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This review aims at highlighting the contribution of marine chemistry in the field of antimalarial research, by reporting the most important results obtained until the beginning of 2009, with particular emphasis on recent discoveries. We have decided to include in this review all those compounds possessing a moderate to high antimalarial activity, thus excluding very weak antimalarials or molecules for which the toxicity toward Plasmodium strains is not specific and/or is clearly due to a general cytotoxicity. An interesting review has been recently published focusing on the synthesis of marine natural products with antimalarial activity ; consequently, we will not discuss in detail synthetic efforts aimed at preparing marine antimalarial leads.
Malaria is an infectious disease causing at least 1 million deaths per year, and, unfortunately, the chemical entities available to treat malaria are still too limited. In this review we highlight the contribution of marine chemistry in the field of antimalarial research by reporting the most important results obtained until the beginning of 2009, with particular emphasis on recent discoveries. About 60 secondary metabolites produced by marine organisms have been grouped into three structural types and discussed in terms of their reported antimalarial activities. The major groups of metabolites include isonitrile derivatives, alkaloids and endoperoxide derivatives. The following discussion evidences that antimalarial marine molecules can efficiently integrate the panel of lead compounds isolated from terrestrial sources with new chemical backbones and, sometimes, with unique functional groups.
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Thiaplakortone A (3a), an antimalarial natural product,was prepared by an operationally simple and scalable synthesis. Inour efforts to deliver a lead compound with improved potency, metabolicstability, and selectivity, the synthesis was diverted to access aseries of analogues. Compounds 3a–d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active againstthe chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compounds are “Rule-of-5” compliant, andwe show that metabolic stability can be enhanced via modificationat either the primary or pyrrole nitrogen. These promising resultslay the foundation for the development of this structurally unprecedentednatural product.
In conclusion, from 3a, an antimalarial natural product,we have developed potent antimalarial compounds with favorable physicochemicaland ADME properties. We have designed and completed the rapid andoperationally simple total synthesis of 3a and have divertedthis synthesis to access analogues 3b–d. Methylation of the thiaplakortone scaffold was well tolerated,and analogues 3b–d showed low nMin vitro activity against drug-sensitive and drug-resistant P. falciparum lines. Methylation of the pyrrole nitrogenwas found to dramatically increase the metabolic stability of analogues,without significant loss of antimalarial activity. These studies pavethe way for the development of structurally unprecedented lead compoundsfor the treatment of malaria.
Marine Nat Prod | Natural Products | Biology
To reach this challenging aim, the identification and selection of new lead compounds constitutes a crucial point. In this regard, living organisms are a recognized source of potentially bioactive molecules which are, commonly, more effective than those obtained through combinatorial synthetic chemistry. Indeed, synthetic libraries are straightforward to assemble, this representing an advantage but also a drawback: the use of a relatively limited number of synthetic reactions as well as of structurally diverse building blocks to library construction implies that combinatorial libraries often lack the structural diversity required for fully exploring the biological space. On the other hand, having been enzymatically engineered and biologically validated, the “quality” of both terrestrial and marine natural products is higher and they represent the ideal tool to harvest the fruits encrypted in a genomic text.
Thus, not surprisingly, the most significant advancements in malaria therapy have been made with the introduction of natural leads. The treatment of malaria infections holds a venerable place both in the history of medicinal chemistry and of natural product chemistry. Indeed, malaria was the first disease to be treated with an active principle isolated from a natural source, quinine, isolated from the Cinchona bark in 1820, and until the 20th century many of the active medicines were developed based on the structure of quinine. A more recent breakthrough in the fight against malaria came with the discovery of artemisinin, an endoperoxide sesquiterpene from Artemisia annua , an herbal remedy used in Chinese folk medicine. It is now expected that the next significant advancement in the field of antimalarial drugs will not be reached through the discovery of a single potent compound, but through the introduction of an innovative drug to be used in a combined therapy, preferably composed by molecules acting at different stages of the malaria parasite life cycle.
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natural products with selective antimalarial activity
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Hopefully, the new breakthrough in the malaria treatment will come with the development of a marine lead compound. The incredible potential of even a single marine organism (mostly invertebrates, as sponges, tunicates, soft corals) to produce a large array of secondary metabolites can be interpreted by considering the common features of the secondary metabolism in all the living organisms as well as some peculiar features of the marine environment. In addition, the contribution of the symbiotic population to the metabolic work of a marine invertebrate is an important point to be taken into account. Indeed, marine invertebrates harbor in their tissues a series of microorganisms such as bacteria, cyanobacteria and fungi and, in some cases, associated micro-organisms may constitute up to 40% of the biomass [,], this bacterial concentration exceeding that of the surrounding sea water by two or three orders of magnitude. Although the real contribution of the microorganisms to the secondary metabolism of marine invertebrates has not yet been fully evaluated, essentially because of the difficulties encountered in culturing sponge-associated bacteria, it is generally accepted that these harbored microorganisms play a significant role in the biosynthesis of the natural products isolated from the invertebrate. Furthermore, the recent impressive advances in molecular genetics, currently allowing the identification of biosynthetic genes in the producing organisms and their cloning in bacteria suitable for large-scale fermentation  could represent a solution for the problem of compound supply. If these techniques will be fully developed and utilized, the last obstacle to consider marine organisms as a potentially sustainable drug source would be overcome.
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One of the more substantial breakthroughs in malaria chemotherapy has been the discovery and development of endoperoxide-containing drugs. Research in this field began with the discovery that artemisinin (35, ), an endoperoxide cadinane sesquiterpene lactone possessing a 1,2,4-trioxane moiety, isolated from Artemisia annua (Compositae) leaves, possessed nanomolar activity also against chloroquine-resistant strains of Plasmodium [, ]. With its unique juxtaposition of peracetal, acetal and lactone functionalities, artemisinin possesses structural features very appealing to organic chemists. Totally synthetic routes to artemisinin have been developed , but their complexity suggests that they will very unlikely supplant the natural extract as a drug supply.
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