Antimalarial activity, reviews

One of the most important developments in the biochemistry and biology of xanthones is surely the recent discovery of their antimalarial activity, and attempts to understand their mode of action. In the last few years, a large number of polyoxygenated, prenylated and non-prenylated xanthones have been reported for their antimalarial activity, and the advance in the understanding of their mode of action has progressed quicker than any other known antimalarials (cf. 14 for a review). 

As in the case of the 1,2-dioxins, the 1,2-dithiins exist in various states of saturation, oxidation, and benzoannelation (cf. Scheme 1, 17-27) and they have been studied in detail both theoretically and experimentally. Not only were the conformations of the ring and attached substituents investigated, but the valence isomerism of 1,2-dithiin by both NMR and high-level ab initio molecular orbital (MO) calculations and the dithiol/disulfide equilibrium by MP2 calculations were also examined. The latter equilibrium has been applied successfully as a luminescent molecular switch (cf. Section 8.10.2.1). Finally, as a very interesting 1,2-dithiin derivative, the synthesis, structure, and reactivity of the (-l-)-camphor-derived analog 25 and its sulfoxide 26 and sulfone 27 have been reported. Both the synthesis and the antimalarial activity of the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore 28, which contains the 1,2-dioxane moiety, have been reviewed recently <2006BML2991>. 

Since the 1990s, many research studies have demonstrated that 1,2,4-trioxanes and 1,2,4,5-tetraoxanes are important qinghaosu analogs. Some compounds are promising because of their high antimalarial activity and easy preparation. Some reviews about these peroxides have been pubhshed. ... 

Palmer KJ, Holliday SM, Brogden RN. Mefloquine a review of its antimalarial activity, pharmacokinetic properties, and therapeutic efficacy. Drugs 1993 45 430-475. 

Febrifugine (9) is perhaps one of the most interesting quinazoline alkaloids. Information on this alkaloid has been summarized in the earlier reviews published in this treatise (1,2) readers are also referred to the authoritative book by Armarego (33). The antimalarial activity of 9 especially provided a strong stimulus for the synthesis and biological screening of a vast number of quinazoline derivatives. 

Many different types of structure have been shown to possess antimalarial activity, and much of the current synthetic work is based upon leads from the World War II programme [4, 5]. In general, most of the compounds in this section have been tested only against non-human plasmodia although human data are mentioned where appropriate. The selection is very much a personal one of compounds which we feel offer promise for future development, and readers who desire a comprehensive listing are directed to the review by Aviado [31] and the yearly reviews by Cain [247]. 

A review has been recently published focusing on the antimalarial activity of FQ [35]. Consequently, we will not discuss in detail IC50 and IC90 values for all clones. In brief, FQ antimalarial activity was systematically compared with that of CQ with standard in vitro P. falciparum growth inhibition method [36]. Although the response to CQ can always be dissociated between susceptible and resistant clones, FQ is equally active on both types of clone. FQ is at least as active as CQ, and often more active than CQ on CQ-susceptible strains of parasites. No resistance to FQ occurred in CQ-resistant clones, and no correlation was found between susceptibility to FQ and polymorphism in transport proteins implicated in quinoline resistance [37]. 

The investigation of the antimalarial properties of quassinoids then restarted at a significant rate in the mid-1980s and has remained relatively constant since then. Review articles on the antimalarial activity of quassinoids were published by Muhammad and Samoylenko in 2007 [59] and Guo et al. in 2005 [47]. 

Endoperoxides (also 1,2-dioxetanes) are versatile starting materials for further transformations. In view of the weak 0-0 bond, these peroxides are thermally sensitive to homolytic cleavage, a feature that makes most of them ha2aidous. Ring opening opens up attractive opportunities for selective transformations that include reductions (diols), oxidations (dicarbonyl products), rearrangements (hydroxy carbonyl compounds, epoxy carbonyl compounds, fo/s-epoxides, ene diones, etc.) and additions (polycycKc dioxanes or trioxanes, some of which display antimalarial activity). The synthesis and the subsequent reactions of the 2,3-dioxabicyclo[2.2.2]oct-7-en-5-one skeleton have been studied by Adam etak An impressive number of chemical transformations and examples for applications in organic synthesis have been collected in several reviews. 

The large diversity of biological activities including antimalarial, antioxoplasmosis, antileishmaniasis, antishistosomiasis, antitrypanosomiasis, antiviral, antifugal and even anticancer activities displayed by artemisinin and artemisinin derivatives (cf. Ref. 55 for a review) added to the multitude of artemisinin-inspired trioxanes, trioxolanes, tetraoxa-cycloalkanes and peroxide, homodimeric-, trimeric- and even tetrameric artemisinin derivatives recently designed and synthesized is a clear indication that in the future, these compounds will become even more important in the chemotherapy of various diseases, perhaps even above and beyond those mentioned here. 

In conclusion, the vast literature and its derivatives, particularly artesunate, artemether, and arteether, point out to the need to make these derivatives in quantities that would reduce their current production cost to make these drugs accessible to the economically underprivileged societies that are often the victims of malaria. A recent promising method in which artemisinic acid, a precursor to artemisinin, has been produced in engineered yeast. Therefore, microbially produced artemisinic acid holds promise to the syntheses of antimalarial drugs at affordable prices <2006N940>. Furthermore, anticancer activities of artemisinin 1 and its derivatives have been reviewed <2005MI995>. 

During the last decades several drugs and compounds have been identified that to different degrees are able to overcome MDR so that the cells resemble sensitive cells in their chemosensitivity. These drugs mainly include catamphiphilic, membrane-active compounds and belong to various classes of drugs such as calcium channel blockers (verapamil), neuroleptics (flupentixol), anesthetics, antimalarial drugs (quinidine), antiarrhythmics (amiodarone), and many other compounds. Reviews were recently published [61, 157]. 

Foumet and Munoz published a review on natural products as trypanocidal, antileishmanial and antimalarial drugs. Among the active natural products, they include some naphthoquinones related to lapachol [194]. 

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. 

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