Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The emergence and spread of drug-resistant malaria parasites is a serious public health problem in the tropical world. Malaria control has relied upon the traditional quinoline, antifolate and artemisinin compounds. Very few new antimalarials were developed in the last quarter of the 20th century. An alarming increase in drug-resistant strains of the malaria parasite poses a significant problem for effective control. Recent advances in our knowledge of parasite biology as well as the availability of the genome sequence provide a wide range of novel targets for drug design. Gene products involved in controlling vital aspects of parasite metabolism and organelle function could be attractive targets. It is expected that the application of functional genomic tools in combination with modern approaches such as structure-based drug design and combinatorial chemistry will lead to the development of effective new drugs against drug-resistant malaria strains. This review discusses novel molecular targets of the malaria parasite available to the drug discovery scientist.
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PMID:Novel molecular targets for antimalarial chemotherapy. 1733 2

Malaria is one of the most severe tropical parasitic disease causing 1-3 million deaths annually. In the last 25 years very few new antimalarial molecules have been developed and only a limited number of them are currently in various stages of clinical development. The presently available antimalarial drugs include artemisinin analogs, quinoline derivatives and antifolates. This review summarizes recent advances in antimalarial drug development and world patents published between 2000-2006 claiming new synthetic antimalarial compounds and their activities. The most over-represented classes of compounds in malaria patent literature in order of frequency are artemisinin analogs, quinoline derivatives, DOXP reductoisomerase inhibitors, antifolates and febrifugine analogues. Many of these patents describe the novelty and potential of these synthetic derivatives with an attempt to identify the next generation antimalarials that may have potential commercial advantages.
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PMID:Recent advances in antimalarial compounds and their patents. 1734 61

Mutations in the Plasmodium falciparum pfcrt gene cause resistance to the 4-amino quinoline chloroquine (CQ) and other antimalarial drugs. Mutations and/or overexpression of a P. falciparum multidrug resistance gene homologue (pfmdr1) may further modify or tailor the degree of quinoline drug resistance. Recently [Ferdig MT, Cooper RA, Mu JB, et al. Dissecting the loci of low-level quinine resistance in malaria parasites. Mol Microbiol 2004;52:985-97] QTL analysis further implicated a region of P. falciparum chromosome 13 as a partner (with pfcrt) in conferring resistance to the first quinoline-based antimalarial drug, quinine (QN). Since QN resistance (QNR) and CQR are often (but not always) observed together in parasite strains, since elevated cytosolic pH is frequently (but not always) found in CQR parasites, and since the chr 13 segment linked to QNR prominently harbors a gene encoding what appears to be a P. falciparum Na(+)/H(+) exchanger (PfNHE), we have systematically measured cytosolic pH and PfNHE activity for an extended series of parasite strains used in the QTL analysis. Altered PfNHE activity does not correlate with CQR as previously proposed, but significantly elevated PfNHE activity is found for strains with high levels of QNR, regardless their CQR status. We propose that either an elevated pH(cyt) or a higher vacuolar pH-to-cytosolic pH gradient contributes to one common route to malarial QNR that is also characterized by recently defined chr 13-chr 9 pairwise interactions. Based on sequence analysis we propose a model whereby observed polymorphisms in PfNHE may lead to altered Na(+)/H(+) set point regulation in QNR parasites.
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PMID:Plasmodium falciparum Na+/H+ exchanger activity and quinine resistance. 1942 65

Quinoline hexose analogs are expected to be useful as novel agents for treatment of chloroquine-resistant malaria. Here, we report preparation of 4-hydroxy quinoline-beta-glucosides from anilines in 4 steps.
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PMID:Preparation of quinoline hexose analogs as novel chloroquine-resistant malaria treatments (1). Synthesis of 4-hydroxyquinoline-beta-glucosides. 1747 79

Massive haemoglobinuria is encountered rarely during the course of malaria. It is usually considered a diagnostic criterion for severe malaria, together with anaemia, acute renal failure and jaundice. Haemoglobinuria can also present among expatriates travelling to endemic areas following repeated exposure to quinoline or arylaminoalcohol drugs. A case is described of haemoglobinuria developing in a 38-year-old French expatriate diagnosed concurrently with numerous tropical infections, and treated on presumptive basis with an antimalarial regimen containing artemisinin derivatives. Haemoglobinuria resolved spontaneously within a few days. Although this case does not definitely indicate a causal link between haemoglobinuria and artemisinin derivatives, the risk of such infrequent side-effects should be taken into account in pharmacovigilance monitoring. Moreover, the patient illustrates the multifaceted pathology that can be encountered with tropical infections.
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PMID:Haemoglobinuria in a 38-year-old French expatriate man living in Cameroon following artemisinin-based antimalarial treatment. 1757 51

