Anti-trypanosomal activities and structural chemical properties of selected compound classes
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Potent compounds do not necessarily make the best drugs in 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, N-Arylpyridinium 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 chemical characteristics of the compounds. Interestingly, the 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.
KeywordsCompound design Drug potency Drug targets Electron microscopy Ligand efficiency Trypanosoma brucei
This work was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG Collaborative Research Center 630, “Recognition, Preparation, and Functional Analysis of Agents against Infectious Diseases”; projects A1, A2, A4, B8, C7, Z1, and QM). We thank Daniela Bunsen and Claudia Gehrig from the University of Würzburg, (Core Unit for Electron Microscopy) and Martina Schultheis, Elena Katzowitsch, and Svetlana Sologub (Institute for Molecular Infection Biology, University of Würzburg) for the technical assistance. APS had the support of the Alexander von Humboldt Foundation, Germany.
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