蒿甲醚 | 71963-77-4

• 物质功能分类: 原料药 - 抗寄生虫病药 - 抗疟药
• 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: 蒿甲醚
• 中文别名: (3R,5aS,6R,8aS,9R,10S,12R,12aR)-十氢-10-甲氧基-3,6,9-三甲基-3,12-桥氧-12H-吡喃并[4,3-j]-1,2-苯并二塞平；青蒿醚；青蒿素甲醚；(3R,5aS,6R,8aS,9R,10S,12R,12aR)-十氢-10-甲氧基-3,6,9-三甲基-3,12-桥氧-12H-吡喃并[4,3-j]-1,2-
• 英文名称: artemether
• 英文别名: β-artemether；coartem；ATM；ARTIMIST；(1R,4S,5R,8S,9R,10S,12R,13R)-10-methoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecane
• CAS: 71963-77-4
• 化学式: C₁₆H₂₆O₅
• mdl: MFCD00866205
• 分子量: 298.379
• InChiKey: SXYIRMFQILZOAM-HVNFFKDJSA-N

物化性质

• 熔点：
  86-88°C
• 比旋光度：
  D19.5 +171° (c = 2.59 in CHCl3)
• 沸点：
  359.79°C (rough estimate)
• 密度：
  1.0733 (rough estimate)
• 溶解度：
  二甲基亚砜：≥20mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  Crystals
• 蒸汽压力：
  4X10-5 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation = 177 deg at 19.5 °C
• LogP：
  3.53

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  46.2
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

迅速代谢为其活性代谢物，二氢青蒿素。

Rapidly metablized to its active metabolite, dihydroartemisinin.

来源:DrugBank

代谢

Artemether ... /被/转化为二氢青蒿素 ... 青蒿素化合物的抗疟疾效果主要是由于二氢青蒿素 ...

Artemether ... /is/ converted to dihydroartemisinin ... The antimalarial effect of artemisinin compounds results primarily from dihydroartemisinin ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

青蒿素在大鼠口服给药后可以完全且迅速地被吸收。然而，即使在300毫克/千克的剂量下，也获得了非常低的血浆水平。肝脏被发现是失活的主要场所。当青蒿素通过肌肉注射给药时，可以检测到显著且更持久的血浆水平。青蒿素在静脉注射后能够通过血脑屏障和血胎盘屏障。无论给药途径如何，在48小时内尿液或粪便中几乎未发现未改变青蒿素。在人给药后确定的代谢物包括去氧青蒿素、去氧二氢青蒿素和9,10-二羟基去氧青蒿素。/青蒿素/

Artemisinin is completely and rapidly absorbed after oral administration in rats. However, a very low plasma level was obtained even after a dose of 300 mg/kg. Liver was found to be the chief site of inactivation. When artemisinin was given i.m., significant and more persistent plasma levels were detected. Artemisinin was shown to pass the blood-brain and blood-placenta barriers after i.v. injection. Very little unchanged artemisinin was found in the urine or feces in 48 hours regardless of the route of administration. Metabolites identified after administration to humans include deoxyartemisinin, deoxydihydroartemisinin, and 9,10-dihydroxydeoxyartemisinin. /Artemisinin/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

本研究旨在评估葡萄柚汁对青蒿琥酯生物利用度随时间下降的影响。在一项随机、两阶段交叉研究中，八名健康男性受试者每天一次服用100毫克口服青蒿琥酯，并配以350毫升水或350毫升双重浓度的新鲜冷冻葡萄柚汁，持续5天。在第1天和第5天，收集了17个血液样本，持续8小时。在第5天最后一次给药后的平均青蒿琥酯血药浓度峰值（Cmax）和平均药时曲线下面积（AUC）约为第1天的一半，而在水（P = .006对于Cmax；P = .005对于AUC）和葡萄柚汁（P < .001对于Cmax和AUC）摄入后的消除半衰期没有变化。葡萄柚汁使第1天（P = .021）和第5天（P = .05对于Cmax；P = .004对于AUC）的Cmax和AUC增加了一倍。活性代谢物双氢青蒿素在葡萄柚汁作用下Cmax（P = .006）和AUC（P = .001）也增加了一倍，且药代动力学参数没有随时间变化。葡萄柚汁显著增加了青蒿琥酯的口服生物利用度，但并未阻止生物利用度随时间的降低。这表明肠道壁中的CYP3A4是青蒿琥酯的代谢酶之一，但似乎不参与自诱导过程。

