Neue Antimalaria‐Wirkstoffe

Wiesner, Jochen; Ortmann, Regina; Jomaa, Hassan; Schlitzer, Martin

doi:10.1002/ange.200200569

Cited by 72 publications

(40 citation statements)

References 170 publications

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“…[143,181,201] Another argument in favor of choosing a host cell enzyme as a target is the a priori prevention of drug resistance. [135][136][137] In conclusion, on a short term basis the structure-based development of P. falciparum glutathione reductase-specific inhibitors will have high priority; on a long term basis, however, compounds inactivating both P. falciparum and erythrocyte glutathione reductase might become equally important for the chemotherapy of malaria.…”

Section: Outlook On Drug Developmentmentioning

confidence: 98%

“…[107,135] Past achievements and new developments in antimalarial drug research have been reviewed recently. [136,137] Inexpensive drugs against uncomplicated malaria in children are urgently required. In many African countries, and elsewhere in the world, the 10-cent drugs chloroquine and sulfadoxin/pyrimethamine lose efficiency because resistance against these compounds spreads rapidly.…”

Section: Drug Therapy and Prophylaxis Of Malariacurrent Problemsmentioning

confidence: 99%

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Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

2005

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Parasitic diseases such as sleeping sickness, Chagas' heart disease, and malaria are major health problems in poverty-stricken areas. Antiparasitic drugs that are not only active but also affordable and readily available are urgently required. One approach to finding new drugs and rediscovering old ones is based on enzyme inhibitors that paralyze antioxidant systems in the pathogens. These antioxidant ensembles are essential to the parasites as they are attacked in the human host by strong oxidants such as peroxynitrite, hypochlorite, and H2O2. The pathogen-protecting system consists of some 20 thiol and dithiol proteins, which buffer the intraparasitic redox milieu at a potential of -250 mV. In trypanosomes and leishmania the network is centered around the unique dithiol trypanothione (N1,N8-bis(glutathionyl)spermidine). In contrast, malaria parasites have a more conservative dual antioxidative system based on glutathione and thioredoxin. Inhibitors of antioxidant enzymes such as trypanothione reductase are, indeed, parasiticidal but they can also delay or prevent resistance against a number of other antiparasitic drugs.

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Section: Outlook On Drug Developmentmentioning

confidence: 98%

Section: Drug Therapy and Prophylaxis Of Malariacurrent Problemsmentioning

confidence: 99%

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

2005

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“…Reduction of benzamide into benzylamine decreases antimalarial activity (15c vs. 19). As previously seen for other series of FTase mammalian inhibitors with potent antimalarial activities, 4,18,19) no correlation can be observed between the two biological activities. The most potent inhibitor of FTase in the series (19) displays the lowest antimalarial activity.…”

Section: Resultsmentioning

confidence: 52%

“…Taken together, these results suggest that in the set of compounds reported here, inhibitory activity of mammalian FTase is not sufficient to explain the antimalarial activities observed. Several works 16,18,19) suggest that the active-site recognition properties of malarial FTase should be different from those of the mammalian enzyme. This difference could partly account for the lack of correlation noted between the two activities.…”

Section: Resultsmentioning

confidence: 99%

Novel N-(4-Piperidinyl)benzamide Antimalarials with Mammalian Protein Farnesyltransferase Inhibitory Activity

