基于小分子组合文库中单个席夫碱的抗结核活性构建药效团模型。
Pharmacophoric model building for antitubercular activity of the individual Schiff bases of small combinatorial library.
机构信息
Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
出版信息
Eur J Med Chem. 2010 Mar;45(3):1098-106. doi: 10.1016/j.ejmech.2009.12.005. Epub 2009 Dec 11.
Synthesis and evaluation of anti-TB activity of individual compounds of Schiff bases combinatorial library were done against Mycobacterium tuberculosis H(37)Rv at a single concentration of 6.25mug/mL according to the protocol of TAACF. Compounds 2C and 3D produced 99% inhibitory activity on the investigated organism, while the other tested compounds showed lower activity ranging from 35 to 84%. It was found that there are no relation between the anti-TB activity of the tested compounds and their lipophilicity expressed by ClogP of these compounds. A 3D pharmacophoric model has been generated by Molecular Operating Environment (MOE) using a training set of 10 reported anti-TB compounds and testing the synthesized compounds (1A, 1B, 1D, 1E, 2C, 3A, 3C, 3D, 3E and 4A-4E). The generated pharmacophoric features include, F1: hydrogen bond donors (Don), F2: aromatic rings (Aro), F3: hydrogen bond acceptors (Acc)/metal ligator (ML), F4: Aro/hydrophobic (Hyd). In all hit set, it was found that the amidic nitrogen CONH-NC fitted the region of the Don, F1, while the amidic carbonyl group fitted the region of the Acc/ML, F3. The distances bridging F1 to F2, F3 and F4 were essential for anti-TB activity in the developed pharmacophore model, as it was confirmed from model validation procedure.
根据 TAACF 方案，以 6.25μg/mL 的单一浓度，对单个希夫碱组合文库化合物进行了抗结核活性的合成和评估，针对结核分枝杆菌 H(37)Rv。化合物 2C 和 3D 对所研究的生物产生了 99%的抑制活性，而其他测试化合物的活性则较低，范围为 35%至 84%。研究发现，所测试化合物的抗结核活性与这些化合物的亲脂性（ClogP）之间没有关系。使用分子操作环境（MOE），通过一个由 10 个报道的抗结核化合物组成的训练集生成了一个 3D 药效团模型，并测试了合成的化合物（1A、1B、1D、1E、2C、3A、3C、3D、3E 和 4A-4E）。生成的药效团特征包括，F1：氢键供体（Don），F2：芳环（Aro），F3：氢键受体（Acc）/金属配体（ML），F4：芳环/疏水性（Hyd）。在所有命中集，发现酰胺氮 CONH-NC 适合于 Don，F1 区域，而酰胺羰基适合于 Acc/ML，F3 区域。在开发的药效团模型中，F1 与 F2、F3 和 F4 之间的距离对于抗结核活性是必不可少的，这从模型验证过程中得到了证实。
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