6-(4-fluorophenyl)-2-methylnicotinohydrazide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 6-(4-fluorophenyl)-2-methylnicotinohydrazide
• 英文别名: 6-(4-Fluorophenyl)-2-methylpyridine-3-carbohydrazide
• 化学式: C₁₃H₁₂FN₃O
• 分子量: 245.256
• InChiKey: HVAGKFNSBDOINT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  68
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(4-fluorophenyl)-2-methylnicotinohydrazide 在 盐酸 、 sodium nitrite 作用下， 以 水 为溶剂， 以77 %的产率得到6-(4-fluorophenyl)-2-methylpyridine-3-carbonyl azide
  参考文献：
  名称：

  设计和合成 6-芳基吡啶系磺酰胺作为碳酸酐酶 IX 的新型选择性抑制剂，对人类结直肠癌具有良好的抗肿瘤特性

  摘要：

  缺氧是实体瘤的一个特征，是由于细胞过度增殖和肿瘤快速生长超过氧气供应而产生的，可导致血管生成激活、侵袭性、侵袭性和转移性增加，从而提高肿瘤存活率并抑制抗癌作用。药物治疗的影响。SLC-0111 是一种脲基苯磺酰胺，是一种选择性人碳酸酐酶(hCA) IX 抑制剂，目前正在临床试验中用于治疗缺氧恶性肿瘤。在此，我们描述了新型 6-芳基吡啶8a-l和9a-d作为 SLC-0111 结构类似物的设计和合成，旨在探索癌症相关 hCA IX 亚型的新选择性抑制剂。SLC-0111 中的对氟苯基尾部被特殊的 6-芳基吡啶基序取代。此外，还开发了邻位磺酰胺区域异构体和间磺酰胺区域异构体以及乙烯延伸类似物。使用停流 CO 2水合酶测定，体外筛选所有基于 6-芳基吡啶的 SLC-0111 类似物对一组 hCA（hCA I、II、IV 和 IX 亚型）的抑制潜力。此外，美国 NCI 开发治疗计划首次针对一组 57

  DOI：

  10.1016/j.ejmech.2023.115538
• 作为产物：
  描述：

  3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one 在 ammonium acetate 、 一水合肼 作用下， 以 溶剂黄146 为溶剂， 反应 8.0h， 生成 6-(4-fluorophenyl)-2-methylnicotinohydrazide
  参考文献：
  名称：

  Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides

  摘要：

  合成了三系列6-芳基-2-甲基烟碱酰肼4a–i、N'-芳亚甲基-6-(4-溴苯基)-2-甲基烟碱酰肼7a–f和N'-(未/取代的2-氧代吲哚啉-3-亚甲基)-6-(4-氟苯基)-2-甲基烟碱酰肼8a–c，并评估了它们对结核杆菌的体外抗菌活性。结果显示，靛红酰肼8a–c相较于母体酰肼4c活性显著更高。酰肼8b和8c在所有测试化合物中显示出最高的活性（MIC分别为12.5和6.25 µg/mL）。化合物8b和8c对HT-29、PC-3、A549、HepG2和MCF-7癌细胞系也无明显细胞毒性。此外，8b和8c显示出良好的类药性得分，分别为0.62和0.41。这两个靛红酰肼为未来开发更强效的抗结核药物提供了极佳的基础。SAR研究表明，合成衍生物的亲脂性是影响其抗结核活性的关键因素。最后，建立了理论动力学研究来预测活性衍生物的ADME。

  DOI：

  10.3390/molecules20058800

文献信息

• Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides
  作者：Wagdy Eldehna、Mohamed Fares、Marwa Abdel-Aziz、Hatem Abdel-Aziz

