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

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• 作者：Janina Preuss ; Patrick Maloney ; Satyamaheshwar Peddibhotla ; Michael P. Hedrick ; Paul Hershberger ; Palak Gosalia ; Monika Milewski ; Yujie Linda Li ; Eliot Sugarman ; Becky Hood ; Eigo Suyama ; Kevin Nguyen ; Stefan Vasile ; Eduard Sergienko ; Arianna Mangravita-Novo ; Michael Vicchiarelli ; Danielle McAnally ; Layton H. Smith ; Gregory P. Roth ; Jena Diwan ; Thomas D.Y. Chung ; Esther Jortzik ; Stefan Rahlfs ; Katja Becker ; Anthony B. Pinkerton ; Lars Bode
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7262-7272
• 全文大小：623K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

A high-throughput screen of the NIH鈥檚 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-benzo[b][1,4]thiazine-6-carboxamide, 11 (ML276), is a submicromolar inhibitor of PfG6PD (IC₅₀ = 889 nM). It is completely selective for the enzyme鈥檚 human isoform, displays micromolar potency (IC₅₀ = 2.6 渭M) against P. falciparum in culture, and has good drug-like properties, including high solubility and moderate microsomal stability. Studies testing the potential advantage of inhibiting PfG6PD in vivo are in progress.