title: Glycosylated metal chelators as anti-parasitic agents with tunable selectivity.
abstract: Trypanosoma cruzi and Leishmania amazonensis are the causative agents of Chagas' disease and leishmaniasis, respectively. These conditions affect millions of people worldwide, especially in developing countries. As such, there is an urgent need for novel, efficient and cost-effective treatments for these diseases, given the growing resistance and side-effects of current therapies. This work details the synthesis and evaluation of the anti-parasitic activity of novel amino- and iminopyridyl metal chelators, their glycosylated derivatives and some of their metal complexes. Our results revealed the potent and metal-dependent activity for the aminopyridyl compounds: Cu(ii) complexes were most effective against T. cruzi trypomastigotes, while Zn(ii) complexes presented excellent activity against L. amazonensis promastigotes. In addition, the compounds showed excellent selectivity indexes and very low relative toxicity as judged by in vitro and in vivo studies, respectively, using RAW macrophages and Galleria mellonella larvae model.
authors.affiliation: Department of Chemistry, Maynooth University, Maynooth, Co. Kildare, Ireland. trinidad.velascotorrijos@nuim.ie.
authors.forename: Andrew
authors.initials: A
authors.lastname: Reddy
authors.forename: Leandro Stefano
authors.initials: LS
authors.lastname: Sangenito
authors.forename: Arthur de Azevedo
authors.initials: AA
authors.lastname: Guedes
authors.forename: Marta Helena
authors.initials: MH
authors.lastname: Branquinha
authors.forename: Kevin
authors.initials: K
authors.lastname: Kavanagh
authors.forename: John
authors.initials: J
authors.lastname: McGinley
authors.forename: André Luis Souza
authors.initials: ALS
authors.lastname: Dos Santos
authors.forename: Trinidad
authors.initials: T
authors.lastname: Velasco-Torrijos
mesh_terms: D000631:Aminopyridines / Q000737:chemistry; D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007814:Larva / Q000187:drug effects; D007891:Leishmania / Q000187:drug effects*; D051379:Mice; D009036:Moths; D000067996:RAW 264.7 Cells; D012680:Sensitivity and Specificity; D014349:Trypanosoma cruzi / Q000187:drug effects*; D015032:Zinc / Q000737:chemistry
chemical_list: D000631:Aminopyridines; D000977:Antiparasitic Agents; D002614:Chelating Agents; D003300:Copper; D015032:Zinc