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Título : Anti-trypanosomal activities and structural chemical properties of selected compound classes
Autor : Ponte-Sucre, Alicia
Bruhn, Heike
Schirmeister, Tanja
Cecil, Alexander
Albert, Christian R.
Buechold, Christian
Tischer, Maximilian
Schlesinger, Susanne
Goebel, Tim
Fuß, Antje
Mathein, Daniela
Merget, Benjamin
Sotriffer, Christoph
Stich, August
Krohne, Georg
Engstler, Markus
Bringmann, Gerhard
Ulrike, Holzgrabe
Palabras clave : anti-trypanosomal
structural properties
compound families
Fecha de publicación : 5-Mar-2015
Citación : Parasitology Research;114:501-12, 2015
Resumen : the market. Consequently, with the aim to describe tools that may be fundamental for refining the screening of candidates for animal and preclinical studies and further development, molecules of different structural classes synthesized within the frame of a broad screening platform were evaluated for their trypanocidal activities, cytotoxicities against murine macrophages J774.1 and selectivity indices, as well as for their ligand efficiencies and structural chemical properties. To advance into their modes of action, we also describe the morphological and ultrastructural changes exerted by selected members of each compound class on the parasite Trypanosoma brucei. Our data suggest that the potential organelles targeted are either the flagellar pocket (compound 77, N-Arylpyridinium salt; 15, amino acid derivative with piperazine moieties), the endoplasmic reticulum membrane systems (37, bisquaternary bisnaphthalimide; 77, NArylpyridinium salt; 68, piperidine derivative), or mitochondria and kinetoplasts (88, N-Arylpyridinium salt; 68, piperidine derivative). Amino acid derivatives with fumaric acid and piperazine moieties (4, 15) weakly inhibiting cysteine proteases seem to preferentially target acidic compartments. Our results suggest that ligand efficiency indices may be helpful to learn about the relationship between potency and correlations found between the physico-chemical parameters of the selected compounds and those of commercial molecules that target specific organelles indicate that our rationale might be helpful to drive compound design toward high activities and acceptable pharmacokinetic properties for all compound families.
ISSN : 0932-0113
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