Antimalarial artemisinin

A high level of activity continues in connection with the synthesis of antimalarial artemisinin analogues and congeners, in which the 1,2-dioxepane moiety is embedded. Recent examples include the syntheses of various 10-substituted deoxoartemisinins of type 123 (eg. R1 = Cl COMe) from dihydroartemisinin acetate, and of type 124 (eg. R2 = a-OH, R3 = Me), from Grignard reagent addition to 10-(2-oxoethyl)deoxoartemisinin . 

J.P. Begue, D. Bonnet-Delpon, The future of antimalarials Artemisinins and synthetic endoperoxides, Drugs Fut. 30 (2005) 509-518. 

As in more recent years, the chemistry of seven-membered ring systems has been dominated by the chemistry of oxygen heterocycles in the form of the marine toxins and, to a lesser extent, the antimalarial artemisinin. Indeed, if it were not for the interest in these systems it would have been a sparse year indeed. For this reason the division of this report will be into just three section, nitrogen, oxygen, and other systems. 

In addition to the CIEEL mechanism, peroxides and endoperoxides are key intermediates in a number of chemical and biological processes. There are a growing number of examples where ET to the 0-0 bond in these systems is accepted as an important step in their activity. For example, it is now generally agreed that the first step in the bioactivity of the recently discovered potent antimalarial, artemisinin, involves an ET from Fe-heme to the 0-0 bond, leading to fragmentation and a number of psytotoxic radical intermediates. " In contrast to the enormous amount of literature on the thermal and photochemical reactivity of peroxides, there is relatively little known about their ET chemistry. It is this lack of kinetic data on ET to peroxides and endoperoxides and the possible relationship of this data to Saveant s model for dissociative ET that initiated our own interest in this chemistry.22 23 2 - - - ... 

This chapter comprises an update on the chemistry of 1,2-dioxepines, 1,2-oxathiepines, and 1,2-dithiepines which appeared in Chapter 9.10 in CHEC-II(1996). It is evident that the structural nature, in terms of construction and/or stability of each of these seven-membered heterorings, which include a relatively weak O-O, O-S, or S-S bond, lies behind the paucity of publications in this area. However, the literature on the effective antimalarial artemisinin 1, a remarkably stable endoperoxide, and especially its derivatives more than make up for this deficiency. 

Some alkoxy-substituted dioxetanes yield a-peroxy ketones and esters via zwitterionic intermediates which are formed by heterolytic C-O bond cleavage as proven by trapping with acetaldehyde [135]. This behavior which has been fully explored by Jefford [135b], has been exploited for the total synthesis of the antimalarial (+)artemisinin [136a-c] and related analogs [136d-f]. One recent example is reported in Sch. 83 [136f ]. 

The antimalarial, artemisinin, which has an embedded 1,2-dioxepane moiety within its structure, together with a range of related synthetic peroxides, is treated in a detailed review by Jefford [01MI1803] structure-activity and mode of action considerations are also reviewed. 

Artemisia annua (sweet wormwood, qing hao) has been used in Chinese medicine for well over 1000 years. The earliest recommendation is for the treatment of hemorrhoids, but there is a written record of use in fevers dated 340 A.D. Modem development dates from the isolation of a highly active antimalarial, artemisinin (qing-haosu), in 1972, and has been carried out almost entirely in China. Much of the original 1 iterature is therefore in Chinese, but there is an excellent review on qinghaosu by Trigg (196) and an account of the uses of A annua (197). This section is largely a summary of these two articles. 

The synthesis of (-)-Cio-desmethyl arteannuin B, a structural analog of the antimalarial artemisinin, was developed by D. Little et a. In their approach, the absolute stereochemistry was introduced early in the synthesis utilizing the Enders SAMP/RAMP hydrazone alkylation method. The sequence begins with the conversion of 3-methylcyclohexenone to the corresponding (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone. Deprotonation with lithium diisopropylamide, followed by alkylation in the presence of lithium chloride at -95 °C afforded the product as a single diastereomer. The SAMP chiral auxiliary was removed by ozonolysis. 

