3(R)-2-(2-chloroacetyl)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester | 1018815-64-9

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 3(R)-2-(2-chloroacetyl)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester
• 英文别名: methyl (3R)-2-(2-chloroacetyl)-1-(3,4-dimethoxyphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate
• CAS: 1018815-64-9
• 化学式: C₂₃H₂₃ClN₂O₅
• 分子量: 442.899
• InChiKey: CRDWLMUQUOSGIO-PLEWWHCXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  80.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3(R)-2-(2-chloroacetyl)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester 、 (R)-1-苄基-3-氨基吡咯烷 以 甲醇 为溶剂， 以23%的产率得到(6S,12aR)-2-((R)-1-benzylpyrrolidin-3-yl)-6-(3,4-dimethoxyphenyl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
  参考文献：
  名称：

  Drug-to-Genome-to-Drug, Step 2: Reversing Selectivity in a Series of Antiplasmodial Compounds

  摘要：

  In a recent paper, we have described the discovery of antimalarial compounds derived from tadalafil, using a drug-to-genome-to-drug approach (J. Med. Chem. 2011, 54 (9), pp 3222-3240). We have shown that these derivatives inhibit the phosphodiesterase activity of Plasmodium falciparum and the parasite growth in culture. In this paper, we describe the optimization of these compounds. A direct consequence of our approach based on gene orthology is the lack of selectivity of the compounds over the original activity on the human target. We demonstrate here that it is possible to take advantage of subtle differences in SAR between HsPDE5 inhibition and antiplasmodial activity to improve significantly the selectivity. In particular, the replacement of the piperonyl group in compound 2 by a dimethozyphenyl group was the best way to optimize selectivity. This observation is consistent with the differences between human and plasmodial sequences in the Q2 pocket receiving this group.

  DOI：

  10.1021/jm201422e

文献信息

• [EN] CHIRAL TETRA-HYDRO BETA-CARBOLINE DERIVATIVES, APPLICATIONS THEREOF AS ANTIPARASITIC COMPOUNDS<br/>[FR] DÉRIVÉS CHIRAUX DE TÉTRA-HYDRO BÉTA-CARBOLINE, LEURS APPLICATIONS EN TANT QUE COMPOSÉS ANTIPARASITAIRES
  申请人：UNIV LILLE 2 UNIVERSITE DU DRO

  公开号：WO2008044144A2

  公开（公告）日：2008-04-17

  [EN] The Invention relates to the use of chiral tetra-hydro beta carboline derivatives for the preparation of a pharmaceutical composition for the prevention and/or the treatment of parasitic diseases involving parasites having a phosphodiesterase activity. The invention also relates to some new chiral tetra-hydro beta-carboline derivatives.
  [FR] L'invention concerne des dérivés de tétra-hydro béta carboline utilisés pour la préparation d'une composition pharmaceutique destinée à la prévention et/ou au traitement de maladies parasitaires impliquant des parasites ayant une activité phosphodiestérase. L'invention concerne également certains dérivés chiraux de tétra-hydro béta-carboline.