The aim of this study was to evaluate the effect of grapefruit juice on the decreasing bioavailability over time of artemether. In a randomized, two-phase crossover study, eight healthy male subjects took 100 mg oral artemether with 350 mL water or with 350 mL double-strength fresh frozen grapefruit juice once daily for 5 days. On day 1 and day 5, 17 blood samples were collected over a period of 8 hours. The mean peak artemether plasma concentration (Cmax) and the mean area under the concentration-time curve (AUC) after the last dose at day 5 were about one third compared with day 1, without a change in the elimination half-life after intake with water (P = .006 for Cmax; P = .005 for AUC) and with grapefruit juice (P < .001 for Cmax and AUC). Grapefruit juice increased Cmax (P = .021) and AUC (P < .001) twofold on day 1 (P = .021) and day 5 (P = .05 for Cmax; P = .004 for AUC). Dihydroartemisinin, the active metabolite, showed a twofold increase in Cmax (P = .006) and AUC (P = .001) with grapefruit juice, without time-dependent changes of pharmacokinetic parameters. Grapefruit juice significantly increased the oral bioavailability of artemether but did not prevent the time-dependent reduction in bioavailability. It suggests that CYP3A4 in the gut wall is one of the metabolizing enzymes of artemether but seems to not be involved in the autoinduction process.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

关于退热药可能削弱宿主对疟疾防御能力的担忧，因为使用退热药与寄生虫清除延迟有关。然而，这似乎是由于延迟了细胞粘附，这很可能是有益的。在疟疾治疗中没有理由不使用退热药。对乙酰氨基酚（扑热息痛）和布洛芬是降低发热的首选药物。

There has been some concern that antipyretics might attenuate the host defense against malaria, as their use is associated with delayed parasite clearance. However, this appears to result from delaying cytoadherence, which is likely to be beneficial. There is no reason to withhold antipyretics in malaria. ...Paracetamol (acetaminophen) and ibuprofen are the preferred options for reducing fever.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。必要时进行吸痰。观察呼吸不足的迹象，并在需要时辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预测癫痫并必要时进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在转运过程中用0.9%的生理盐水（NS）连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔并给予5毫升/千克，最多200毫升的水进行稀释……。在去污染后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒物A和B/

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿...。对于严重的支气管痉挛，可以考虑使用β激动剂，如沙丁胺醇...。监测心率和必要时治疗心律失常...。开始静脉输注D5W/SRP：“保持开放”，最低流速/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象...。用地西泮或劳拉西泮治疗癫痫...。使用丙美卡因氢氯化物协助眼部冲洗...。/毒物A和B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/病例报告/ 总共有83名患有恶性疟疾的孕妇接受了青蒿琥酯或青蒿素的给药，通常随后再使用奎宁或氯喹，每周随访直到分娩。总体而言，73例妊娠（88%）以活产告终，3例（4%）流产，2例（3%）死产。没有发现先天性异常，46名随访超过一年的儿童都正常发育。

/CASE REPORTS/ A total of 83 pregnant women with Plasmodium falciparum malaria, administered artesunate or artemether, often followed by quinine or mefloquine, were followed weekly until delivery. Overall 73 pregnancies (88%) resulted in live births, 3 (4%) in abortions, and 2 (3%) in still births. There were no congenital abnormalities and the 46 children followed for more than a year all developed normally

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

食物增加吸收。

Food increases absorption.

