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

Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrP(Sc), a pathogenic misfolded isoform of the normal cellular prion protein (PrP(C)). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure-activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.
 ...
PMID:Similar structure-activity relationships of quinoline derivatives for antiprion and antimalarial effects. 1691 19

The development and spread of resistance to antimalarial drugs poses a severe and increasing public health threat. Failures of prophylaxis or treatment with quinolines, hydroxynaphthoquinones, sesquiterpene lactones, antifolate drugs and sulfamides are involved in a return malaria-related morbidity and mortality. Resistance is associated with a decrease in accumulation of drugs into the vacuole, which results from a reduced uptake of the drug, an increased efflux or a combination of both. A number of candidate genes in P. falciparum have been proposed to be involved in antimalarial resistance, each concerned in membrane transport. Weaker or stronger associations are seen in P. falciparum between the resistance to quinolines or artemisinin derivatives and codon changes in Pfmdr1, a gene which encodes Pgh-1, an ortholog of one of the P-glycoproteins expressed in multi-drug resistant human cancer cells (ABC transporter). Further analysis has revealed a new gene, Pfcrt, encoding a PfCRT protein, which resembles an anion channel. Codon changes found in the Pfcrt sequence in drug resistant isolates could facilitate the drug efflux through a putative channel. It has been proposed that the reversal of quinoline resistance by verapamil is due to hydrophobic binding to the mutated PfCRT protein. Several compounds have demonstrated in the past decade a promising capability to reverse the antimalarial drug resistance in vitro in parasite isolates, in animal models and in human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic and antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and anthracenic derivatives. Here we summarize the progress made in biochemical and genetic basis of antimalarial resistance, emphasizing the recent developments on drugs, which interfere with trans membrane proteins involved in drug efflux or uptake.
 ...
PMID:Chloroquine resistance reversal agents as promising antimalarial drugs. 1691 22

The intraerythrocytic malaria parasite constructs an intracellular haem crystal, called haemozoin, within an acidic digestive vacuole where haemoglobin is degraded. Haem crystallization is the target of the widely used antimalarial quinoline drugs. The intracellular mechanism of molecular initiation of haem crystallization, whether by proteins, polar membrane lipids or by neutral lipids, has not been fully substantiated. In the present study, we show neutral lipid predominant nanospheres, which envelop haemozoin inside Plasmodium falciparum digestive vacuoles. Subcellular fractionation of parasite-derived haemozoin through a dense 1.7 M sucrose cushion identifies monoacylglycerol and diacylglycerol neutral lipids as well as some polar lipids in close association with the purified haemozoin. Global MS lipidomics detects monopalmitic glycerol and monostearic glycerol, but not mono-oleic glycerol, closely associated with haemozoin. The complex neutral lipid mixture rapidly initiates haem crystallization, with reversible pH-dependent quinoline inhibition associated with quinoline entry into the neutral lipid microenvironment. Neutral lipid nanospheres both enable haem crystallization in the presence of high globin concentrations and protect haem from H2O2 degradation. Conceptually, the present study shifts the intracellular microenvironment of haem crystallization and quinoline inhibition from a polar aqueous location to a non-polar neutral lipid nanosphere able to exclude water for efficient haem crystallization.
 ...
PMID:The role of neutral lipid nanospheres in Plasmodium falciparum haem crystallization. 1704 14

Resistance to quinoline antimalarials, especially to chloroquine and mefloquine has had a major impact on the treatment of malaria worldwide. In the period since 2000, significant progress has been made in understanding the origins of chloroquine resistance and to a lesser extent mefloquine resistance in Plasmodium falciparum. Chloroquine resistance correlates directly with mutations in the pfcrt gene of the parasite, while changes in another gene, pfmdr1, may also be related to chloroquine resistance in some strains. Mutations in pfcrt do not appear to correlate with mefloquine resistance, but some studies have implicated pfmdr1 in mefloquine resistance. Its involvement however, has not been definitively demonstrated. The protein products of these genes, PfCRT and Pgh-1 are both located in the food vacuole membrane of the parasite. Current evidence suggests that PfCRT is probably a transporter protein. Chloroquine appears to exit the food vacuole via this transporter in resistant PfCRT mutants. Pgh-1 on the other hand, resembles mammalian multi-drug resistance proteins and appears to be involved in expelling hydrophobic drugs from the food vacuole. Resistance reversing agents are believed to act by inhibiting these proteins. The currently known chloroquine- and mefloquine-resistance reversing agents are discussed in this review. This includes a discussion of structure-activity relationships in these compounds and hypotheses on their possible mechanisms of action. The status of current clinical applications is also briefly discussed.
 ...
PMID:Quinoline-resistance reversing agents for the malaria parasite Plasmodium falciparum. 1706 51

The morphology of micrometer-sized beta-hematin crystals (synthetic malaria pigment) was determined by TEM images and diffraction, and by grazing incidence synchrotron X-ray diffraction at the air-water interface. The needle-like crystals are bounded by sharp {100} and {010} side faces, and capped by {011} and, to a lesser extent, by {001} end faces, in agreement with hemozoin (malaria pigment) crystals. The beta-hematin crystals grown in the presence of 10% chloroquine or quinine took appreciably longer to precipitate and tended to be symmetrically tapered toward both ends of the needle, due to stereoselective additive binding to {001} or {011} ledges. Evidence, but marginal, is presented that additives reduce crystal mosaic domain size along the needle axis, based on X-ray powder diffraction data. Coherent grazing exit X-ray diffraction suggests that the mosaic domains are smaller and less structurally stable than in pure crystals. IR-ATR and Raman spectra indicate molecular based differences due to a modification of surface and bulk propionic acid groups, following additive binding and a molecular rearrangement in the environment of the bulk sites poisoned by occluded quinoline. These results provided incentive to examine computationally whether hemozoin may be a target of antimalarial drugs diethylamino-alkoxyxanthones and artemisinin. A variation in activity of the former as a function of the alkoxy chain length is correlated with computed binding energy to {001} and {011} faces of beta-hematin. A model is proposed for artemisinin activity involving hemozoin nucleation inhibition via artemisinin-beta-hematin adducts bound to the principal crystal faces. Regarding nucleation of hemozoin inside the digestive vacuole of the malaria parasite, nucleation via the vacuole's membranous surface is proposed, based on a reported hemozoin alignment. As a test, a dibehenoyl-phosphatidylcholine monolayer transferred onto OTS-Si wafer nucleated far more beta-hematin crystals, albeit randomly oriented, than a reference OTS-Si.
 ...
PMID:Crystal nucleation, growth, and morphology of the synthetic malaria pigment beta-hematin and the effect thereon by quinoline additives: the malaria pigment as a target of various antimalarial drugs. 1729 Sep 93

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.
 ...
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.
 ...
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.
 ...
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.
 ...
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.
 ...
PMID:Haemoglobinuria in a 38-year-old French expatriate man living in Cameroon following artemisinin-based antimalarial treatment. 1757 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>