Novel hybrid selenosulfonamides as potent antileishmanial agents.
Diselenide and sulfonamide derivatives have recently attracted considerable interest as leishmanicidal agents in drug discovery. In this study, a novel series of sixteen hybrid selenosulfonamides has been synthesized and screened for their in vitro activity against Leishmania infantum intracellular amastigotes and THP-1 cells. These assays revealed that most of the compounds exhibited antileishmanial activity in the low micromolar range and led us to identify three lead compounds (derivatives 2, 7 and 14) with IC50 values ranging from 0.83 to 1.47 μM and selectivity indexes (SI) over 17, much higher than those observed for the reference drugs miltefosine and edelfosine. When evaluated against intracellular amastigotes, hybrid compound 7 emerged as the most active compound (IC50 = 2.8 μM), showing higher activity and much less toxicity against THP-1 cells than edelfosine. These compounds could potentially serve as templates for future drug-optimization and drug-development efforts for their use as therapeutic agents in developing countries.
Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain; Instituto de Salud Tropical, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
Ylenia
Y
Baquedano
Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain; Instituto de Salud Tropical, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
Esther
E
Moreno
Instituto de Salud Tropical, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
Socorro
S
Espuelas
Instituto de Salud Tropical, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
Paul
P
Nguewa
Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain; Instituto de Salud Tropical, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
María
M
Font
Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Carretera Madrid-Barcelona km 33,600, E-28871 Alcalá de Henares, Madrid, Spain.
Kilian Jesús
KJ
Gutierrez
Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Carretera Madrid-Barcelona km 33,600, E-28871 Alcalá de Henares, Madrid, Spain.
Antonio
A
Jiménez-Ruiz
Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain; Instituto de Salud Tropical, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain. Electronic address: jpalop@unav.es.
Juan Antonio
JA
Palop
Departamento de Química Orgánica y Farmacéutica, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain; Instituto de Salud Tropical, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
Carmen
C
Sanmartín
D000981:Antiprotozoal Agents / Q000494:pharmacology*; D007893:Leishmania donovani / Q000187:drug effects*; D018314:Leishmania infantum / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D012643:Selenium / Q000737:chemistry*; D013449:Sulfonamides / Q000494:pharmacology*
D000981:Antiprotozoal Agents; D013449:Sulfonamides; D012643:Selenium
Diselenides; Leishmanicidal agents; Selenocompounds; Sulfonamides