title: Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents.
abstract: A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 μM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3'-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Baquedano
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Alcolea
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Madrid, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Toro
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Madrid, Spain.
authors.forename: Killian Jesús
authors.initials: KJ
authors.lastname: Gutiérrez
authors.affiliation: Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
authors.forename: Paul
authors.initials: P
authors.lastname: Nguewa
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Font
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
authors.forename: Socorro
authors.initials: S
authors.lastname: Espuelas
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jiménez-Ruiz
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Palop
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Plano
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, University of Navarra, Pamplona, Spain Instituto de Salud Tropical, University of Navarra, Pamplona, Spain sanmartin@unav.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartín
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D003485:Cyanates / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D018314:Leishmania infantum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018036:Selenium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D003485:Cyanates; D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D015800:Protozoan Proteins; D018036:Selenium Compounds; D013876:Thiophenes; C053721:selenocyanic acid; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase