Discovery of a Plasmodium falciparum Glucose-6-phosphate Dehydrogenase 6-phosphogluconolactonase Inhibitor (R,Z)-N-((1-Ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (ML276) That Reduces Parasite Growth in Vitro
Autor: | Anthony B. Pinkerton, Gregory P. Roth, Eigo Suyama, Layton H. Smith, Becky Hood, Danielle McAnally, Esther Jortzik, Thomas D.Y. Chung, Palak Gosalia, Michael Vicchiarelli, Arianna Mangravita-Novo, Satyamaheshwar Peddibhotla, Jena Diwan, Stefan Rahlfs, Eduard Sergienko, Paul Hershberger, Kevin Nguyen, Stefan Vasile, Katja Becker, Patrick R. Maloney, Monika Milewski, Yujie Linda Li, Michael P Hedrick, Eliot Sugarman, Janina Preuss, Lars Bode |
---|---|
Rok vydání: | 2012 |
Předmět: |
biology
medicine.drug_class Stereochemistry Dehydrogenase Plasmodium falciparum Carboxamide Pentose phosphate pathway biology.organism_classification chemistry.chemical_compound Metabolic pathway Biochemistry chemistry Thiazine parasitic diseases Drug Discovery medicine Molecular Medicine Glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase |
Zdroj: | Journal of Medicinal Chemistry. 55:7262-7272 |
ISSN: | 1520-4804 0022-2623 |
DOI: | 10.1021/jm300833h |
Popis: | A high-throughput screen of the NIH’s MLSMR collection of ∼340000 compounds was undertaken to identify compounds that inhibit Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD). PfG6PD is important for proliferating and propagating P. falciparum and differs structurally and mechanistically from the human orthologue. The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD) is the first, rate-limiting step in the pentose phosphate pathway (PPP), a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. In P. falciparum, the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) catalyzes the first two steps of the PPP. Because P. falciparum and infected host red blood cells rely on accelerated glucose flux, they depend on the G6PD activity of PfGluPho. The lead compound identified from this effort, (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-be... |
Databáze: | OpenAIRE |
Externí odkaz: |