title: Anti-trypanosomal activities and structural chemical properties of selected compound classes.
abstract: 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.
authors.affiliation: Laboratory of Molecular Physiology, Institute of Experimental Medicine, School of Medicine Luis Razetti, Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela, aiponte@gmail.com.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
authors.forename: Heike
authors.initials: H
authors.lastname: Bruhn
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.forename: Alexander
authors.initials: A
authors.lastname: Cecil
authors.forename: Christian R
authors.initials: CR
authors.lastname: Albert
authors.forename: Christian
authors.initials: C
authors.lastname: Buechold
authors.forename: Maximilian
authors.initials: M
authors.lastname: Tischer
authors.forename: Susanne
authors.initials: S
authors.lastname: Schlesinger
authors.forename: Tim
authors.initials: T
authors.lastname: Goebel
authors.forename: Antje
authors.initials: A
authors.lastname: Fuß
authors.forename: Daniela
authors.initials: D
authors.lastname: Mathein
authors.forename: Benjamin
authors.initials: B
authors.lastname: Merget
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.forename: August
authors.initials: A
authors.lastname: Stich
authors.forename: Georg
authors.initials: G
authors.lastname: Krohne
authors.forename: Markus
authors.initials: M
authors.lastname: Engstler
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000818:Animals; D002460:Cell Line; D057056:Cysteine Proteases / Q000187:drug effects; D005650:Fumarates / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D015388:Organelles / Q000187:drug effects; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: D005650:Fumarates; D010879:Piperazines; D010880:Piperidines; D014344:Trypanocidal Agents; D000077489:Piperazine; C032727:piperidine; C032005:fumaric acid; D057056:Cysteine Proteases