title: Effective anti-leishmanial activity of minimalist squaramide-based compounds.
abstract: In order to evaluate the in vitro leishmanicidal activity of N,N'-Squaramides derivatives, compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites, against Leishmania infantum, Leishmania braziliensis and Leishmania donovani a series of 18compounds was prepared and assayed on extracellular and intracellular parasite forms. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. Changes in metabolite excretion by1H-NMR and the ultrastructural alterations occurring in the parasites treated using transmission electron microscopy (TEM), was analyzed. Compounds 1, 7, 11, 14 and 17 were the more active and less toxic. Infection rates showed that the order of effectiveness was 17 > 11 > 14 > 7 for both L. infantum and L. braziliensis and in the same way, the compound 1 for L. donovani. All these compounds have altered the typical structure of the promastigotes, glycosomes and mitochondria. These severe modifications by the compounds are the ultimate reasons for the alterations observed in the excretion products. The Squaramide 17 (3-(butylamino)-4-((3-(dimetilamino)propyl)(methyl)amino)cyclobut-3-en-1,2-dione) was clearly the most efficient of all compounds. The data appear to confirm that the severe modifications generated in organelles such as glycosomes or mitochondria by the compounds are the ultimate reasons for the alterations observed in the excretion products of all species. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-leishmanial agent.
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.affiliation: Department of Chemistry, Universitat de les Illes Balears, E- 07122 Palma de Mallorca, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ximenis
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ramirez-Macías
authors.affiliation: Department of Chemistry, Universitat de les Illes Balears, E- 07122 Palma de Mallorca, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rotger
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Kristina
authors.initials: K
authors.lastname: Urbanova
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Olmo
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Martín-Escolano
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Rosales
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Cañas
authors.affiliation: Departamento de Estadística, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Gutierrez-Sánchez
authors.affiliation: Department of Chemistry, Universitat de les Illes Balears, E- 07122 Palma de Mallorca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Costa
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/Universidad de Granada, Granada, Spain. Electronic address: msanchem@ugr.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
mesh_terms: D000818:Animals; D002460:Cell Line; D005434:Flow Cytometry; D020128:Inhibitory Concentration 50; D007892:Leishmania braziliensis / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018314:Leishmania infantum / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D011803:Quinine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: C000609819:squaramide; D011803:Quinine
keywords: L. braziliensis; L. donovani; Leishmania infantum; Metabolite excretion; Squaramides; Ultrastructural alterations