3-(4-methylsulfanylphenyl)-1-(4-ethylphenyl)prop-2-yn-1-ol | 742699-22-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: 3-(4-methylsulfanylphenyl)-1-(4-ethylphenyl)prop-2-yn-1-ol
• 英文别名: 1-(4-Ethylphenyl)-3-(4-methylsulfanylphenyl)prop-2-yn-1-ol
• CAS: 742699-22-5
• 化学式: C₁₈H₁₈OS
• 分子量: 282.406
• InChiKey: ZDKYGBFUHHTLEC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  45.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-(4-methylsulfanylphenyl)-1-(4-ethylphenyl)prop-2-yn-1-ol 在 manganese(IV) oxide 、 sodium hydride 作用下， 以 二甲基亚砜 、 丙酮 为溶剂， 反应 1.0h， 生成 6-(4-ethylphenyl)-4-(4-methylsulfanylphenyl)-3-phenylpyran-2-one
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationship Studies of 3,4,6-Triphenylpyran-2-ones as Selective Cyclooxygenase-2 Inhibitors

  摘要：

  A group of regioisomeric 3,4,6-triphenylpyran-2-ones with a MeSO2 pharmacophore at the paraposition of either a C-3 phenyl or a C-4 phenyl substituent on the central six-membered pyran-2-one ring were prepared and evaluated in vitro for their abilities to inhibit the isozymes COX-1 and COX-2. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position of the C-6 phenyl ring attached to the central pyranone, showed that 6-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was the most potent and selective COX-2 inhibitor (COX-2 IC50 = 0.02 muM; COX-1 IC50 > 100 muM) with a high COX-2 selectivity index (SI > 5000) relative to the reference drugs celecoxib (COX-2 IC50 = 0.07 muM; SI = 474) and rofecoxib (COX-2 IC50 = 0.50 muM; SI > 200). 6-(4-Methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was a more potent oral antiinflammatory agent (ID50 = 5.6 mg/kg) than celecoxib (ID50 = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. In a 4% NaCl-induced abdominal constriction assay, a 5 mg/kg oral dose of 12e exhibited good analgesic activity at different time intervals producing 37.5 and 69% inhibition of writhing at 30 and 60 min, respectively. In contrast, the corresponding 6-(4-methoxyphenyl)-4-(4-methanesulfonylphenyl)-3-phenylpyran-2-one regiosiomer (12o) was a less potent and selective COX-2 inhibitor (COX-2 IC50 = 0.45 muM; SI = 70). A molecular modeling study for 12e indicated that the p-OMe substituent on the C-6 phenyl ring interacts with the COX-2 binding site amino acids Ile(345), Val(349), Leu(359), Leu(531), and Met(535) and that the OMe substituent may be responsible for proper orientation of the C-3 p-SO2Me-phenyl ring within the COX-2 secondary pocket (Gln(192), Arg(513), and Phe(518)). These results show that the COX-2 selectivity and potency of 3,4,6-triphenylpyranone regioisomers can be modulated by appropriate placement of the p-SO2Me pharmacophore on either the C-3 or C-4 phenyl moiety. In addition, electronic properties at the para-position of a C-6 phenyl substituent on the central pyranone ring govern COX-2 inhibitory potency and selectivity by controlling the orientation of the p-SO2Me pharmacophore within the COX-2 secondary pocket.

  DOI：

  10.1021/jm049939b
• 作为产物：
  描述：

  4-ethynylthioanisole 、 4-乙基苯甲醛 在 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 0.05h， 以71.2%的产率得到3-(4-methylsulfanylphenyl)-1-(4-ethylphenyl)prop-2-yn-1-ol
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationship Studies of 3,4,6-Triphenylpyran-2-ones as Selective Cyclooxygenase-2 Inhibitors