  DOI：10.3390/molecules20058800

  日期：——

  Three series of 6-aryl-2-methylnicotinohydrazides 4a–i, N′-arylidene-6-(4-bromophenyl)-2-methylnicotino hydrazides 7a–f, and N′-(un/substituted 2-oxoindolin-3-ylidene)-6-(4-fluorophenyl)-2-methylnicotinohydrazides 8a–c were synthesized and evaluated for their potential in vitro antimycobacterial activity against M. tuberculosis. The results showed that isatin hydrazides 8a–c are remarkably more active than the parent hydrazide 4c. Hydrazides 8b and 8c exhibited the highest activity among all the tested compounds (MIC = 12.5 and 6.25 µg/mL, respectively). Compounds 8b and 8c were also devoid of apparent cytotoxicity to HT-29, PC-3, A549, HepG2 and MCF-7 cancer cell lines. Besides, 8b and 8c showed good drug-likeness scores of 0.62 and 0.41, respectively. Those two isatin hydrazides could offer an excellent framework for future development to obtain more potent antitubercular agents. The SAR study suggested that lipophilicity of the synthesized derivatives is a crucial element that accounts for their antimycobacterial activity. Finally, a theoretical kinetic study was established to predict the ADME of the active derivatives.

  合成了三系列6-芳基-2-甲基烟碱酰肼4a–i、N'-芳亚甲基-6-(4-溴苯基)-2-甲基烟碱酰肼7a–f和N'-(未/取代的2-氧代吲哚啉-3-亚甲基)-6-(4-氟苯基)-2-甲基烟碱酰肼8a–c，并评估了它们对结核杆菌的体外抗菌活性。结果显示，靛红酰肼8a–c相较于母体酰肼4c活性显著更高。酰肼8b和8c在所有测试化合物中显示出最高的活性（MIC分别为12.5和6.25 µg/mL）。化合物8b和8c对HT-29、PC-3、A549、HepG2和MCF-7癌细胞系也无明显细胞毒性。此外，8b和8c显示出良好的类药性得分，分别为0.62和0.41。这两个靛红酰肼为未来开发更强效的抗结核药物提供了极佳的基础。SAR研究表明，合成衍生物的亲脂性是影响其抗结核活性的关键因素。最后，建立了理论动力学研究来预测活性衍生物的ADME。
• Synthesis and<i>in vitro</i>anticancer activity of certain novel 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas as apoptosis-inducing agents
  作者：Wagdy M. Eldehna、Ghada S. Hassan、Sara T. Al-Rashood、Tarfah Al-Warhi、Ahmed E. Altyar、Hamad M. Alkahtani、Abdulrahman A. Almehizia、Hatem A. Abdel-Aziz

  DOI：10.1080/14756366.2018.1547286

  日期：2019.1.1

  Abstract In connection with our research program on the development of novel anticancer candidates, herein we report the design and synthesis of novel series of 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas 5a–l. The target pyridins were evaluated for their in vitro anticancer activity against two cancer cell lines: non-small cell lung cancer A549 cell line and colon cancer HCT-116 cell line. Compound

  抽象的 结合我们关于新型抗癌候选药物开发的研究计划，在此我们报告新型1-（2-甲基-6-芳基吡啶3-3-基）-3-苯基脲5a-1的设计和合成。评价目标吡啶类化合物对两种癌细胞系的体外抗癌活性：非小细胞肺癌A549细胞系和结肠癌HCT-116细胞系。化合物5l是A549和HCT-116细胞系中活性最高的同源物，IC 50值分别等于3.22±0.2和2.71±0.16 µM，与阿霉素相当。分别为2.93±0.28和3.10±0.22。此外，化合物5l在US-NCI发展治疗计划抗癌试验中，脱氧核糖核酸是最有效的吡啶衍生物（平均GI = 40），对所有亚板中测试最多的癌细胞系均具有广谱抗肿瘤活性。化合物51能够在HCT-116细胞中引起凋亡，这由抗凋亡Bcl-2蛋白的表达降低和促凋亡蛋白水平的表达增强所证明。Bax，细胞色素C，p53，caspase-3和caspase-9。此外，5l通过改变Sub-G
• Protective effect of novel substituted nicotine hydrazide analogues against hypoxic brain injury in neonatal rats via inhibition of caspase
  作者：Chang-bo Deng、Juan Li、Lu-yi Li、Feng-jie Sun

