School of Chemistry, The University of Sydney, NSW 2006, Australia.
ChemMedChem. 2010 Jul 5;5(7):1067-79. doi: 10.1002/cmdc.201000137.
Mycobacterium tuberculosis salicylate synthase (MbtI), a member of the chorismate-utilizing enzyme family, catalyses the first committed step in the biosynthesis of the siderophore mycobactin T. This complex secondary metabolite is essential for both virulence and survival of M. tuberculosis, the etiological agent of tuberculosis (TB). It is therefore anticipated that inhibitors of this enzyme may serve as TB therapies with a novel mode of action. Herein we describe the first inhibition study of M. tuberculosis MbtI using a library of functionalized benzoate-based inhibitors designed to mimic the substrate (chorismate) and intermediate (isochorismate) of the MbtI-catalyzed reaction. The most potent inhibitors prepared were those designed to mimic the enzyme intermediate, isochorismate. These compounds, based on a 2,3-dihydroxybenzoate scaffold, proved to be low-micromolar inhibitors of MbtI. The most potent inhibitors in this series possessed hydrophobic enol ether side chains at C3 in place of the enol-pyruvyl side chain found in chorismate and isochorismate.
结核分枝杆菌水杨酸合酶（MbtI）是分支酸利用酶家族的成员，催化生物合成铁载体 mycobactin T 的第一步。这种复杂的次生代谢物对于结核分枝杆菌（导致结核病的病原体）的毒力和生存都是必不可少的。因此，预计该酶的抑制剂可能成为具有新型作用模式的结核病治疗方法。本文首次利用一系列基于苯甲酸的功能化抑制剂文库对结核分枝杆菌 MbtI 进行了抑制研究，这些抑制剂旨在模拟 MbtI 催化反应的底物（分支酸）和中间产物（异分支酸）。所制备的最有效的抑制剂是模拟酶中间产物异分支酸的抑制剂。这些基于 2,3-二羟基苯甲酸支架的化合物被证明是 MbtI 的低微摩尔抑制剂。该系列中最有效的抑制剂在 C3 位具有疏水性烯醇醚侧链，而不是在分支酸和异分支酸中发现的烯醇-丙酮酸侧链。