来源:DrugBank

吸收、分配和排泄

给予的药物或二氢青蒿素很少或没有在尿液中回收。/二氢青蒿素/

Little or none of the administered drugs or dihydroartemisinin is recovered in urine. /Dihydroartemisinin/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

肌肉给药后，药代动力学显示阿莫地喹（AM）在给药后2到4小时达到血浆峰值水平，消除缓慢，并且随着重复给药有累积倾向。主要代谢物二氢青蒿素（DHA）的水平很低。脑脊液（CSF）中的AM水平低于血浆水平的10%。口服给药后，AM的浓度远低于肌肉给药。DHA在第1天的浓度很高，但在第7天几乎为零，这表明在狗体内它迅速失活。第8次口服给药后2小时，CSF中未检测到AM或DHA，这可能是狗口服AM后未出现神经毒性的原因。

After intramuscular administration pharmacokinetics indicated peak plasma levels of artemether (AM) at 2 to 4 hours post-dose, slow elimination and a tendency to accumulate after repeated administration. Only low levels of the major metabolite, dihydroartemisinin (DHA), were found. AM levels in the cerebrospinal fluid (CSF) were < 10% of plasma levels. After oral administration AM concentrations were considerably lower than after i.m. administration. The concentration of DHA was high on day 1 but almost nil on day 7 indicating its fast inactivation in dogs. Two hours after the 8th oral administration neither AM nor DHA was detected in CSF which may explain the absence of neurotoxicity in dogs after oral administration of AM.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

这项研究调查了肌肉注射蒿甲醚及其主要血浆代谢物双氢青蒿素的药代动力学，研究对象是恶性疟疾严重发作的患者。研究纳入了6名急性肾衰竭（ARF）的重症恶性疟疾患者和11名没有ARF的患者。他们接受了肌肉注射蒿甲醚的负荷剂量160毫克，随后连续6天每天80毫克（总剂量640毫克）。有无ARF的患者对治疗的初始反应良好；寄生虫和发热清除时间分别为66（30至164）和76（36至140）小时（中位数（范围））。在治疗开始的7天内，没有人外周血涂片中再次出现寄生虫血症。昏迷患者的意识恢复时间为51.6（22至144）小时。蒿甲醚在注射160毫克剂量后1小时就可以在血浆中检测到，在大多数情况下，24小时内降至检测不到的水平。与没有ARF的患者相比，ARF患者的Cmax显著更高（2.38（1.89至3.95）vs 1.56（1.05至3.38）ng/mL/mg剂量），Vz/F更低（5.45（3.2至6.9）vs 8.6（4.2至12.3）L/kg）和CL/F更低（7.4（5.4至13.8）vs 19.1（8.5至25.1）mL/min/kg）。此外，ARF患者的t1/2z显著更长（7.0（5.5至10.0）vs 5.7（4.2至6.6）小时）。两组之间双氢青蒿素的药代动力学相似。ARF显著改变了肌肉注射蒿甲醚的药代动力学。这些变化可能是由于吸收/生物利用度提高、系统性清除率降低或药物血浆蛋白结合改变所贡献的。

