蒿醚林酸 | 120020-26-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 中文名称: 蒿醚林酸
• 英文名称: artelinic acid
• 英文别名: 4-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxymethyl]benzoic acid
• CAS: 120020-26-0
• 化学式: C₂₃H₃₀O₇
• 分子量: 418.487
• InChiKey: UVNHKOOJXSALHN-ILQPJIFQSA-N

物化性质

• 溶解度：
  二甲基亚砜：100 mg/mL（238.96 mM）

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  83.4
• 氢给体数：
  1
• 氢受体数：
  7

ADMET

代谢

_beta-阿特拉林酸已知的人类代谢物包括二氢青蒿素（DQHS）。_

Beta-artelinic acid has known human metabolites that include Dihydroqinghaosu (DQHS).

来源:NORMAN Suspect List Exchange

制备方法与用途

生物活性

Artelinic acid 是一种青蒿素衍生物，可用于研究恶性疟原虫多药耐药的抗疟作用。该化合物可以通过静脉、肌肉和口服等多种途径给药。

体内研究

• 静脉注射 (i.v.)：10 mg/kg Artelinic acid 的消除半衰期（t_1/2）为 0.37 小时，清除率（CL）为 14.99 mL/min/kg，表观分布容积（V_ss）为 9.52 L，12 小时内的药-时曲线下面积（AUC_0-12h）为 11219 ng h/mL。

• 肌肉注射：同样剂量的 Artelinic acid （10 mg/kg），其消除半衰期（t_1/2）为 6.14 小时，清除率（CL）为 14.58 mL/min/kg，表观分布容积（V_ss）为 36.1 L，12 小时内的药-时曲线下面积（AUC_0-12h）为 96372 ng h/mL。

• 口服：10 mg/kg Artelinic acid 的消除半衰期（t_1/2）为 2.21 小时，清除率（CL）为 14.6 mL/min/kg，表观分布容积（V_ss）为 16.2 L，12 小时内的药-时曲线下面积（AUC_0-12h）为 8839 ng h/mL。

动物模型：

• 成年雄性比格犬，年龄 3-5 岁

给药剂量：

• 10 mg/kg

给药途径：

• 静脉注射（用于药代动力学分析）

结果：

• 消除半衰期（t_1/2）为 0.37 小时，清除率（CL）为 14.99 mL/min/kg，表观分布容积（V_ss）为 9.52 L，12 小时内的药-时曲线下面积（AUC_0-12h）为 11219 ng h/mL。

反应信息

• 作为反应物：
  描述：

  蒿醚林酸 在 lithium aluminium tetrahydride 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 4-((((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)methyl)benzaldehyde
  参考文献：
  名称：

  伯氨喹-青蒿素杂种的设计和评估作为多阶段抗疟策略。

  摘要：

  人们普遍认为，抗击疟疾取决于制定抗击感染的新策略。被认为是根除所需的“灵丹妙药”不仅应该为所有疟原虫提供治疗。感染人类红细胞，但也应消除寄生虫的复制和休眠肝脏形式。此外，理想情况下，这些目标应该通过使用不同的作用机制来实现，以避免产生耐药性。为此，合成了两种具有共价连接的伯氨喹和青蒿素部分的杂合分子，并在体外和体内将它们对感染的肝脏和血液阶段的有效性与母体化合物进行了比较。相对于母体化合物，两种杂合体都显示出增强的体外活性，抗疟原虫肝脏阶段。两种化合物对培养的恶性疟原虫（50% 抑制浓度 [IC(50)]，约 10 nM）的效力与青蒿素差不多。当用于治疗鼠类伯氏疟原虫感染时，其中一种分子表现出比母体药效团的等摩尔混合物更好的功效，从而提高治愈率和存活率。这些结果揭示了一种基于作用于寄生虫生命周期不同阶段的分子的共价组合来设计和评估抗疟药的新方法。其中一种分子表现出比母体药效团的等摩尔混合物

