Abdu-Allah Hajjaj H M, Youssif Bahaa G M, Abdelrahman Mostafa H, Abdel-Hamid Mohammed K, Reshma Rudraraju Srilakshmi, Yogeeswari Perumal, Aboul-Fadl Tarek, Sriram Dharmarajan
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.
Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka, 42421, Saudi Arabia.
Arch Pharm Res. 2017 Feb;40(2):168-179. doi: 10.1007/s12272-016-0882-x. Epub 2016 Dec 27.
The antitubercular drug; para-aminosalicylic acid (PAS) was used as the core scaffold for the design of a series of 1H-1,2,3-triazolylsalicylhydrazones upon coupling with triazole and arylhydrazone moietis to furnish a single molecular architecture. The obtained derivatives were screened against Mycobacterium tuberculosis H37Rv revealing good to high activity for the active compounds (MIC values of 0.39-1.5 μg/mL) compared to the marketed drugs isoniazid, rifampicin and ethambutol. Moreover, the most active analogue N-(1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxy-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-benzohydrazide (20) was found to be ten-fold more potent than PAS and equipotent to rifampicin (MIC 0.39 µg/mL), while exhibiting low cytotoxicity with a selectivity index of >128. In addition, this compound was shown to be active against persistent forms of mycobacteria comparable to standard drugs in nutrient starvation model. Accordingly, we introduce compound 20 as a valuable lead for further development. A 3D-QSAR study was also conducted to help in explaining the observed activity and to serve as a tool for further development.
抗结核药物对氨基水杨酸（PAS）被用作核心骨架，通过与三唑和芳基腙部分偶联，设计了一系列1H-1,2,3-三唑基水杨酰腙，以提供单一的分子结构。将所得衍生物针对结核分枝杆菌H37Rv进行筛选，结果显示，与市售药物异烟肼、利福平和乙胺丁醇相比，活性化合物具有良好至高活性（MIC值为0.39-1.5μg/mL）。此外，发现活性最高的类似物N-(1-(4-氯苄基)-2-氧代吲哚啉-3-亚基)-2-羟基-4-(4-苯基-1H-1,2,3-三唑-1-基)-苯甲酰肼（20）的效力比PAS高10倍，与利福平相当（MIC 0.39μg/mL），同时表现出低细胞毒性，选择性指数>128。此外，在营养饥饿模型中，该化合物对持续存在的分枝杆菌形式具有与标准药物相当的活性。因此，我们将化合物20作为进一步开发的有价值先导化合物。还进行了3D-QSAR研究，以帮助解释观察到的活性，并作为进一步开发的工具。