The pharmacokinetics of intramuscular artemether and its major plasma metabolite-dihydroartemisinin, were investigated in patients with severe manifestations of falciparum malaria. Six severe falciparum malaria patients with acute renal failure (ARF) and 11 without ARF were recruited into the study. They were treated with intramuscular artemether at a loading dose of 160 mg, followed by daily doses of 80 mg for another 6 days (total dose 640 mg). Patients with and without ARF showed a good initial response to treatment; the parasite and fever clearance times were 66 (30 to 164) and 76 (36 to 140) hr (median (range)), respectively. None had reappearance of parasitaemia in their peripheral blood smear within 7 days of initiation of treatment. In comatose patients, the time to recovery of consciousness was 51.6 (22 to 144) hr. Artemether was detected in plasma as early as 1hr after a 160 mg dose, and declined to undetectable levels within 24 hr in most cases. Patients with ARF had significantly higher Cmax (2.38 (1.89 to 3.95) vs 1.56 (1.05 to 3.38) ng/mL/mg dose), and lower Vz/F (5.45 (3.2 to 6.9) vs 8.6 (4.2 to 12.3) L/kg) and CL/F (7.4 (5.4 to 13.8) vs 19.1 (8.5 to 25.1) mL/min/kg) when compared to those without ARF. In addition, t1/2z, was significantly longer in ARF patients (7.0 (5.5 to 10.0) vs 5.7 (4.2 to 6.6) hr). The parmacokinetics of dihydroartemisinin in the two groups were comparable. ARF significantly modified the pharmacokinetics of intramuscular artemether. The changes could be contributed to either improved absorption/bioavailability, a reduction of systemic clearance, or a change in plasma protein binding of the drug.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Dihydroartemisinin 口服给药后迅速吸收，大约在2.5小时后达到峰值。通过直肠给药的吸收较慢，峰值在大约给药后4小时出现。血浆蛋白结合率约为55%。通过肠道和肝脏葡萄糖醛酸化的消除半衰期大约为45分钟。/Dihydroartemisinin/

Dihydroartemisinin is rapidly absorbed following oral administration, reaching peak levels after around 2.5 hr. Absorption via the rectal route is somewhat slower, with peak levels occurring around 4 hr after administration. Plasma protein binding is around 55%. Elimination half-life is approximately 45 min via intestinal and hepatic glucuronidation. /Dihydroartemisinin/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S24/25
• 危险类别码：
  R22
• WGK Germany：
  3
• 海关编码：
  2932999099
• 危险品运输编号：
  OTH
• 危险标志：
  GHS07
• 危险性描述：
  H302

制备方法与用途

简介

蒿甲醚和本芴醇是近年来研制成功的两种结构和作用不同的新型抗疟药。此两药通常都用单药治疗。蒿甲醚的作用特点是杀疟原虫快速，但杀虫不彻底，治疗后病人血中残留的原虫复燃率高。

性状

白色结晶或结晶性粉末，味苦，无臭。

性质

本品在丙酮、三氯甲烷中极易溶解，在乙醇或乙酸乙酯中易溶，在水中几乎不溶。

用途

蒿甲醚对疟原虫红内期有直接杀灭作用，对组织期无效，对实验动物毒性很低，在机体内吸收块、分布广、排泄快。电镜观察可见本品对鼠疟原虫的作用部位主要是膜系结构，其抗疟作用机理认为是干扰了疟原虫的表膜一线粒体的功能。

化学性质 

白色粒状结晶，可溶于甲醇、乙醇、DMSO等有机溶剂，来源于黄花蒿叶。

用途 

一种青蒿素的甲醚衍生物。

用途 

用作抗疟药

类别

有毒物品

毒性分级

中毒

急性毒性

口服-小鼠 LD50: 1000 毫克/公斤; 皮下-小鼠 LD50: 390 毫克/公斤

可燃性危险特性

可燃; 燃烧产生刺激烟雾

储运特性

通风低温干燥

灭火剂

干粉,泡沫,沙土,二氧化碳, 雾状水

反应信息

• 作为反应物：
  描述：

  蒿甲醚 在 锌 作用下， 以 溶剂黄146 为溶剂， 反应 1.0h， 以72%的产率得到deoxy-β-artemether
  参考文献：
  名称：

  青蒿素和青蒿素的脱氧和异构化作用及其与抗疟作用的关系†

  摘要：

  用锌溶解在AcOH中的青蒿素（1）和β-蒿甲醚（6）处理数小时会导致单脱氧，分别得到脱氧青蒿素（5）和脱氧-β-蒿甲醚（7）作为唯一产品​​。相比之下，室温下在MeCN中向FeCl 2 ·4 H 2 O中1提交15分钟只会引起异构化（3a S，4 R，6a S，7 R，10 S，10a R）-八氢-4， 7-二甲基-8-氧代-2 H -10 H-呋喃[3,2- i ]苯并吡喃-10-乙酸基酯（（8）和（3 R）-3-羟基脱氧青蒿素（9）的产率分别为78％和17％。FeCN 2 ·4 H 2 O在MeCN中对6的作用相似。在相同条件下，6产生类似于8和9的产物，并带有2- [4-甲基-2-氧代-3-（3-氧代丁基）环己基]丙醛的差向异构体混合物，产率分别为32％，23％和16％ ， 分别。在环己烯的存在下重复最后两个实验不会形成环氧化物。就其亲氧性质而言，锌对1和6的脱氧是合理的。1的催化异构化Fe

