title: Antimalarial dual drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum.
abstract: Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems providing a steady glutathione flux. As a future generation of dual drugs, 18 naphthoquinones and phenols (or their reduced forms) containing three different linkers between the 4-aminoquinoline core and the redox active component were synthesized. Their antimalarial effects have been characterized in parasite assays using chloroquine-sensitive and -resistant strains of Plasmodium, alone or in drug combination, and in the Plasmodium berghei rodent model. In particular, two tertiary amides 34 and 36 showed potent antimalarial activity in the low nanomolar range against CQ-resistant parasites. The ability to compete both for (Fe (III))protoporphyrin and for chloroquine transporter was determined. The data are consistent with the presence of a carrier for uptake of the short chloroquine analogue 2 but not for the potent antimalarial amide 34, suggesting a mode of action distinct from chloroquine mechanism.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Friebolin
authors.forename: Beate
authors.initials: B
authors.lastname: Jannack
authors.forename: Nicole
authors.initials: N
authors.lastname: Wenzel
authors.forename: Julien
authors.initials: J
authors.lastname: Furrer
authors.forename: Thomas
authors.initials: T
authors.lastname: Oeser
authors.forename: Cecilia P
authors.initials: CP
authors.lastname: Sanchez
authors.forename: Michael
authors.initials: M
authors.lastname: Lanzer
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: C529288:6-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)hexanoic acid (2-(7-chloroquinolin-4-ylamino)ethyl)-N-isopropylamide; D000962:Antimalarials; C529289:N-(2-(7-chloroquinolin-4-ylamino)ethyl)-N'-isopropyl-2-(4-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylmethyl)phenyl)acetamide; D009281:Naphthalenes; D002738:Chloroquine; D005980:Glutathione Reductase