Amodiaquine is an amino-4-quinoline with the basic spectrum of activity of chloroquine. It has been used widely to treat and prevent malaria. From the mid-1980s, there were reports of fatal adverse drug reactions described in travelers using amodiaquine as antimalarial prophylaxis. In 1990, the World Health Organization (WHO) stopped using this drug in malaria control programs. The WHO Expert Committee on Malaria modified this in 1993 and reported that amodiaquine could be used for treatment if the risk of infection outweighs the potential for adverse drug reactions. Currently, amodiaquine is a potential useful drug, especially if used with artemisinin-based combination therapy and with sulfadoxine-pyrimethamine to improve treatment efficacy for chloroquine-resistant strains of Plasmodium falciparum and P. vivax. We report a case of fulminant hepatitis induced by antimalarial prophylactic use of amodiaquine that necessitated emergency orthotopic liver transplantation.
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PMID:Emergency liver transplantation in amodiaquine-induced fulminant hepatitis. 1762 Jun 24

There are consistent differences in cardiovascular state between acute illness in malaria and recovery that prolong the electrocardiographic QT interval and have been misinterpreted as resulting from antimalarial cardiotoxicity. Of the different classes of antimalarial drugs, only the quinolines, and structurally related antimalarial drugs, have clinically significant cardiovascular effects. Drugs in this class can exacerbate malaria-associated orthostatic hypotension and several have been shown to delay ventricular depolarisation slightly (class 1c effect), resulting in widening of the QRS complex, but only quinidine and halofantrine have clinically significant effects on ventricular repolarisation (class 3 effect). Both drugs cause potentially dangerous QT prolongation, and halofantrine has been associated with sudden death. The parenteral quinoline formulations (chloroquine, quinine, and quinidine) are predictably hypotensive when injected rapidly, and cardiovascular collapse can occur with self-poisoning. Transiently hypotensive plasma concentrations of chloroquine can occur when doses of 5 mg base/kg or more are given by intramuscular or subcutaneous injection. At currently recommended doses, other antimalarial drugs do not have clinically significant cardiac effects. More information on amodiaquine, primaquine, and the newer structurally related compounds is needed.
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PMID:Cardiotoxicity of antimalarial drugs. 1764 28

8-Aminoquinolines are an important class of antiparasitic agents, with broad utility and excellent efficacy, but also limitations due to hematological toxicities, primarily methemoglobinemia and hemolysis. One representative from this class, (+/-)-8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate (NPC1161C), proved extremely efficacious in animal models of malaria and pneumocystis pneumonia. This racemic mixture was separated into its component enantiomers by chemical and chromatographic means. The enantiomers were evaluated for antiparasitic activity in murine models of Plasmodium berghei, Pneumocystis carinii, and Leishmania donovani infection, as well as the propensity to elicit hematotoxicity in dogs. The (-)-enantiomer NPC1161B was found to be more active (by severalfold, depending on the dosing regimen) than the (+)-enantiomer NPC1161A in all of these murine models. In addition, the (-) enantiomer showed markedly reduced general toxicity in mice and reduced hematotoxicity in the dog model of methemoglobinemia. It is concluded that the configuration at the asymmetric center in the 8-amino side chain differentially affects efficacy and toxicity profiles and thus may be an important determinant of the "therapeutic window" for compounds in this class.
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PMID:Antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate. 1837 16

Plasmodium falciparum is one of the most lethal parasite responsible for human malaria. Until now, the only one solution to counter malaria is the use of antimalarial drugs. Unfortunately, the extensively use of drugs, such as quinolines (i.e. chloroquine, quinine or mefloquine), have led to the emergence of drug resistance. Chloroquine and probably other quinolines act in interfering in the detoxification of hematin in the digestive vacuole. Quinolines are accumulated in P. falciparum digestive vacuole and the accumulation varies from a susceptible strain to a resistant one. Nevertheless, the mechanisms of quinoline resistance are still investigating. Genetic polymorphisms in some strains have been linked to drug resistance. The modifications observed are mutations on genes that encode transport proteins localized in the membrane of digestive vacuole. Three transporters were involved in quinoline resistance: PfCRT (Plasmodium falciparum chloroquine resistance transporter), Pgh1 (P-glycoprotein homologue 1) and PfMRP (Plasmodium falciparum multidrug resistance protein). They could be involved in accumulation or efflux mechanisms of drugs. In order to understand their role in resistance, localization, encoding gene structure, protein structure and endogenous function of these three transporters are reported. Some molecules that have no intrinsic antimalarial effect have been shown to reverse drug resistance when they are combined to chloroquine, quinine or mefloquine. These molecules are a solution to counter resistance but also they are precious tools to elucidate the resistance mechanisms. The molecules that have already shown a capacity to reverse chloroquine, quinine or mefloquine resistances were reported. Some of them could act on one of the three transporters involved in drug resistance, by confirming their role in quinoline resistance. Here we summarize the main elements of quinoline resistance and reversion of quinoline resistance related to malaria.
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PMID:Inhibition of efflux of quinolines as new therapeutic strategy in malaria. 1847 83

Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4-O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4-N, 4-S, and 4-O derivatives vs mu-oxo dimeric heme, measure binding constants for monomeric vs dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs CQR malaria.
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PMID:4-N-, 4-S-, and 4-O-chloroquine analogues: influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria. 1851


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