 80 ]
Fig. 5.23 Chorismate-based MbtI inhibitors [ 81 ]
Fig. 5.24 Chorismate-based MbtI inhibitors. SAR of the C3 position [ 81 ]
Fig. 5.25 Isochorismate-based MbtI inhibitors. SAR of the C3 position [ 81 ]
Substitution at the C3 position was also studied, while preserving the hydroxyl
group at C4 in order to determine its importance in biological activity. Analogs
115 - 118 were prepared as mixtures of inseparable isomers (Fig. 5.24 ). The iso-
mers were moderate to poor inhibitors of MbtI, with 116 (K i = 290 ± 90 μ M)
and 117 (K i = 310 ± 70 μ M) displaying the best activity. While the C4 hydroxyl
group appeared to have little effect on activity, substitution at C3 improved the
activity against MbtI but decreased it in the case of S. marcescens AS, providing a
potential source of selectivity in inhibitor design.
A series of inhibitors designed to mimic the enzyme-bound isochorismate