Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties
Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties
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DOI：
10.1016/j.ejmech.2015.10.047
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发表时间：
2016-01-01
影响因子：
6.7
通讯作者：
Yang, Kap Seung
中科院分区：
文献类型：
--
作者：
Joshi, Shrinivas D.;Dixit, Sheshagiri R.;Yang, Kap Seung
我们在此报告了 61 种带有吡唑啉、异恶唑和苯基硫脲部分的新型吡咯基衍生物的合成、抗菌和抗结核评价。使用 Surflex-Dock 对结核分枝杆菌的烯酰 ACP 还原酶进行了分子对接，该酶是参与结核分枝杆菌 II 型脂肪酸生物合成途径的关键酶之一，是设计新型抗结核药物的有吸引力的靶标。使用 Sybyl-X 2.0 软件中的 Surflex-Dock 对 ENR 晶体结构进行对接分析，表明取代的吡咯衍生物占据了 InhA 酶的疏水口袋。化合物9b和9d表现出最高的抗结核活性，几乎接近异烟肼(0.4μg/mL)，MIC值为0.8μg/mL。所有其他化合物均表现出良好的活性，MIC值为6.25-100 μg/mL。使用人肺癌细胞系（A549）进一步测试了这些化合物的哺乳动物细胞毒性，并且是无毒的。一些化合物表现出对InhA的抑制活性。 (C) 2015 Elsevier Masson SAS。版权所有。
We report here the synthesis, antibacterial and antitubercular evaluation of 61 novel pyrrolyl derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties. Molecular docking was carried out on enoyl ACP reductase from Mycobacterium tuberculsosis using Surflex-Dock, which is one of the key enzymes involved in type II fatty acid biosynthetic pathway of Mycobacterium tuberculosis, an attractive target for designing novel antitubercular agents. Docking analysis of the crystal structure of ENR performed using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of substituted pyrrolyi derivatives into hydrophobic pocket of InhA enzyme. Compounds 9b and 9d exhibited the highest antitubercular activity almost close to isoniazid (0.4 mu g/mL) with a MIC value of 0.8 mu g/mL. All other compounds showed the good activity with a MIC value of 6.25-100 mu g/mL. The compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) and were nontoxic. Some compounds exhibited inhibition activities against InhA. (C) 2015 Elsevier Masson SAS. All rights reserved.