A Golden Phoenix Arising from the Herbal Nest — a Review and Reflection on the Study of Antimalarial Drug Qinghaosu
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Front. Chem. China 2010, 5(4): 357–422 DOI 10.1007/s11458-010-0214-5 FEATURE ARTICLE A golden phoenix arising from the herbal nest — A review and reflection on the study of antimalarial drug Qinghaosu Ying LI (✉)1 and Yu-Lin WU (✉)2 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China 2 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China Qinghaosu (QHS) and its derivatives are a new generation of antimalarial drugs characterized by fast action, high efficacy, and good tolerance. This feature article states the discovery of QHS from traditional Chinese medicine qinghao (Artemisia annua L.) and reviews the progress during the past four decades in the research of phytochemistry of A. annua, chemical reactions and biotransformation of QHS, chemical synthesis and biosynthesis of QHS, synthesis and antimalarial activity of QHS derivatives and analogs, pharmacological studies, clinical application, and the antimalarial mechanism. Undoubtedly, QHS is an example of the value of traditional Chinese medicine in modern medicinal research. 1 Background use in modern clinics. In China, about 2000 years ago, Chang Shan (Dichroa febrifuga Lour) was found to be able to treat Malaria has been one of the most serious parasitic diseases malaria [2]. In 1940s, Chou et al. extracted antimalarial around the world. In China, the falciparum malaria, known as ingredient febrifugine from it [3]. Chemists from abroad miasma to ancient Chinese, was once widely spread in followed up with structure determination, total synthesis, and Southern China; while in the other areas of China, vivax structure modification. However, it has never been approved malaria was quite common. For many years, the disease has as an antimalarial drug due to its strong vomit-inducing side been a major harm to human health and has claimed numerous effect. victims’ lives. In 1950s and 1960s, there were still about ten There are also a lot of therapies for malaria recorded in millions of malaria patients in China, where chloroquine and many traditional Chinese medicine classics. However, there other antimalarial drugs were being produced and widely were no in-depth studies. One reason is that a great number of used. In 1970, according to the statistics released by the malaria patients have been cured since 1940s due to the mass- Ministry of Health of China, there was even a record-breaking production of cost-effective synthetic medicines such as number of 30 million of patients. According to the World chloroquine, primaquine, and pyrimethamine (Figure 1). The Health Organization (WHO), Malaria is also endemic in other public believed that the problem had been solved once and for tropical and subtropical areas of the world; it affects all. However, plasmodium fought for its own survival with approximately 200–500 million people each year [1]. gene mutation. Since the early 1960s, drug-resistant malaria Ancient people learned a lot from the disease. For example, started to spread in the South-east Asia and other areas of the aboriginal Indians in Southern America discovered that world. The battle against malaria continued. Even today, over cinchona tree bark could cure malaria. In 1820, European one million victims die due to malaria each year, mostly chemists Caventou and Pelletier extracted quinine from it. children in Africa [1]. Since then quinine became the cure for malaria. Despite of its In early 1960s, the Vietnam War broke out. In the tropical shortcomings such as high toxicity, quinine is still in active forests, military forces of both sides suffered severe casualties caused by drug-resistant falciparum malaria, which far Received January 15, 2010; accepted May 6, 2010 exceeded casualties in the combats by a great margin. To E-mail: [email protected], [email protected] deal with the urgent situation, the US government organized ©Higher Education Press and Springer-Verlag Berlin Heidelberg 2010 358 Ying LI and Yu-Lin WU Figure 1 Chemical structures of known antimalarial drugs before 1986. taskforces responsible for the research and development of ideal compounds. Therefore, researchers combed traditional new drugs treating drug-resistant malaria. During the follow- medical books, learned from the folks in malaria endemic ing 12 years, over 250,000 compounds had been screened in areas about their experience, and collected Chinese medicinal primary tests using mice infected with Plasmodium berghei herbs that were claimed to treat malaria. (P. berghei). As the result of this research program, four new Consequently, some thousands of TCM had been studied chemical groups emerged as potentially