Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse, Cedex 4, France.
Eur J Med Chem. 2010 Oct;45(10):4554-61. doi: 10.1016/j.ejmech.2010.07.016. Epub 2010 Jul 15.
Isoniazid-NAD truncated adducts embedding a lipophilic fragment were designed, synthesized and evaluated as inhibitors of the enoyl-acyl carrier protein (ACP) reductase (InhA) of Mycobacterium tuberculosis and as antimycobacterial agents. These compounds, planned as bi-substrate inhibitors and inspired from the active metabolite of isoniazid, combine both the nicotinamide moiety of the cofactor NAD and a lipophilic hydrocarbon chain mimic of the InhA substrate. The lipophilic fragment was introduced using either Suzuki-Miyaura cross-coupling or a classical nucleophilic substitution reaction. Several compounds developed in this work were indeed able to inhibit the InhA activity and showed promising antimycobacterial activities. However a direct correlation between the expressed activity and the bi-substrate mode of action could not yet be unambiguously demonstrated.
设计、合成并评估了带有亲脂片段的异烟肼-NAD 截断加合物，作为分枝杆菌烯酰基载体蛋白（ACP）还原酶（InhA）的抑制剂和抗分枝杆菌药物。这些化合物作为双底物抑制剂设计，灵感来自异烟肼的活性代谢物，结合了辅因子 NAD 的烟酰胺部分和 InhA 底物的亲脂烃链模拟物。亲脂片段通过 Suzuki-Miyaura 交叉偶联或经典亲核取代反应引入。本工作中开发的几种化合物确实能够抑制 InhA 的活性，并表现出有前景的抗分枝杆菌活性。然而，表达的活性与双底物作用模式之间的直接相关性尚不能明确证明。
