Joshi Shrinivas D, Dixit Sheshagiri R, Kirankumar M N, Aminabhavi Tejraj M, Raju K V S N, Narayan Ramanuj, Lherbet Christian, Yang Kap Seung
Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad, 580 002, India.
Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad, 580 002, India.
Eur J Med Chem. 2016 Jan 1;107:133-52. doi: 10.1016/j.ejmech.2015.10.047. Epub 2015 Oct 31.
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 pyrrolyl derivatives into hydrophobic pocket of InhA enzyme. Compounds 9b and 9d exhibited the highest antitubercular activity almost close to isoniazid (0.4 μg/mL) with a MIC value of 0.8 μg/mL. All other compounds showed the good activity with a MIC value of 6.25-100 μg/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.
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、抗菌和抗结核评估。使用Surflex-Dock对结核分枝杆菌的烯酰基ACP还原酶进行了分子对接，该酶是结核分枝杆菌II型脂肪酸生物合成途径中的关键酶之一，是设计新型抗结核药物的一个有吸引力的靶点。在Sybyl-X 2.0软件中使用Surflex-Dock对ENR晶体结构进行的对接分析表明，取代的吡咯基衍生物占据了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。所有其他化合物表现出良好的活性，MIC值为6.25-100μg/mL。使用人肺癌细胞系（A549）对这些化合物进行了进一步的哺乳动物细胞毒性测试，结果显示它们无毒。一些化合物表现出对InhA的抑制活性。