new antimalarial [4], [5]. A large number of crude extracts from raw materials in which a derivative of a 4-quinolinemethanol (WR 142490) soaked with different solvents and under different temperature was marketed in 1985 under the generic name of mefloquine were screened in mice infected P. berghei, and then, the active (Figure 1). extracts were selected for advanced tests. By the 1970s, In the meantime, the Vietnam government sought support several new active principles were isolated, including from China. The Chinese government agreed to help because qinghaosu (artemisinin) from Qinghao (Artemisia annua L.) the same disease was also hunting China at that time. [6,7], yingzhaosu A from Yingzhao (Artabotrys hexapetalu However, the environment for scientific researches was hard (LF) Bhand) [8], agrimols from Xianhecao (Agrimonia pilosa in China especially during the difficult years of the so-called L.) [9,10], robustanol from Daye’an (Eucalyptus robusta Sm) Cultural Revolution. In 1967, the National Steering Group [11], protopine from Nantianzu (Nandina domestica T.) [12], was established. More than 60 research units joined force, bruceine D and E from Yadanzhi (Brucea javanica (L) Merr) with more than 500 researchers from institutions, colleges, [13], and anluosu from Lingshui’anluo (Polyalthia nemoralis pharmaceutical factories, and hospitals over the nation. Their A. (DC)) [14]. Afterwards, their structure determination and goals included researches of new mosquito repellants, malaria structure modification were conducted (their structures are prevention drug, treatment drugs, radical medicine, and shown in Figure 2). Based on their chemical stability, mosquito killer equipment [5]. antimalarial activity, toxicity, and availability, qinghaosu became the most promising drug candidate. 2 Discovery of qinghaosu The history of Qinghao as a medicine could be traced back to 2000 years ago. The Recipes for Fifty-two Kinds of Many Chinese researchers were convinced that the best Diseases (Wu Shi Er Bing Fang) among archeological solution on drug-resistant malaria was to find active findings in the Mawangdui Tomb in Changsha mentioned compounds with new chemical structures. The problem was that Qinghao could be used to treat hemorrhoids. how to find such compounds. Researchers thought about Ge Hong (283–343/363) first recorded Qinghao as an traditional Chinese medicine (TCM). Chinese ancestors antimalarial drug in his The Handbook of Prescriptions for gathered rich experience after thousands years of battles Emergency Treatment (Zhou Hou Bei Ji Fang), “take a against malaria and recorded it in various medical books. handful of Qinghao, soak in 2 liters of water, wring out the Modern researchers could follow and screen these leads for liquid and drink” (Figure 3). The Compendium of Materia Frontiers of Chemistry in China Vol. 5, No. 4, 2010 A golden phoenix arising from the herbal nest — A review and reflection on the study of antimalarial drug Qinghaosu 359 Figure 2 Antimalarial natural products. Medica (Ben Cao Gang Mu) written by Li Shizhen in the in mice. Thus, in the summer of 1972, after the tests of animal Ming Dynasty and other traditional medical books also toxicity and trials by a few subjects, the neutral crude extract recorded many therapies on malaria treatment by Qinghao or was put under small-scale clinical observation in Hainan Qinghao mixing with other herbal medicines. Island and Beijing, and the clinic results were satisfactory. In 1950s and 1960s, there were quite a few clinical reports Thereafter, Chinese herb Qinghao became the focus of the on treatment of malaria by Qinghao published on medical project. However, “Qinghaosu II” isolated by the Institute of journals in Jiangsu, Hunan, Guangxi, and Sichuan Provinces. Chinese Materia Medica did not show expected results in the The usual preparation methods included pressing for juice, clinical trial of 1973. boiling in water, or grinding to powder. It was noticed that in At the same time, the Yunnan Institute of Materia Medica some areas of Gaoyou County, Jiangsu Province, residents and Shandong Institute of Traditional Medicine and Materia were asked to drink an aqueous decoction of Qinghao, and Medica successfully extracted the crystalline principle from malaria was under effective control. However, some research Artemisia annua by petroleum ether or ethyl acetate and groups found that Qinghao extracts gathered by heating raw gained exciting results from their clinical trials for the materials in water, ethanol, or benzene did not show treatment of P. vivax and P. falciparum cases. They named antimalarial activity on animal models. In the second half of the antimalarial principle as huanghaosu or huanghuahaosu, 1971, researchers from the Institute