Ryckebusch

Gilleron

Millet

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Antimalarial drugs saved millions of lives during the 20th century. However, owing to the onset of drug resistance, there is now an urgent need to identify new drug targets in Plasmodium falciparum and to develop effective new antimalarial agents. 1,2) Prenylated proteins have been shown to function in important cellular processes including signal transductions. Among them, protein farnesyl transferase (PFT) has been a major target in the conception of new anticancer drugs. 3) In an effort to identify a new and more effective drug target, Chakrabarti 4,5) found that the peptidomimetic L-745,631 (Chart 1) was the best inhibitor of P. falciparum PFT and also a good inhibitor of parasite growth.This finding suggests the real potential of designing or identifying inhibitors of P. falciparum prenyl transferase as an approach to malaria therapy. In addition, several works have reported mammalian PFT inhibitors displaying potent antimalarial activities in vitro and more recently in vivo. 6) Small inhibitors of mammalian FTase developed as anticancer drugs like BMS-214662 [7][8][9][10][11] are also effective inhibitors of P. falciparum growth. 12,13) Results and DiscussionOur work has focused on peptidomimetic inhibitors based on the CA 1 A 2 X tetrapeptide, known to be responsible for interaction with the mammalian FTase, where the A 1 A 2 peptide is replaced by the structurally restricted N-(4-piperidinyl)benzamide scaffold. Initial studies 14) led us to compound 1 which possessed an IC 50 (isolated enzyme FTase) as low as 22.8 nM, but did not inhibit the proliferation of tumor cells in culture (Chart 2). More recently, 15) we synthesized a series of derivatives of compound 1, of general structure 2 which was the outcome of three structural modifications: (i) replacement of methioninate by phenylalaninate or isoleucinate (R 1 ) with the aim of increasing selectivity versus geranylgeranyl transferase, based on our previous results 14) (ii) replacement of the cysteinyl moiety by a known metal chelator, i.e. (1-benzylimidazol-5-yl)methyl substituted in para position (R 2 ) of benzyl in order to increase cellular uptake (iii) reduction of the benzoyl group into benzyl (R 3 ) in order to introduce flexibility into this region of the molecule. Target compounds 15a-c, 16c, 17c, 18 were obtained by reductive amination between adequate imidazolylcarbaldehydes 8a-c and 4-aminopiperidines 12-14. The synthesis of 5-formylimidazoles 8a-c was completed (Chart 3) in 5 steps according to a strategy 16,17) described for the preparation of regiochemically substituted imidazoleacetic esters: tritylation of N 1 -imidazole (4), protection of primary alcohol as ester (5), benzylation of N 3 and detritylation of N 1 (6a-c). The aldehyde function was finally created by chemical oxidation of the hydroxymethyl group (7a-c) resulting from hydrolysis of the ester (6a-c). Piperidines 9-11 were also prepared (Chart 4) from reductive amination of N-Bocpiperidone with adequate a-amino esters. Benzoylation and deprotection of piperidine (compounds 1...

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“…Bisher wurden nur auf Phosphaten oder Phosphonaten basierende Liganden mit bescheidenen bis mäßigen Affinitäten für einige der Enzyme (DXS, IspC, IspF) des mevalonatfreien Biosyntheseweges veröffentlicht. [6] Diese Tatsache veranlasste uns, die molekulare Erkennung von Phosphaten in biologischen Systemen genauer zu studieren. Ein [7] und leitet die Ablagerung von Eisen in Apoferritin ein.…”

Section: Introductionunclassified

Molekulare Erkennung von Phosphaten in der Strukturbiologie

2006

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Die medizinisch‐chemische Forschung hat sich in den letzten Jahren Proteinen zugewandt, die wie Proteinkinasen und Proteinphosphatasen eine Phosphatbindungsstelle aufweisen. Dieser Aufsatz versucht, mithilfe von Datenbankrecherchen einen Überblick über die wichtigsten Prinzipien der molekularen Erkennung von Phosphatgruppen durch Enzyme zu geben. 3003 Kristallstrukturen von Proteinen mit gebundenem organischem Phosphat aus der RCSB‐Proteindatenbank wurden im Hinblick auf H‐Brücken zwischen Protein und Ligand untersucht. Die bekannten Bindungsmotive für Phosphate werden behandelt und Ähnlichkeiten bei der Komplexierung von Phosphaten durch synthetische Rezeptoren hervorgehoben. Eine Analyse der Häufigkeit, mit der spezifische Aminosäuren in unterschiedlichen phosphatbindenden Enzymklassen H‐Brücken eingehen, führt zu einer für die Enzymklasse charakteristischen Verteilung. Der Aufsatz zeigt, dass bei strukturbasierter Ligandenentwicklung und ‐optimierung die Umgebung der Phosphatbindungsstelle sorgfältig mitberücksichtigt werden sollte und weist gleichzeitig auf Alternativen hin, wie diese Bindungstaschen zu füllen sind.

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Neue Antimalaria‐Wirkstoffe

Cited by 72 publications

References 170 publications

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

Dithiol Proteins as Guardians of the Intracellular Redox Milieu in Parasites: Old and New Drug Targets in Trypanosomes and Malaria‐Causing Plasmodia

Novel N-(4-Piperidinyl)benzamide Antimalarials with Mammalian Protein Farnesyltransferase Inhibitory Activity

Molekulare Erkennung von Phosphaten in der Strukturbiologie

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