title: Conjugation of quinones with natural polyamines: toward an expanded antitrypanosomatid profile.
abstract: A combinatorial library of quinone-polyamine conjugates designed to optimize the antitrypanosomatid profile of hit compounds 1 and 2 has been prepared by a solid-phase approach. The conjugates were evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and several showed promising activity. A subset also inhibited trypanothione reductase in vitro and induced oxidase activity of the enzyme. A highly potent analogue (7) was identified with activity against T. brucei as low as 70 nM and a selectivity index of 72. Interestingly, the presence of a cadaverine tail confers to 7 the ability to target mitochondrial function in Leishmania. In fact, in L. donovani promastigotes, we verified for 7 a decrease of cytoplasmic ATP and mitochondrial potential. Therefore, the current results support the suitability of the conjugation approach for the development of novel polyamine conjugates with enhanced therapeutic potential.
authors.affiliation: Department of Pharmacy and Biotechnologies, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Lizzi
authors.forename: Giacomo
authors.initials: G
authors.lastname: Veronesi
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.forename: Almudena
authors.initials: A
authors.lastname: López-Sánchez
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: R Luise
authors.initials: RL
authors.lastname: Krauth-Siegel
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Hall
authors.forename: Luis
authors.initials: L
authors.lastname: Rivas
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
mesh_terms: D000818:Animals; D007893:Leishmania donovani / Q000187:drug effects; D011073:Polyamines / Q000737:chemistry* / Q000494:pharmacology*; D011809:Quinones / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D011073:Polyamines; D011809:Quinones; D014344:Trypanocidal Agents