title: Leishmanicidal activities of novel methylseleno-imidocarbamates.
abstract: The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives stand out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations, and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug similarity parameters, we observed that two of them, called compounds 2b [methyl-N,N'-di(thien-2-ylcarbonyl)-imidoselenocarbamate] and 4b [methyl-N,N'-di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate], exhibit low 50% inhibitory concentrations (IC50s) (<3 μM) and good selectivity indexes (SIs) (>5) in Leishmania major promastigotes and lack toxicity on macrophages. In addition, in analysis of their therapeutic potential against L. major in vitro infection, both compounds display a dramatic reduction of amastigote burden (∼80%) with sublethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for defense against intracellular pathogens. Compounds 2b and 4b were demonstrated to cause cell cycle arrest in G1. Interestingly, evaluation of expression of genes related to proliferation (PCNA), treatment resistance (ABC transporter and alpha-tubulin), and virulence (quinonoid dihydropteridine reductase [QDPR]) showed several alterations in gene expression profiling. All these results prompt us to propose both compounds as candidates to treat leishmanial infections.
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Department of Microbiology and Parasitology, University of Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Fernández-Rubio
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Department of Microbiology and Parasitology, University of Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Daphne
authors.initials: D
authors.lastname: Campbell
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Department of Microbiology and Parasitology, University of Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Vacas
authors.affiliation: Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Ibañez
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Pharmacy and Pharmaceutical Technology Department, University of Navarra, Pamplona, Spain.
authors.forename: Socorro
authors.initials: S
authors.lastname: Espuelas
authors.affiliation: Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Organic and Pharmaceutical Chemistry Department, University of Navarra, Pamplona, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Palop
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Organic and Pharmaceutical Chemistry Department, University of Navarra, Pamplona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Plano
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Organic and Pharmaceutical Chemistry Department, University of Navarra, Pamplona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartin
authors.affiliation: Instituto de Salud Tropical (ISTUN), University of Navarra, Pamplona, Spain Department of Microbiology and Parasitology, University of Navarra, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain panguewa@unav.es.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Nguewa
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D002460:Cell Line; D018320:Leishmania major / Q000187:drug effects* / Q000472:pathogenicity*; D007896:Leishmaniasis / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D009569:Nitric Oxide