title: Effects of 5,8-dimethylthieno[2,3-b]quinoline-2-carboxylic acid on the antioxidative defense and lipid membranes in Plasmodium berghei-infected erythrocytes.
abstract: Plasmodium parasites degrade hemoglobin producing reactive oxygen species as toxic byproducts which are detoxified by a series of antioxidant mechanisms. Quinoline compounds have demonstrated activity against hemoglobin degradation with 5,8-dimethylthieno[2,3-b]quinoline-2-carboxylic acid (TQCA) representing a recent compound inhibiting this process. Thus, this study was undertaken to determine the ability of TQCA to modify the oxidative status in Plasmodium berghei-infected erythrocytes. After hemolysis, activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and dehydrogenase enzymes as well as lipid peroxidation were investigated by spectrophotometry. Saturated and unsaturated fatty acids were determined by gas-liquid chromatography and the in vivo effects of TQCA were confirmed by a malaria murine model (Rane test). The activity of glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) in infected cells was diminished by this compound compared to control infection in 75.1 ± 3.5% and 26.5 ± 0.3%, respectively, while that of GPx and GR was also lowered (p <0.05). As an adaptive response we appreciated a 2.3-fold increase of SOD activity compared to control infection. Lipid peroxidation and the saturated/unsaturated fatty acids ratio were also decreased by this quinoline derivate in 49.2 ± 1.32% and 37 ± 0.06%, respectively, protecting the cells from hemolysis caused by the infection. The in vitro results were in concordance with the potential in vivo activity of this compound in an established malaria murine model in which TQCA showed significant decrease in the parasitemia levels and increased the mean survival days of infected mice. In conclusion, the antioxidant defense represents a biochemical target for TQCA actions as a potent antimalarial whose effects were also confirmed in vivo.
authors.affiliation: Unidad de Bioquímica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, Caracas 1041-A, Venezuela.
authors.forename: N D
authors.initials: ND
authors.lastname: Gamboa de Domínguez
authors.affiliation: Unidad de Síntesis Orgánica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, Caracas 1041-A, Venezuela.
authors.forename: J
authors.initials: J
authors.lastname: Charris
authors.affiliation: Unidad de Síntesis Orgánica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, Caracas 1041-A, Venezuela.
authors.forename: J
authors.initials: J
authors.lastname: Domínguez
authors.affiliation: Unidad de Síntesis Orgánica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, Caracas 1041-A, Venezuela.
authors.forename: M
authors.initials: M
authors.lastname: Monasterios
authors.affiliation: Laboratorio de Síntesis y Diseño de Fármacos, Dpto. de Química, Facultad Experimental de Ciencias, Universidad del Zulia, Maracaibo, Venezuela.
authors.forename: J
authors.initials: J
authors.lastname: Angel
authors.affiliation: Unidad de Bioquímica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, Caracas 1041-A, Venezuela. Electronic address: juanricardorodrigues@gmail.com.
authors.forename: J
authors.initials: J
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D004910:Erythrocyte Membrane / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D008563:Membrane Lipids / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D010734:Phosphogluconate Dehydrogenase / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology*; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000600818:5,8-dimethylthieno(2,3-b)quinoline-2-carboxylic acid; D000962:Antimalarials; D000975:Antioxidants; D008563:Membrane Lipids; D011804:Quinolines; D013876:Thiophenes; D010734:Phosphogluconate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase
keywords: Antioxidant enzymes; Malaria; Oxidative stress; Plasmodium berghei; Quinolines