Antimalarial Dual Drugs Based on Potent Inhibitors of Glutathione Reductase from Plasmodium falciparum Export

@article{Friebolin09, 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 (FeIII)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.}, author = {Friebolin, Wolfgang and Jannack, Beate and Wenzel, Nicole and Furrer, Julien and Oeser, Thomas and Sanchez, Cecilia P. and Lanzer, Michael and Yardley, Vanessa and Becker, Katja and Davioud-Charvet, Elisabeth}, citeulike-article-id = {4324839}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/jm7009292}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/jm7009292}, day = {1}, doi = {10.1021/jm7009292}, journal = {Journal of Medicinal Chemistry}, keywords = {4-aminoquinoline, antioxidant, chloroquine, core, malaria, transporter}, month = {March}, number = {5}, pages = {1260--1277}, posted-at = {2009-04-16 07:55:34}, priority = {2}, title = {Antimalarial Dual Drugs Based on Potent Inhibitors of Glutathione Reductase from Plasmodium falciparum}, url = {http://dx.doi.org/10.1021/jm7009292}, volume = {51}, year = {2008} }

TY - JOUR ID - Friebolin09 L3 - citeulike-article-id:4324839 N2 - 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 (FeIII)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. IS - 5 JF - Journal of Medicinal Chemistry EP - 1277 TI - Antimalarial Dual Drugs Based on Potent Inhibitors of Glutathione Reductase from Plasmodium falciparum VL - 51 SP - 1260 KW - 4-aminoquinoline KW - antioxidant KW - chloroquine KW - core KW - malaria KW - transporter AU - Friebolin, Wolfgang AU - Jannack, Beate AU - Wenzel, Nicole AU - Furrer, Julien AU - Oeser, Thomas AU - Sanchez, Cecilia AU - Lanzer, Michael AU - Yardley, Vanessa AU - Becker, Katja AU - Davioud-Charvet, Elisabeth PY - 2008/03/01/ UR - http://dx.doi.org/10.1021/jm7009292 ER -