N-(3-chloro-4-fluorophenyl)-2-acetylacetamide | 712308-71-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3-chloro-4-fluorophenyl)-2-acetylacetamide
• 英文别名: N-(3-chloro-4-fluorophenyl)-3-oxobutanamide
• CAS: 712308-71-9
• 化学式: C₁₀H₉ClFNO₂
• 分子量: 229.638
• InChiKey: XUWXXFCFTRKNHP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  46.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(3-chloro-4-fluorophenyl)-2-acetylacetamide 、 氰乙酰胺 在 吗啉 、 1,2,3,4,5,6,7,8-八硫杂环辛烷 作用下， 以 乙醇 为溶剂， 以82%的产率得到5-amino-N2-(3-chloro-4-fluorophenyl)-3-methylthiophene-2,4-dicarboxamide
  参考文献：
  名称：

  5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors

  摘要：

  Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 mu M, CC50 > 100 mu M = 25%) and 19k (EC50 = 0.31 mu M, CC50 > 100 mu M, F = 46%), displayed overall lead profiles superior to reported CAEs 7-10 used in our studies. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.12.047
• 作为产物：
  描述：

  3-氯-4-氟苯胺 、 乙酰乙酸乙酯 以 甲苯 为溶剂， 生成 N-(3-chloro-4-fluorophenyl)-2-acetylacetamide
  参考文献：
  名称：

  Targeting Dormant Tuberculosis Bacilli: Results for Molecules with a Novel Pyrimidone Scaffold

  摘要：

  Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug‐resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M. tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC50 values. This study reports the second molecule after TMC‐207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach – recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E‐state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure–activity relationships that will guide the design of more potent inhibitors.

  DOI：

  10.1111/cbdd.12373

文献信息

• A Concise [3 + 3] Heteroaromatization Synthetic Strategy Afford Dicarboxamide Functionalized Novel Pyrazolo[1,5-<i>a</i>]Pyrimidines
  作者：Anilkumar S. Patel、Naval P. Kapuriya、Yogesh T. Naliapara

  DOI：10.1002/jhet.2860

  日期：2017.9

  A concise and effective approach to dicarboxamide functionalized novel pyrazolo[1,5‐a]pyrimidine has been developed. The method involves [3 + 3] hetroaromatization of oxoketene dithioacetals (16a–x) with 5‐amino‐N‐cyclohexyl‐3‐(methylthio)‐1H‐pyrazole‐4‐carboxamide (12) in the presence of K2CO3. This method has advantages of excellent yields, operational simplicity, and avoidance of hazardous base

  已经开发出一种简洁有效的方法将二甲酰胺官能化的新型吡唑并[1,5- a ]嘧啶。该方法涉及在存在K 2 CO的情况下，用5-氨基-N-环己基-3-（甲硫基）-1H-吡唑-4-羧酰胺[ 12 +3]氧化氧杂环丁二硫缩醛（16a–x）的芳香化。3。该方法的优点是产率高，操作简单并且避免了诸如哌啶的有害碱。
• Synthesis, screening for antitubercular activity and 3D-QSAR studies of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides
  作者：Vijay Virsodia、Raghuvir R.S. Pissurlenkar、Dinesh Manvar、Chintan Dholakia、Priti Adlakha、Anamik Shah、Evans C. Coutinho

  DOI：10.1016/j.ejmech.2007.08.004

  日期：2008.10

  Multi-drug resistance to commonly used antitubercular drugs has propelled the development of new structural classes of antitubercular agents. This paper reports the synthesis, evaluation and 3D-QSAR analysis of a set of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamides as antitubercular agents. Substituted acetoacetanilides were reacted with various aromatic aldehydes and urea which yielded the tetrahydropyrimidine derivatives with a phenyl carbamoyl group at C-5 position, and with various substitutions on the 4-phenyl and the N-phenyl aromatic rings. All compounds were screened for antitubercular activity against Mycobacterium tuberculosis H(37)Rv strain. The QSAR models were generated on a training set of 23 molecules. The molecules were aligned using the atom-fit and field-fit techniques. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r(2)) of 0.98 and 0.95 with cross-validated r(2)(q(2)) of 0.68 and 0.58, respectively. The 3D-QSAR models were externally validated against a test set of 7 molecules for which the predictive r(2) (r(pred)(2)) is recorded as 0.41 and 0.32 for the CoMFA and CoMSIA models, respectively. The CoMFA and CoMSIA contours helped to design some new molecules with improved activity. (C) 2007 Elsevier Masson SAS. All rights reserved.
• Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents
  作者：Rong-geng Fu、Qi-dong You、Lei Yang、Wu-tong Wu、Cheng Jiang、Xiao-li Xu

  DOI：10.1016/j.bmc.2010.09.020

  日期：2010.11.15

  Four series of dihydropyrazolo[3,4-b]pyridines and benzo[4,5]imidazo[1,2-a]pyrimidines were designed and synthesized as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents by introducing some fragments of Aurora-A kinase inhibitors into our KSP inhibitor CPUYL064. A total of 19 target compounds were evaluated by two related enzyme inhibition assays and a cytotoxicity assay in vitro. The results showed that some target compounds could inhibit both enzymes, and several of them showed significant inhibition activity against HCT116 cell line. Despite showing moderate KSP and Aurora-A kinase inhibition, the lead compounds 6a and 6e displayed significant cytotoxic activity in the micromolar range, especially against the HCT116 cell line and HepG2 cell line. The results may be useful for developing a new class of inhibitors having a dual function, KSP inhibition and Aurora-A kinase inhibition, for the treatment of cancer. (C) 2010 Elsevier Ltd. All rights reserved.
• Targeting Dormant Tuberculosis Bacilli: Results for Molecules with a Novel Pyrimidone Scaffold
  作者：Rohit R. Joshi、Avinash Barchha、Vijay M. Khedkar、Raghuvir R. S. Pissurlenkar、Sampa Sarkar、Dhiman Sarkar、Rohini R. Joshi、Ramesh A. Joshi、Anamik K. Shah、Evans C. Coutinho

  DOI：10.1111/cbdd.12373

  日期：2015.2

  Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug‐resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M. tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC50 values. This study reports the second molecule after TMC‐207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach – recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E‐state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure–activity relationships that will guide the design of more potent inhibitors.
• Synthesis, characterization, anticancer activity, and QSAR-studies of some new tetrahydropyrimidines
  作者：N. C. Desai、M. T. Chhabaria、Amit Dodiya、Ajit M. Bhavsar、B. B. Baldaniya

  DOI：10.1007/s00044-010-9481-4

  日期：2011.11

  Several new substituted 1,2,3,4 tetrahydropyrimidine derivatives have been synthesized and evaluated for their in vitro anticancer activity on various cell lines. Some of the molecules have exhibited significantly potent inhibition on several cell lines. To find out inter correlation between anticancer activity and molecular descriptors, QSAR study was carried out. Molecular descriptors used for the study were ClogP (lipophilic), CMR (steric), and polarity (electronic). Anticancer activity is expressed in the form of LogGI(50) (+). Activity on different cell lines was independently correlated with molecular descriptors. On the basis of the results, significant correlation between anticancer activity on some of the cell lines and molecular descriptor was observed.