Recent Advances in Antimalarial Drug Development

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.
Medicinal Research Reviews (Impact Factor: 8.43). 05/2007; 27(1):65-107. DOI: 10.1002/med.20062
Source: PubMed


Malaria caused by protozoa of the genus Plasmodium, because of its prevalence, virulence, and drug resistance, is the most serious and widespread parasitic disease encountered by mankind. The inadequate armory of drugs in widespread use for the treatment of malaria, development of strains resistant to commonly used drugs such as chloroquine, and the lack of affordable new drugs are the limiting factors in the fight against malaria. These factors underscore the continuing need of research for new classes of antimalarial agents, and a re-examination of the existing antimalarial drugs that may be effective against resistant strains. This review provides an in-depth look at the most significant progress made during the past 10 years in antimalarial drug development.

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Available from: Rahul Jain, Jul 19, 2015
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    • "Artemisinin is a sesquiterpene lactone extracted from the leaves of Artemisia annua that has been used in China for the treatment of fever for over a thousand years. It has a potent and rapid activity against asexual parasites of all Plasmodium species, killing all stages from young rings to schizonts [108]; in P. falciparum malaria, artemisinin also eliminates the gametocytes, which are otherwise sensitive only to primaquine (see below). Artemisinin and its derivatives are safe and remarkably well tolerated [124], having given way to the Fig. (2). "
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    ABSTRACT: Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease and the complexity of the life cycle of its causative agent, the protist Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells. Different types of encapsulating structure, targeting molecule, and antimalarial compound will be discussed for the assembly of Trojan horse nanocapsules capable of targeting with complete specificity diseased cells and of delivering inside them their antimalarial cargo with the objective of eliminating the parasite with a single dose. Nanotechnology can also be applied to the discovery of new antimalarials through single-molecule manipulation approaches for the identification of novel drugs targeting essential molecular components of the parasite. Finally, methods for the diagnosis of malaria can benefit from nanotools applied to the design of microfluidic-based devices for the accurate identification of the parasite's strain, its precise infective load, and the relative content of the different stages of its life cycle, whose knowledge is essential for the administration of adequate therapies. The benefits and drawbacks of these nanosystems will be considered in different possible scenarios, including cost-related issues that might be hampering the development of nanotechnology-based medicines against malaria with the dubious argument that they are too expensive to be used in developing areas.
    Full-text · Article · Oct 2013 · Current Medicinal Chemistry
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    • "Clinical manifestations are fever, chills, prostration, and anemia, whereas severe disease can include metabolic acidosis, cerebral malaria, and multiorgan system failure, and coma and death may ensue. More than 40% of the world's population lives with some risk of contracting malaria, with most recent estimates suggesting several hundred million clinical cases and 800,000 deaths each year [1,2], of which the large majority are children below 5 years [3,4]. The recent call for the elimination and eradication of the disease requires research from multiple fronts, including developing strategies for the efficient delivery of new medicines [5]. "
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    ABSTRACT: Paul Ehrlich's dream of a 'magic bullet' that would specifically destroy invading microbes is now a major aspect of clinical medicine. However, a century later, the implementation of this medical holy grail continues being a challenge in three main fronts: identifying the right molecular or cellular targets for a particular disease, having a drug that is effective against it, and finding a strategy for the efficient delivery of sufficient amounts of the drug in an active state exclusively to the selected targets. In a previous work, we engineered an immunoliposomal nanovector for the targeted delivery of its contents exclusively to Plasmodium falciparum-infected red blood cells [pRBCs]. In preliminary assays, the antimalarial drug chloroquine showed improved efficacy when delivered inside immunoliposomes targeted with the pRBC-specific monoclonal antibody BM1234. Because difficulties in determining the exact concentration of the drug due to its low amounts prevented an accurate estimation of the nanovector performance, here, we have developed an HPLC-based method for the precise determination of the concentrations in the liposomal preparations of chloroquine and of a second antimalarial drug, fosmidomycin. The results obtained indicate that immunoliposome encapsulation of chloroquine and fosmidomycin improves by tenfold the efficacy of antimalarial drugs. The targeting antibody used binds preferentially to pRBCs containing late maturation stages of the parasite. In accordance with this observation, the best performing immunoliposomes are those added to Plasmodium cultures having a larger number of late form-containing pRBCs. An average of five antibody molecules per liposome significantly improves in cell cultures the performance of immunoliposomes over non-functionalized liposomes as drug delivery vessels. Increasing the number of antibodies on the liposome surface correspondingly increases performance, with a reduction of 50% parasitemia achieved with immunoliposomes encapsulating 4 nM chloroquine and bearing an estimated 250 BM1234 units. The nanovector prototype described here can be a valuable platform amenable to modification and improvement with the objective of designing a nanostructure adequate to enter the preclinical pipeline as a new antimalarial therapy.
    Full-text · Article · Dec 2011 · Nanoscale Research Letters
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    • "The most prevalent theory is the interference in heme polymerization, an essential detoxification mechanism of the free heme from red blood cell hemoglobin. The mechanism of action of chloroquine involves entry into the food vacuole, possibly by diffusion of the free base across membranes (Vangapandu et al., 2007; Egan and Marques, 1999). After accumulation of the drug in the food vacuole, possibly by pH trapping of the protonated drug, chloroquine forms p–p complexes with heme ferriprotoporphyrin IX (Fe(III)PPIX) (Egan et al., 1996; Shelnutt, 1983). "
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    ABSTRACT: AbstractMalaria is re-emerging in many tropical areas of the world and is often fatal due to drug resistance, leading to about a million deaths each year. Multiple drug resistance has required new efforts in drug discovery and development. Thus, the search for new drugs operating by novel mechanisms of action is receiving increased attention. Herein we report the synthesis and biological evaluation of a novel anti-malarial with micromolar activity against resistant strains of the parasite. Graphical Abstract KeywordsMalaria–Plasmodium–Diamine–Imidazole
    Full-text · Article · May 2011 · Medicinal Chemistry Research
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