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.
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-benzo[b][1,4]thiazine-6-carboxamide, 11 (ML276), is a submicromolar inhibitor of PfG6PD (IC(50) = 889 nM). It is completely selective for the enzyme's human isoform, displays micromolar potency (IC(50) = 2.6 μM) 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.
Department of Pediatrics, University of California, San Diego, La Jolla, California 92037, United States.
Janina
J
Preuss
Patrick
P
Maloney
Satyamaheshwar
S
Peddibhotla
Michael P
MP
Hedrick
Paul
P
Hershberger
Palak
P
Gosalia
Monika
M
Milewski
Yujie Linda
YL
Li
Eliot
E
Sugarman
Becky
B
Hood
Eigo
E
Suyama
Kevin
K
Nguyen
Stefan
S
Vasile
Eduard
E
Sergienko
Arianna
A
Mangravita-Novo
Michael
M
Vicchiarelli
Danielle
D
McAnally
Layton H
LH
Smith
Gregory P
GP
Roth
Jena
J
Diwan
Thomas D Y
TD
Chung
Esther
E
Jortzik
Stefan
S
Rahlfs
Katja
K
Becker
Anthony B
AB
Pinkerton
Lars
L
Bode
D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D004355:Drug Stability; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors*; D057166:High-Throughput Screening Assays; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D009097:Multienzyme Complexes; C576404:N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo(b)(1,4)thiazine-6-carboxamide; D054852:Small Molecule Libraries; D013843:Thiazines; C560097:glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase, Plasmodium falciparum; D005954:Glucosephosphate Dehydrogenase; D002265:Carboxylic Ester Hydrolases