2-(2,5-dimethylphenyl)-6-fluorobenzo[d]isothiazol-3(2H)-one | 727664-91-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: 2-(2,5-dimethylphenyl)-6-fluorobenzo[d]isothiazol-3(2H)-one
• 英文别名: 2-(2,5-Dimethylphenyl)-6-fluoro-1,2-benzothiazol-3-one
• CAS: 727664-91-7
• 化学式: C₁₅H₁₂FNOS
• mdl: MFCD05859599
• 分子量: 273.331
• InChiKey: GRGDWLDSVPJEJU-UHFFFAOYSA-N

物化性质

• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.133
• 拓扑面积：
  45.6
• 氢给体数：
  0
• 氢受体数：
  3

制备方法与用途

生物活性

MLS0315771 是一种来源于有效的磷酸甘露糖异构酶（MPI）的竞争性抑制剂，其 IC50 值约为 1 μM，Ki 值为 1.4 μM。

靶点

IC50: ~1 μM (MPI)。

体外研究

MLS0315771 能增加甘露糖向糖基化方向的代谢流。在较高浓度时，MLS0315771 的毒性是由于非靶标效应引起的。在高于 2 μM 的浓度下，MLS0315771 对斑马鱼胚胎具有毒性；在 8-10 μM 浓度下，约 50% 的胚胎在 20 分钟内表现出生病症状，并且大多数在 30 到 60 分钟内死亡。

反应信息

• 作为产物：
  描述：

  N-(2,5-dimethylphenyl)-4-fluoro-2-mercaptobenzamide 在 三氟乙酸 、 [双(三氟乙酰氧基)碘]苯 作用下， 以 二氯甲烷 为溶剂， 生成 2-(2,5-dimethylphenyl)-6-fluorobenzo[d]isothiazol-3(2H)-one
  参考文献：
  名称：

  Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1

  摘要：

  We report the discovery and characterization of a series of benzoisothiazolone inhibitors of PHOSPHO1, a newly identified soluble phosphatase implicated in skeletal mineralization and soft tissue ossification abnormalities. High-throughput screening (HTS) of a small molecule library led to the identification of benzoisothiazolones as potent and selective inhibitors of PHOSPHO1. Critical structural requirements for activity were determined, and the compounds were subsequently derivatized and measured for in vitro activity and ADME parameters including metabolic stability and permeability. On the basis of its overall profile the benzoisothiazolone analogue 2q was selected as MLPCN probe ML086.

  DOI：

  10.1016/j.bmcl.2014.07.013

文献信息

• Potent, Selective, and Orally Available Benzoisothiazolone Phosphomannose Isomerase Inhibitors as Probes for Congenital Disorder of Glycosylation Ia
  作者：Russell Dahl、Yalda Bravo、Vandana Sharma、Mie Ichikawa、Raveendra-Panickar Dhanya、Michael Hedrick、Brock Brown、Justin Rascon、Michael Vicchiarelli、Arianna Mangravita-Novo、Li Yang、Derek Stonich、Ying Su、Layton H. Smith、Eduard Sergienko、Hudson H. Freeze、Nicholas D. P. Cosford

  DOI：10.1021/jm101401a

  日期：2011.5.26

  We report the discovery and validation of a series of benzoisothiazolones as potent inhibitors of phosphomannose isomerase (PM), an enzyme that converts mannose-6-phosphate (Man-6-P) into fructose-6-phosphate (Fru-6-P) and, more importantly, competes with phosphomannomutase 2 (PMM2) for Man-6-P, diverting this substrate from critical protein glycosylation events. In congenital disorder of glycosylation type Ia, PMM2 activity is compromised.; thus, PMI inhibition is a potential strategy for the development of therapeutics. High-throughput screening (HTS) and subsequent chemical optimization led to the identification of a novel class of benzoisothiazolones as potent PMI inhibitors having little or no PMM2 inhibition. Two complementary synthetic routes were developed, enabling the critical structural requirements for activity to be determined, and the compounds were subsequently profiled in biochemical and cellular assays to assess efficacy. The most promising compounds were also profiled for bioavailability parameters, including metabolic stability, plasma stability, and permeability. The pharmacokinetic profile of a representative of this series (compound 19; ML089) was also assessed, demonstrating the potential of this series for in vivo efficacy when dosed orally in disease models.
• Design, synthesis and evaluation of benzoisothiazolones as selective inhibitors of PHOSPHO1
  作者：Yalda Bravo、Peter Teriete、Raveendra-Panickar Dhanya、Russell Dahl、Pooi San Lee、Tina Kiffer-Moreira、Santhi Reddy Ganji、Eduard Sergienko、Layton H. Smith、Colin Farquharson、José Luis Millán、Nicholas D.P. Cosford

  DOI：10.1016/j.bmcl.2014.07.013

  日期：2014.9

  We report the discovery and characterization of a series of benzoisothiazolone inhibitors of PHOSPHO1, a newly identified soluble phosphatase implicated in skeletal mineralization and soft tissue ossification abnormalities. High-throughput screening (HTS) of a small molecule library led to the identification of benzoisothiazolones as potent and selective inhibitors of PHOSPHO1. Critical structural requirements for activity were determined, and the compounds were subsequently derivatized and measured for in vitro activity and ADME parameters including metabolic stability and permeability. On the basis of its overall profile the benzoisothiazolone analogue 2q was selected as MLPCN probe ML086.