Bhattacharjee, A.K and Karle, J.M. (1999) Stereoelectronic properties of antimalarial artemisinin analogues in relation to neurotoxicity. Chem. Res. Toxicol., 12, 422-428. 

Burk, O., Arnold, K. A., Nussler, A. K., Schaeffeler, E., Efimova, E., Avery, B. A., Avery, M. A., Fromm M. F., and Eichelbaum, M. (2005) Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol. Pharmacol. 67,1954-1964. 

In research of the chemical components of Chinese medicines, the structures and bioactivities of more than a thousand new natural product compounds have been studied, published, and reviewed [2-5]. A notorious example is the study of antimalarial artemisinin (qinghaosu) and its derivatives [6,7],... 

Plants accumulate STLs as a means of chemical defence. Thus, one of the primary ecological benefits of these compounds is certainly the fact that they are toxic to all kinds of microorganisms. Once more it is their alkylant potency that is most obviously responsible. The work on antimicrobial activity of earlier years has been summarized in various reviews, e.g. [1-3]. More recent work has indicated that some STLs may have potential as leads for new antiprotozoal drugs. Apart from the prominent antimalarial artemisinin which will be treated separately in the following section, several more common STLs have been demonstrated to possess antiplasmodial [77-79], antileishmanial [80] and antitrypanosomal activity [81-84], Unfortunately, in most cases such activities are accompanied by high non-specific cytotoxicity so that it is always necessary to compare the antiprotozoal activity with cytotoxic effects determined under the same conditions. 

Begue, J.-R Bonnet-Delpon, D. Fluoroartemisinins metabolically more stable antimalarial artemisinin derivatives. ChemMedChem 2007, 2(5), 608-624. 

Bruns, R. Scarminio, I. Barrros Neto, B. (2006) Statistical Design - Chemometrics, Elsevier, ISBN 978-0-444-52181-1, Amsterdan, The Netherlands Cardoso, R Figueiredo, A. Lobato, M. Miranda, R. Almeida, R. Pinheiro, J. (2008). A Study on Antimalarial Artemisinin Derivatives Using MEP Maps and Multivariate QSAR. Journal of Molecular Modeling, Vol. 14, No. 1, (January 2008), pp. 39-48, ISSN 0948-5023 Doweyko, A. (2008). QSAR Dead or Alive Journal of Computer-Aided Molecular Design, Vol. 22, No. 2, (February 2008), pp. 81-89, ISSN 1573-4951... 

Paddon, C.J. et al (2013) High-level semi-synthetic production of the potent antimalarial artemisinin. Nature, 496 (7446), 528 -532. 

The antimalarial artemisinin (qinghaosu. Figure 6.25) is derived from the Chinese herb quing hao (Artemisia annua)However, its bioavailability is low and esters. 

An electrochemical study of the mechanism of action of the naturally occuring antimalarial artemisinin, shown in (Figure 3-34a) illustrates how a cyclic voltammetric diagram of a process involving adsorption was useful in developing an understanding of a pharmacological mechanism. ... 

Taxus cuspidata cells [47], ginsenosides in similarly induced Panax ginseng hairy roots cultures [48], or antimalarial artemisinin in Artemisia annua trichomes [49-51], In the latter case, candidate gene selection was also supported by conservation of ESTs from different Asteraceae. 

Artemisinin ( qinghaosu ) (12), a sesquiterpene lactone possessing animusual endoperoxide bridge, is a compormd discovered in the People s Republic of China flora Artemisia annua, which has long been used as a traditional medicinal plant for the treatment of fever. As a naturally occurring antimalarial, artemisinin may be employed as an option for the treatment of chloroquine-resistant malaria in China and some... 

SCHEME 1.13 The FOS strategy toward a simplified but still potent analog of the antimalarial artemisinin. 

This report on the mechanism of action of antimalarial artemisinin derivatives and the design of trioxaquines is an example of the key role of a biological metal complex (heme in the present case) acting both as trigger and target for the drug. 

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