http://www.mdpi.com/journal/molecules/special_issues/artemisinin/ Submission All papers should be submitted to molecules@mdpi.org with copy to the guest editor. To be published continuously until the deadline and papers will be listed together at the special websites. Submitted papers should not have been previously published nor be currently under consideration for publication elsewhere. All papers are refereed through a peer review process. A guide for authors, sample copies and other relevant information for submitting papers are available on the Instructions for Authors page. Molecules is an international peer-reviewed monthly journal published by Molecular Diversity Preservation International. Please visit the Instructions for Authors page before submitting a paper. Open Access publication fees are 800 CHF per paper. English correction fees (250 CHF) will be added in certain cases (1050 CHF per paper for those papers that require extensive additional formatting and/or English corrections.). http://www.mdpi.com/1420-3049/15/3/1705/ Despite international efforts to ‘roll back malaria’ the 2008 World Malaria Report revealed the disease still affects approximately 3 billion people in 109 countries; 45 within the WHO African region. The latest report however does provide some ‘cautious optimism’; more than one third of malarious countries have documented greater than 50% reductions in malaria cases in 2008 compared to 2000. The goal of the Member States at the World Health Assembly and ‘Roll Back Malaria’ (RBM) partnership is to reduce the numbers of malaria cases and deaths recorded in 2000 by 50% or more by the end of 2010. Although malaria is preventable it is most prevalent in poorer countries where prevention is difficult and prophylaxis is generally not an option. The burden of disease has increased by the emergence of multi drug resistant (MDR) parasites which threatens the use of established and cost effective antimalarial agents. After a major change in treatment policies, artemisinins are now the frontline treatment to aid rapid clearance of parasitaemia and quick resolution of symptoms. Since artemisinin and its derivatives are eliminated rapidly, artemisinin combination therapies (ACT’s) are now recommended to delay resistance mechanisms. In spite of these precautionary measures reduced susceptibility of parasites to the artemisinin-based component of ACT’s has developed at the Thai-Cambodian border, a historical ‘hot spot’ for MDR parasite evolution and emergence. This development raises serious concerns for the future of the artemsinins and this is not helped by controversy related to the mode of action. Although a number of potential targets have been proposed the actual mechanism of action remains ambiguous. Interestingly, artemisinins have also shown potent and broad anticancer properties in cell lines and animal models and are becoming established as anti-schistosomal agents. In this review we will discuss the recent evidence explaining bioactivation and potential molecular targets in the chemotherapy of malaria and cancer. http://www.mdpi.com/1420-3049/15/3/1705/ Fri, 12 Mar 2010 00:00:00 CET Molecules 2010-03-12 15 3 Review 1705 1721 1420-3049 The Molecular Mechanism of Action of Artemisinin—The Debate Continues 2010-03-12 doi: 10.3390/molecules15031705 O’Neill Barton Ward http://www.mdpi.com/1420-3049/15/3/1378/ Artemisinins have become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although tremendous efforts have been devoted to decipher how this class of molecules works, their exact antimalarial mechanism is still an enigma. Several hypotheses have been proposed to explain their actions, including alkylation of heme by carbon-centered free radicals, interference with proteins such as the sarcoplasmic/endoplasmic calcium ATPase (SERCA), as well as damaging of normal mitochondrial functions. Besides artemisinins, other endoperoxides with various backbones have also been synthesized, some of which showed comparable or even higher antimalarial effects. It is noteworthy that among these artemisinin derivatives, some enantiomers displayed similar in vitro malaria killing efficacy. In this article, the proposed mechanisms of action of artemisinins are reviewed in light of medicinal chemistry findings characterized by efficacy-structure studies, with the hope of gaining more insight into how these potent drugs work. http://www.mdpi.com/1420-3049/15/3/1378/ Mon, 08 Mar 2010 00:00:00 CET Molecules 2010-03-08 15 3 Review 1378 1397 1420-3049 Biological Actions of Artemisinin: Insights from Medicinal Chemistry Studies 2010-03-08 doi: 10.3390/molecules15031378 Jian Li Bing Zhou http://www.mdpi.com/1420-3049/15/3/1309/ Since its identification in the early 1970s, artemisinin, as well as semi-synthetic derivatives and synthetic trioxanes, have been used in malaria therapy. Reduction of artemisinin by NaBH4 produced dihydroartemisinin (DHA), and yielded a new stereochemically labile centre at C-10, which, in turn, provided two interconverting lactol hemiacetal