  DOI：

  10.1002/hlca.19960790520
• 作为产物：
  描述：

  蒿甲醚相关物质B 在 三甲基氯硅烷 作用下， 以 甲苯 为溶剂， 反应 12.0h， 生成 蒿甲醚
  参考文献：
  名称：

  [EN] A PROCESS FOR PREPARATION OF ETHER DERIVATIVES OF DIHDROARTEMISININ
  [FR] PROCÉDÉ DE PRÉPARATION DE DÉRIVÉS ÉTHER DE LA DIHYDROARTÉMISININE

  摘要：

  公开号：

  WO2012042536A3
• 作为试剂：
  描述：

  artemisinin 、 硼氢化钠 、 三氟乙酸 在 蒿甲醚 作用下， 以 甲醇 为溶剂， 反应 7.0h， 以to yield 46 mg (46%) pure alpha, beta artemether的产率得到蒿甲醚
  参考文献：
  名称：

  Single pot conversion of artemisinin into artemether

  摘要：

  本发明涉及一种改进的青蒿酯制备方法。从该过程中制备的青蒿酯可用于治疗非并发症、严重并发症和多药耐药性疟疾。

  公开号：

  US06683193B2

文献信息

• 一种青蒿琥酯的生产方法
  申请人：吴珊

  公开号：CN106565738A

  公开（公告）日：2017-04-19

  本发明涉及一种青蒿琥酯的生产方法，其特征在于包含有以下步骤：a.反应：在二氯甲烷中加入双氢青蒿蒿素，再加入甲醇、高氯酸，反应10-15分钟；加入无水碳酸钠终止反应；反应液过滤；b.浓缩：在55℃左右水浴中浓缩经过滤的反应液；d.结晶：经浓缩后的母液冷冻结晶，离心过滤，即得粗晶；e.精制：粗晶用甲醇65℃热溶成饱和溶液，冷却结晶，离心过滤；f.烘干：将结晶在温度55℃，真空干燥120分钟，即得成品。本发明通过在没有对产生母液处理的情况下，可使产率达到76％，反应时间短，节能，降低生产成本。
• β-蒿甲醚的制备工艺
  申请人：上海佰纳医药科技有限公司

  公开号：CN104557965B

  公开（公告）日：2017-04-12

  本发明涉及一种β‑蒿甲醚的制备工艺，包括以下步骤：①将双氢青蒿素和醚化试剂分别加入醇中形成反应体系；②向步骤①所述的反应体系中加入酸，使反应体系的pH值为0.5～4；③反应完毕后，将水或非碱性水溶液直接加入到步骤②所述的反应体系中，析出固体，即为β‑蒿甲醚。该制备工艺有效的抑制了反应中异构体α‑蒿甲醚的产生，且可以使醚化反应温和的进行，后处理简单，纯度高，从反应体系中析出的固体，其纯度均高于99％，甚至可以达到99.8％以上，无需再经过一步重结晶即可达到要求。
• One-pot green synthesis of β-artemether/arteether
  作者：Atul Kumar、Ajay Kumar Bishnoi

  DOI：10.1039/c4ra05531d

  日期：——

  We have developed an efficient one pot green synthesis of β-artemether/arteether from artemisinin, which involves combination of a sodium borohydride – cellulose sulfuric acid (CellSA) catalyst system. This green methodology is high yielding and the catalyst has good recyclability. The developed methodology is simple, cost-effective and the catalyst used is eco-friendly, reusable, and biodegradable.