  DOI：

  10.1128/aac.05133-11
• 作为产物：
  描述：

  以55的产率得到蒿醚林酸
  参考文献：
  名称：

  Novel antimalarial dihydroartemisinin derivatives

  摘要：

  本发明涉及新颖的双氢青蒿素衍生物，包括其药学上可以接受的盐，其在疟疾感染的预处理和后处理中具有治疗效果。

  公开号：

  US04791135A1

文献信息

• ——
  作者：Olutosin R. Idowu、Ai J. Lin、James M. Grace、James O. Peggins

  DOI：10.1023/a:1012185124972

  日期：——

  PURPOSE To study the reaction of artelinic acid with chemical model systems of cytochrome P-450 as a means of obtaining authentic samples of the putative metabolites necessary for identification of the mammalian metabolites of artelinic acid. METHODS Artelinic acid was reacted with different organic complexes of iron(II). The reaction products were isolated and characterized by NMR and thermospray

  目的研究青蒿酸与细胞色素P-450化学模型系统的反应，作为获得鉴定鉴定为青蒿酸哺乳动物代谢物所必需的推定代谢物的真实样品的一种手段。方法青蒿酸与铁（II）的不同有机络合物反应。分离反应产物，并通过NMR和热喷雾质谱表征。结果从这些反应中分离出5种化合物（假定为青蒿酸的代谢产物）并进行了明确鉴定，而另外两种化合物的身份尚待最终确认。结论通过化合物与可模拟细胞色素P-450催化异源生物代谢的亚铁配合物的反应，可制得可能的青蒿酸代谢产物标准品。
• Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: Design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition
  作者：Rita Capela、Rudi Oliveira、Lídia M. Gonçalves、Ana Domingos、Jiri Gut、Philip J. Rosenthal、Francisca Lopes、Rui Moreira

  DOI：10.1016/j.bmcl.2009.04.100

  日期：2009.6

  A series of artemisinin-vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range. (C) 2009 Elsevier Ltd. All rights reserved.
• Effects of highly active novel artemisinin–chloroquinoline hybrid compounds on β-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum
  作者：Tzu-Shean Feng、Eric M. Guantai、Margo Nell、Constance E.J. van Rensburg、Kanyile Ncokazi、Timothy J. Egan、Heinrich C. Hoppe、Kelly Chibale

  DOI：10.1016/j.bcp.2011.04.018

  日期：2011.8

  4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent beta-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials. (C) 2011 Elsevier Inc. All rights reserved.
• Novel Endoperoxide-Based Transmission-Blocking Antimalarials with Liver- and Blood-Schizontocidal Activities
  作者：Daniela Miranda、Rita Capela、Inês S. Albuquerque、Patrícia Meireles、Isa Paiva、Fátima Nogueira、Richard Amewu、Jiri Gut、Philip J. Rosenthal、Rudi Oliveira、Maria M. Mota、Rui Moreira、Francesc Marti、Miguel Prudêncio、Paul M. O’Neill、Francisca Lopes

  DOI：10.1021/ml4002985

  日期：2014.2.13

  In a search for effective compounds against both the blood- and liver-stages of infection by malaria parasites with the ability to block the transmission of the disease to mosquito vectors, a series of hybrid compounds combining either a 1,2,4-trioxane or 1,2,4,5-tetraoxane and 8-aminoquinoline moieties were synthesized and screened for their antimalarial activity. These hybrid compounds showed high potency against both exoerythrocytic and erythrocytic forms of malaria parasites, comparable to representative trioxane-based counterparts. Furthermore, they efficiently blocked the development of the sporogonic cycle in the mosquito vector. The tetraoxane-based hybrid 5, containing an amide linker between the two moieties, effectively cleared a patent blood-stage P. berghei infection in mice after i.p. administration. Overall, these results indicate that peroxide-8-aminoquinoline hybrids are excellent starting points to develop an agent that conveys all the desired antimalarial multistage activities in a single chemical entity and, as such, with the potential to be used in malaria elimination campaigns.
• US9603831B2
  申请人：——

  公开号：US9603831B2

  公开（公告）日：2017-03-28