epimers (namely a and b), whose rate of interconversion depends on buffer, pH, and solvent polarity. Since interconversion of the two epimers occurred on a chromatographic time-scale, this prompted a thorough investigation of the phenomenon as a crucial requisite of any analytical method aimed at quantitating this family of drugs. In this critical review we discuss the current importance of the on-column epimerization of DHA in the development of analytical methods aimed at quantifying the drug, with the purpose of identifying the optimal conditions to minimize on-column epimerization while achieving the best selectivity and efficiency of the overall separation. http://www.mdpi.com/1420-3049/15/3/1309/ Fri, 05 Mar 2010 00:00:00 CET Molecules 2010-03-05 15 3 Review 1309 1323 1420-3049 Stereodynamic Investigation of Labile Stereogenic Centres in Dihydroartemisinin 2010-03-05 doi: 10.3390/molecules15031309 Ilaria D’Acquarica Francesco Gasparrini Dorina Kotoni Marco Pierini Claudio Villani Walter Cabri Michela Di Mattia Fabrizio Giorgi http://www.mdpi.com/1420-3049/15/2/804/ Ancient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions. http://www.mdpi.com/1420-3049/15/2/804/ Thu, 04 Feb 2010 00:00:00 CET Molecules 2010-02-04 15 2 Article 804 812 1420-3049 Ancient Chinese Methods Are Remarkably Effective for the Preparation of Artemisinin-Rich Extracts of Qing Hao with Potent Antimalarial Activity 2010-02-04 doi: 10.3390/molecules15020804 Colin W. Wright Peter A. Linley Reto Brun Sergio Wittlin Elisabeth Hsu http://www.mdpi.com/1420-3049/15/1/40/ Preclinical studies in rodents have demonstrated that artemisinins, especially injectable artesunate, can induce fetal death and congenital malformations at a low dose range. The embryotoxicity can be induced in those animals only within a narrow window in early embryogenesis. Evidence was presented that the mechanism by which embryotoxicity of artemisinins occurs seems to be limited to fetal erythropoiesis and vasculogenesis/ angiogenesison the very earliest developing red blood cells, causing severe anemia in the embryos with higher drug peak concentrations. However, this embryotoxicity has not been convincingly observed in clinical trials from 1,837 pregnant women, including 176 patients in the first trimester exposed to an artemisinin agent or artemisinin-based combination therapy (ACT) from 1989 to 2009. In the rodent, the sensitive early red cells are produced synchronously over one day with single or multiple exposures to the drug can result in a high proportion of cell deaths. In contrast, primates required a longer period of treatment of 12 days to induce such embryonic loss. In humans only limited information is available about this stage of red cell development; however, it is known to take place over a longer time period, and it may well be that a limited period of treatment of 2 to 3 days for malaria would not produce serious toxic effects. In addition, current oral intake, the most commonly used route of administration in pregnant women with an ACT, results in lower peak concentration and shorter exposure time of artemisinins that demonstrated that such a concentration–course profile is unlikely to induce the embryotoxicity. When relating the animal and human toxicity of artemisinins, the different drug sensitive period and pharmacokinetic profiles as reviewed in the present report may provide a great margin of safety in the pregnant women. http://www.mdpi.com/1420-3049/15/1/40/ Fri, 25 Dec 2009 00:00:00 CET Molecules 2009-12-25 15 1 Review 40 57 1420-3049 Severe Embryotoxicity of Artemisinin Derivatives in Experimental Animals, but Possibly Safe in Pregnant Women 2009-12-25 doi: 10.3390/molecules15010040 Qigui Li Peter J. Weina http://www.mdpi.com/1420-3049/14/12/5362/ Artemisinin (Qinghaosu), a new antimalarial drug, was discovered in China in the early 1970s. The discovery of artemisinin is attributed to You-You Tu, at that time a middle-aged phytochemist working in the Institute of Chinese Materia Medica, China Academy of Traditional Chinese Medicine. The following paragraph provides a brief summary of her discovery. [...] http://www.mdpi.com/1420-3049/14/12/5362/ Mon, 21 Dec 2009 00:00:00 CET Molecules 2009-12-21 14 12 Editorial 5362 5366 1420-3049 Discovery of Artemisinin (Qinghaosu) 2009-12-21 doi: 10.3390/molecules14125362 Fulong Liao http://www.mdpi.com/1420-3049/14/10/4120/ This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC50 lower than 1 μM. These compounds were also tested for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic option for the treatment of malaria. http://www.mdpi.com/1420-3049/14/10/4120/ Wed, 14 Oct 2009 00:00:00 CEST Molecules 2009-10-14 14 10 Article 4120 4135 1420-3049 New 1-Aryl-3-Substituted Propanol Derivatives as Antimalarial Agents 2009-10-14 doi: 10.3390/molecules14104120 Silvia Pérez-Silanes Luis Berrade Rory N. García–Sánchez Adela Mendoza Silvia Galiano Berta Martín Pérez-Solórzano Juan J. Nogal-Ruiz Antonio R. Martínez-Fernández Ignacio Aldana Antonio Monge