title: In vitro activity and mode of action of distamycin analogues against African trypanosomes.
abstract: Distamycin, a natural polyamide containing three heterocycle rings with a polar end, has inspired several groups to prepare synthetic analogues, which proved to have anti-trypanosomal and anti-tumoral activity. We describe the synthesis of bi and tri thiazoles amides that harbor different substitutions at their ends and the evaluation of their anti-Trypanosoma brucei activity. The most active compound 10b showed better biological activity (EC50310 nM and selectivity index 16) than the control drug nifurtimox (EC5015 μM and selectivity index 10). Studies on the mode of action show that the parasiticidal activity of 10b originates from disruption of lysosomal homeostasis, which is followed by release of redox active iron, an increase in oxidizing species and collapse of cell membrane integrity. In this respect, our study suggests that non-charged lipophylic distamycins destabilize cell membranes.
authors.affiliation: Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay; Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay.
authors.forename: Jaime
authors.initials: J
authors.lastname: Franco
authors.affiliation: Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Andrea
authors.initials: A
authors.lastname: Medeiros
authors.affiliation: Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay.
authors.forename: Diego
authors.initials: D
authors.lastname: Benítez
authors.affiliation: Cell Biology Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay.
authors.forename: Karen
authors.initials: K
authors.lastname: Perelmuter
authors.affiliation: Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
authors.forename: Gloria
authors.initials: G
authors.lastname: Serra
authors.affiliation: Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay. Electronic address: mcomini@pasteur.edu.uy.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Comini
authors.affiliation: Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address: laurito@fq.edu.uy.
authors.forename: Laura
authors.initials: L
authors.lastname: Scarone
mesh_terms: D000349:Africa; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D004214:Distamycins / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D013844:Thiazoles / Q000138:chemical synthesis; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014345:Trypanosoma / Q000187:drug effects*; D014346:Trypanosoma brucei brucei / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004214:Distamycins; D013844:Thiazoles; D014344:Trypanocidal Agents
keywords: Iron; Lysosome; Membrane damage; Thiazole; Trypanosoma brucei