Université de Toulouse, UPS, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France.
J Med Chem. 2011 Mar 10;54(5):1449-61. doi: 10.1021/jm101510d. Epub 2011 Feb 10.
Tuberculosis, HIV coinfection with TB, emergence of multidrug-resistant TB, and extensively drug-resistant TB are the major causes of death from infectious diseases worldwide. Because no new drug has been introduced in the last several decades, new classes of molecules as anti-TB drugs are urgently needed. Herein, we report the synthesis and structure-activity relationships of a series of thioester, amide, hydrazide, and triazolophthalazine derivatives of 4-alkoxy cinnamic acid. Many compounds exhibited submicromolar minimum inhibitory concentrations against Mycobacterium tuberculosis strain (H(37)Rv). Interestingly, compound 13e, a 4-isopentenyloxycinnamyl triazolophthalazine derivative, was found to be 100-1800 times more active than isoniazid (INH) when tested for its ability to inhibit the growth of INH-resistant M. tuberculosis strains. The results also revealed that 13e does not interfere with mycolic acid biosynthesis, thereby pointing to a different mode of action and representing an attractive lead compound for the development of new anti-TB agents.
结核病、结核分枝杆菌与 HIV 的合并感染、耐多药结核分枝杆菌和广泛耐药结核分枝杆菌的出现是全球传染病死亡的主要原因。由于近几十年来没有引入新的药物，因此迫切需要新型分子类别作为抗结核药物。在此，我们报告了一系列 4-烷氧基肉桂酸的硫酯、酰胺、酰肼和三唑并邻苯二甲酰亚胺衍生物的合成和构效关系。许多化合物对结核分枝杆菌菌株（H（37）Rv）表现出亚微摩尔最低抑菌浓度。有趣的是，化合物 13e，一种 4-异戊烯氧基肉桂酰基三唑并邻苯二甲酰亚胺衍生物，在抑制异烟肼（INH）耐药结核分枝杆菌菌株生长的能力方面，被发现比异烟肼（INH）活性高 100-1800 倍。结果还表明，13e 不干扰分枝菌酸的生物合成，从而指向不同的作用模式，并代表了开发新型抗结核药物的有吸引力的先导化合物。
