Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India.
School of Electronic Science and Engineering, University of Electronic Science and Technology of China, China.
Bioorg Chem. 2021 Mar;108:104665. doi: 10.1016/j.bioorg.2021.104665. Epub 2021 Jan 27.
N-formyl pyrazoline derivatives (3a-3l) were designed and synthesized via Michael addition reaction through cyclization of chalcones with hydrazine hydrate in presence of formic acid. The structural elucidation of N-formyl pyrazoline derivatives was carried out by various spectroscopic techniques such as H, C NMR, FT-IR, UV-visible spectroscopy, mass spectrometry and elemental analysis. Anticancer activity of the pyrazoline derivatives (3a-3l) was evaluated against human lung cancer (A549), fibrosarcoma cell lines (HT1080) and human primary normal lung cells (HFL-1) by MTT assay. The results of anticancer activity showed that potent analogs 3b and 3d exhibited promising activity against A549 (IC = 12.47 ± 1.08 and 14.46 ± 2.76 µM) and HT1080 (IC = 11.40 ± 0.66 and 23.74 ± 13.30 µM) but low toxic against the HFL-1 (IC = 116.47 ± 43.38 and 152.36 ± 22.18 µM). The anticancer activity of potent derivatives (3b and 3d) against A549 cancer cell line was further confirmed by flow cytometry based approach. DNA binding interactions of the pyrazoline derivatives 3b and 3d have been carried out with calf thymus DNA (Ct-DNA) using absorption, fluorescence and viscosity measurements, circular dichroism and cyclic voltammetry. Antioxidant potential of N-formyl pyrazoline derivatives (3a-3l) has been also estimated through DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical and HO Results revealed that all the compounds exhibited significant antioxidant activity. In silico molecular modelling and ADMET properties of pyrazoline derivatives were also studied using PyRx software against topoisomerase II receptor with PDB ID: 1ZXM to explore their best hits. MD simulation of 3b and 3d was also carried out with topoisomerase II for structure-function correlation in a protein. HuTopoII inhibitory activity of the analogs (3a-3l) was examined by relaxation assay at varying concentrations 100-1000 µM.
N-甲酰基吡唑啉衍生物（3a-3l）是通过迈克尔加成反应设计和合成的，该反应是通过查尔酮与水合肼在甲酸存在下环化得到的。N-甲酰基吡唑啉衍生物的结构通过各种光谱技术（如 H、C NMR、FT-IR、UV-可见光谱、质谱和元素分析）进行了阐明。通过 MTT 测定法评估了吡唑啉衍生物（3a-3l）对人肺癌（A549）、纤维肉瘤细胞系（HT1080）和人原代正常肺细胞（HFL-1）的抗癌活性。抗癌活性结果表明，具有潜力的类似物 3b 和 3d 对 A549（IC=12.47±1.08 和 14.46±2.76µM）和 HT1080（IC=11.40±0.66 和 23.74±13.30µM）具有有希望的活性，但对 HFL-1（IC=116.47±43.38 和 152.36±22.18µM）的毒性较低。通过基于流式细胞术的方法进一步证实了具有潜力的衍生物（3b 和 3d）对 A549 癌细胞系的抗癌活性。使用吸收、荧光和粘度测量、圆二色性和循环伏安法研究了吡唑啉衍生物 3b 和 3d 与小牛胸腺 DNA（Ct-DNA）的 DNA 结合相互作用。还通过 DPPH（2,2-二苯基-1-苦基肼）自由基和 HO 结果表明，所有化合物均表现出显著的抗氧化活性。还使用 PyRx 软件对 N-甲酰基吡唑啉衍生物（3a-3l）进行了分子模拟和 ADMET 性质研究，针对拓扑异构酶 II 受体（PDB ID：1ZXM）进行了最佳命中分析。还对 3b 和 3d 与拓扑异构酶 II 进行了 MD 模拟，以在蛋白质中进行结构-功能相关性研究。通过在 100-1000µM 不同浓度下的松弛测定法检查了类似物（3a-3l）对 HuTopoII 的抑制活性。