  DOI：10.1016/j.bmcl.2016.04.031

  日期：2016.7

  In hypoxic-ischemic injury of the brain of neonates, the level of caspase-3 was found to be aberrantly activated. Its overexpression leads to the alteration of cytoskeleton protein fodrin and loss of DNA repair enzyme which ultimately results in neurological impairment and disability. Concerning this, the present study was intended to develop novel nicotine hydrazide analogues as caspase inhibitors via efficient synthetic route. These compounds were subsequently tested for inhibitory activity against caspase-3 and -7 where they exhibit highly potent activity against caspase-3 revealing compound 5k as most potent inhibitor (IC50 = 19.4 +/- 2.5 mu M). In Western blot analysis, 5k considerably inhibits the overexpression of caspase-3. The aryl nicotinate of compound 5k, as indicated by molecular docking was found to engage His121 and critical enzyme thiols, i.e., Cys163 of caspase-3 for its potent activity. Moreover, histopathological examination of brain tissues and hippocampus neurons showed that compound 5k considerably improves the brain injury and exert neuroprotective effects in hypoxic-ischemic (HI). In brain homogenate, 5k significantly improves the activity of MDA, SOD, GSH-Px, CAT and T-AOC to exert its beneficial effect against oxidative stress induced by HI injury. (C) 2016 Elsevier Ltd. All rights reserved.
• Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents
  作者：Wagdy M. Eldehna、Ayman Altoukhy、Hoda Mahrous、Hatem A. Abdel-Aziz

  DOI：10.1016/j.ejmech.2014.12.010

  日期：2015.1

  A hybrid pharmacophore approach was adopted to design and synthesize new series of isatin-pyridine hybrids. All the newly prepared hybrids (5a-o, 8 and 11a-d) were in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely HepG2 hepatocellular carcinoma, A549 lung cancer and MCF-7 breast cancer. Compound 8 emerged as the most active member against HepG2 cell line (IC50 = 2.5 +/- 0.39 mu M), with 2.7-fold increased activity than the reference drug, doxorubicin (IC50 = 6.9 +/- 2.05 mu M). Whilst, compound 11c was found to be the most potent counterpart against A549 and MCF-7 cell lines with IC50 values of 10.8 +/- 1.15 and 6.3 +/- 0.79, respectively. The weightiness of the utilization of non-cleavable linker, as the chalcone linker, and simplification of the first group, was explored via the SAR study. Furthermore, a QSAR model was built to explore the structural requirements controlling the cytotoxic activities. Notably, the predicted activities by the QSAR model were very close to those experimentally observed, hinting that this model could be safely applied for prediction of more efficacious hits comprising the same skeletal framework. Finally, a theoretical kinetic study was established to predict the ADME of the active hybrids. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Novel 1,3,5‐triazine‐nicotinohydrazide derivatives induce cell arrest and apoptosis in osteosarcoma cancer cells and inhibit osteosarcoma in a patient‐derived orthotopic xenograft mouse model
  作者：Qing Su、Baolin Xu、Zhoubin Tian、Ziling Gong

  DOI：10.1111/cbdd.13986

  日期：2022.2

  AbstractThe present study deals with developing novel 1,3,5‐triazine‐nicotinohydrazide derivatives as potent CDK9 inhibitors in a straightforward synthetic route with potent anti‐osteosarcoma activity. The most potent CDK9 inhibitor compound 5k inhibits proliferation of MG‐63 cells via induction of apoptosis and G2/M cell cycle arrest. It reduces tumor progression in the patient‐derived orthotopic xenograft (PDOX) mouse model with significant antioxidant and anti‐inflammatory activity. In tumor tissue homogenates, it caused significant inhibition of CDK9 and inhibited the phosphorylation of RNAPII ser2 and reduced MCL‐1 expression in Western blot analysis. Compound 5k also showed considerable bioavailability in SD mice. Our results demonstrated that compound 5k inhibits growth of OS in vitro and in vivo via inhibition of CDK9 which attenuated the downstream phosphorylation of RNAPII ser2 and represses expression of the anti‐apoptotic protein, MCL‐1 for the induction of apoptosis in OS.