Journal article

Publication year: 2012

Pages: 7262-7272

Journal: Journal of Medicinal Chemistry

Volume number: 55

Issue number: 16

ISSN: 0022-2623

eISSN: 1520-4804

Open access status: Green

DOI Link: https://doi.org/10.1021/jm300833h

Publisher: American Chemical Society

Abstract: 
A high-throughput screen of the NIH's MLSMR collection of similar to 340000 compounds was undertaken to identify compounds that inhibit Plasmodium falciparum glucose-6-phosphate dehydrogenase (Pf G6PD). 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 (Pf GluPho) 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 Pf GluPho. 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-carbon-amide, 11 (ML276), is a submicromolar inhibitor of Pf G6PD (IC50 = 889 nM). It is completely selective for the enzyme's human isoform, displays micromolar potency (IC50 = 2.6 mu 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 Pf G6PD in vivo are in progress.

Harvard Citation style: Preuss, J., Maloney, P., Peddibhotla, S., Hedrick, M., Hershberger, P., Gosalia, P., et al. (2012) 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, Journal of Medicinal Chemistry, 55(16), pp. 7262-7272. https://doi.org/10.1021/jm300833h

APA Citation style: Preuss, J., Maloney, P., Peddibhotla, S., Hedrick, M., Hershberger, P., Gosalia, P., Milewski, M., Li, Y., Sugarman, E., Hood, B., Suyama, E., Nguyen, K., Vasile, S., Sergienko, E., Mangravita-Novo, A., Vicchiarelli, M., McAnally, D., Smith, L., Roth, G., ...Bode, L. (2012). 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. Journal of Medicinal Chemistry. 55(16), 7262-7272. https://doi.org/10.1021/jm300833h