  我们已经开发出一种高效的一锅绿色合成β-青蒿素/青蒿醚的方法，该方法涉及将硼氢化钠和纤维素硫酸催化剂（CellSA）系统结合在一起。这种绿色方法产率高，催化剂具有良好的可回收性。所开发的方法简单、成本效益高，所使用的催化剂环保、可重复使用且可生物降解。
• Unified Mechanistic Framework for the Fe(II)-Induced Cleavage of Qinghaosu and Derivatives/Analogues. The First Spin-Trapping Evidence for the Previously Postulated Secondary C-4 Radical
  作者：Wen-Min Wu、Yikang Wu、Yu-Lin Wu、Zhu-Jun Yao、Cheng-Ming Zhou、Ying Li、Feng Shan

  DOI：10.1021/ja973080o

  日期：1998.4.1

  Qinghaosu and derivatives were easily reduced by ferrous sulfate in aqueous acetonitrile to give results different from those reported for other reducing systems. The unstable epoxide 7, a compound that was postulated earlier as a species responsible for the antimalarial activity, now has been isolated and characterized. The earlier speculative secondary C-4 radical has also been trapped with 2-me

  青蒿素及其衍生物在乙腈水溶液中很容易被硫酸亚铁还原，结果与其他还原体系报道的结果不同。不稳定的环氧化物 7 是一种较早被假定为具有抗疟活性的物质的化合物，现在已被分离和表征。早期推测的二级 C-4 自由基也被 2-甲基-2-亚硝基丙烷捕获，因此为自由基参与 QHS 型化合物的体外裂解提供了第一个直接证据。对于亚铁离子诱导的 1,2,4-三恶烷（即 QHS 等）裂解，提出了具有可互换自由基阴离子和可逆分子内自由基反应的统一机制。在此框架的基础上，结合反离子和溶剂效应的考虑，
• Facile Oxidation of Leucomethylene Blue and Dihydroflavins by Artemisinins: Relationship with Flavoenzyme Function and Antimalarial Mechanism of Action
  作者：Richard K. Haynes、Wing-Chi Chan、Ho-Ning Wong、Ka-Yan Li、Wai-Keung Wu、Kit-Man Fan、Herman H. Y. Sung、Ian D. Williams、Davide Prosperi、Sergio Melato、Paolo Coghi、Diego Monti

  DOI：10.1002/cmdc.201000225

  日期：——

  oxygen with generation of ROS. Reduction of the artemisinin is proposed to occur via hydride transfer from LMB or the dihydroflavin to O1 of the peroxide. This hitherto unrecorded reactivity profile conforms with known structure–activity relationships of artemisinins, is consistent with their known ability to generate ROS in vivo, and explains the synergism between artemisinins and redox‐active antimalarial

  抗疟药亚甲蓝（MB）影响寄生虫黄素依赖性二硫键还原酶（如谷胱甘肽还原酶（GR））的氧化还原行为，该酶控制疟疾寄生虫中的氧化应激。还原的黄素腺嘌呤二核苷酸辅因子FADH 2引发还原为亚乙蓝（LMB），其被氧气氧化以生成活性氧（ROS）和MB。然后，MB充当NADPH的颠覆性底物，而NADPH通常是再生FADH 2所需的酶功能。MB与过氧化抗疟疾青蒿素衍生物青蒿琥酯之间的协同作用表明青蒿素具有互补的作用方式。我们发现青蒿素被MB和抗坏血酸（AA）或N生成的LMB转化苄基二氢神经酰胺（BNAH）在生理pH条件下在水性缓冲液中原位转化为单电子转移（SET）重排产物或双电子还原产物，后者以BNAH为主。AA和BNAH均不影响青蒿素。在有氧条件下，AA–MB SET反应会增强，并且此处获得的主要产物在结构上与一种据报道已在细胞内培养基中形成的此类产物密切相关。调用通过SET与青蒿素产生的​​酮基来解释