  摘要：

  A group of regioisomeric 3,4,6-triphenylpyran-2-ones with a MeSO2 pharmacophore at the paraposition of either a C-3 phenyl or a C-4 phenyl substituent on the central six-membered pyran-2-one ring were prepared and evaluated in vitro for their abilities to inhibit the isozymes COX-1 and COX-2. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position of the C-6 phenyl ring attached to the central pyranone, showed that 6-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was the most potent and selective COX-2 inhibitor (COX-2 IC50 = 0.02 muM; COX-1 IC50 > 100 muM) with a high COX-2 selectivity index (SI > 5000) relative to the reference drugs celecoxib (COX-2 IC50 = 0.07 muM; SI = 474) and rofecoxib (COX-2 IC50 = 0.50 muM; SI > 200). 6-(4-Methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was a more potent oral antiinflammatory agent (ID50 = 5.6 mg/kg) than celecoxib (ID50 = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. In a 4% NaCl-induced abdominal constriction assay, a 5 mg/kg oral dose of 12e exhibited good analgesic activity at different time intervals producing 37.5 and 69% inhibition of writhing at 30 and 60 min, respectively. In contrast, the corresponding 6-(4-methoxyphenyl)-4-(4-methanesulfonylphenyl)-3-phenylpyran-2-one regiosiomer (12o) was a less potent and selective COX-2 inhibitor (COX-2 IC50 = 0.45 muM; SI = 70). A molecular modeling study for 12e indicated that the p-OMe substituent on the C-6 phenyl ring interacts with the COX-2 binding site amino acids Ile(345), Val(349), Leu(359), Leu(531), and Met(535) and that the OMe substituent may be responsible for proper orientation of the C-3 p-SO2Me-phenyl ring within the COX-2 secondary pocket (Gln(192), Arg(513), and Phe(518)). These results show that the COX-2 selectivity and potency of 3,4,6-triphenylpyranone regioisomers can be modulated by appropriate placement of the p-SO2Me pharmacophore on either the C-3 or C-4 phenyl moiety. In addition, electronic properties at the para-position of a C-6 phenyl substituent on the central pyranone ring govern COX-2 inhibitory potency and selectivity by controlling the orientation of the p-SO2Me pharmacophore within the COX-2 secondary pocket.

  DOI：

  10.1021/jm049939b

文献信息

• Design, Synthesis, and Structure−Activity Relationship Studies of 3,4,6-Triphenylpyran-2-ones as Selective Cyclooxygenase-2 Inhibitors
  作者：P. N. Praveen Rao、Md. Jashim Uddin、Edward E. Knaus

  DOI：10.1021/jm049939b

  日期：2004.7.1

  A group of regioisomeric 3,4,6-triphenylpyran-2-ones with a MeSO2 pharmacophore at the paraposition of either a C-3 phenyl or a C-4 phenyl substituent on the central six-membered pyran-2-one ring were prepared and evaluated in vitro for their abilities to inhibit the isozymes COX-1 and COX-2. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position of the C-6 phenyl ring attached to the central pyranone, showed that 6-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was the most potent and selective COX-2 inhibitor (COX-2 IC50 = 0.02 muM; COX-1 IC50 > 100 muM) with a high COX-2 selectivity index (SI > 5000) relative to the reference drugs celecoxib (COX-2 IC50 = 0.07 muM; SI = 474) and rofecoxib (COX-2 IC50 = 0.50 muM; SI > 200). 6-(4-Methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was a more potent oral antiinflammatory agent (ID50 = 5.6 mg/kg) than celecoxib (ID50 = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. In a 4% NaCl-induced abdominal constriction assay, a 5 mg/kg oral dose of 12e exhibited good analgesic activity at different time intervals producing 37.5 and 69% inhibition of writhing at 30 and 60 min, respectively. In contrast, the corresponding 6-(4-methoxyphenyl)-4-(4-methanesulfonylphenyl)-3-phenylpyran-2-one regiosiomer (12o) was a less potent and selective COX-2 inhibitor (COX-2 IC50 = 0.45 muM; SI = 70). A molecular modeling study for 12e indicated that the p-OMe substituent on the C-6 phenyl ring interacts with the COX-2 binding site amino acids Ile(345), Val(349), Leu(359), Leu(531), and Met(535) and that the OMe substituent may be responsible for proper orientation of the C-3 p-SO2Me-phenyl ring within the COX-2 secondary pocket (Gln(192), Arg(513), and Phe(518)). These results show that the COX-2 selectivity and potency of 3,4,6-triphenylpyranone regioisomers can be modulated by appropriate placement of the p-SO2Me pharmacophore on either the C-3 or C-4 phenyl moiety. In addition, electronic properties at the para-position of a C-6 phenyl substituent on the central pyranone ring govern COX-2 inhibitory potency and selectivity by controlling the orientation of the p-SO2Me pharmacophore within the COX-2 secondary pocket.