5-Methyl-5-phenyl-6-thia-10b-aza-benzo[e]azulen-4-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 英文名称: 5-Methyl-5-phenyl-6-thia-10b-aza-benzo[e]azulen-4-one
• 英文别名: 6-Methyl-6-phenyl-pyrrolo[2,1-d][1,5]benzothiazepin-7-one；6-methyl-6-phenylpyrrolo[2,1-d][1,5]benzothiazepin-7-one
• 化学式: C₁₉H₁₅NOS
• 分子量: 305.4
• InChiKey: SSDOAOBSEPIANH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  47.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  (+/-)-6-phenylpyrrolo<2,1-d><1,5>benzothiazepin-7(6H)-one 、 碘甲烷 在 potassium hydride 作用下， 生成 5-Methyl-5-phenyl-6-thia-10b-aza-benzo[e]azulen-4-one
  参考文献：
  名称：

  Pyrrolobenzothiazepinones and Pyrrolobenzoxazepinones:  Novel and Specific Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors with Antiviral Activity

  摘要：

  Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepinones were investigated as potential anti-AIDS drugs. These compounds were found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appreciable activity on HIV-2 cytopathic effects, and against HBV as well as calf-thymus DNA alpha-polymerase. Their potency is influenced by substituents at position 6 and on the fused aromatic ring. Specifically, small lipophilic substituents at C-6 were preferred, whereas substitutions on the benzo-fused ring were found to be detrimental to activity, with respect to the unsubstituted compounds. Modification of the pi-system at C-6 is well tolerated, although the replacement of the benzo-fused with a [2,3]naphtho-fused ring leads to a less active compound. Maximum potency and specificity is achieved with a phenyl and an ethyl group at position 6 of the pyrrolobenzoxazepinone system. In the enzymatic assay the oxazepinone derivative (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5] 16e (IC50 = 0.25 mu M) was found to be more potent than nevirapine (IC50 = 0.5 mu M), tested in the same experimental conditions using rC . dG as a template-primer. In cell culture assay benzoxazepine 16e was active against HIV-1, both wild type and AZT-sensitive, and HIV-1 (IIIB) strains, but not against HIV-2. In enzyme assay although 16e inhibited HIV-1 RT, it was inactive against the nevirapine-resistant recombinant RT Y181C at 50 mu M. Molecular modeling studies suggest that these derivatives present a 3D pharmacophoric arrangement similar to that of other nonnucleoside inhibitors such as nevirapine.

  DOI：

  10.1021/jm950702c

文献信息

• Pyrrolobenzothiazepinones and Pyrrolobenzoxazepinones:  Novel and Specific Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors with Antiviral Activity
  作者：Giuseppe Campiani、Vito Nacci、Isabella Fiorini、Maria P. De Filippis、Antonio Garofalo、Giovanni Greco、Ettore Novellino、Sergio Altamura、Laura Di Renzo

  DOI：10.1021/jm950702c

  日期：1996.1.1

  Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepinones were investigated as potential anti-AIDS drugs. These compounds were found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appreciable activity on HIV-2 cytopathic effects, and against HBV as well as calf-thymus DNA alpha-polymerase. Their potency is influenced by substituents at position 6 and on the fused aromatic ring. Specifically, small lipophilic substituents at C-6 were preferred, whereas substitutions on the benzo-fused ring were found to be detrimental to activity, with respect to the unsubstituted compounds. Modification of the pi-system at C-6 is well tolerated, although the replacement of the benzo-fused with a [2,3]naphtho-fused ring leads to a less active compound. Maximum potency and specificity is achieved with a phenyl and an ethyl group at position 6 of the pyrrolobenzoxazepinone system. In the enzymatic assay the oxazepinone derivative (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5] 16e (IC50 = 0.25 mu M) was found to be more potent than nevirapine (IC50 = 0.5 mu M), tested in the same experimental conditions using rC . dG as a template-primer. In cell culture assay benzoxazepine 16e was active against HIV-1, both wild type and AZT-sensitive, and HIV-1 (IIIB) strains, but not against HIV-2. In enzyme assay although 16e inhibited HIV-1 RT, it was inactive against the nevirapine-resistant recombinant RT Y181C at 50 mu M. Molecular modeling studies suggest that these derivatives present a 3D pharmacophoric arrangement similar to that of other nonnucleoside inhibitors such as nevirapine.