title: New hydrazine and hydrazide quinoxaline 1,4-di-N-oxide derivatives: In silico ADMET, antiplasmodial and antileishmanial activity.
abstract: We report the design (in silico ADMET criteria), synthesis, cytotoxicity studies (HepG-2 cells), and biological evaluation of 15 hydrazine/hydrazide quinoxaline 1,4-di-N-oxide derivatives against the 3D7 chloroquine sensitive strain and FCR-3 multidrug resistant strain of Plasmodium falciparum and Leishmania infantum (axenic amastigotes). Fourteen of derivatives are novel quinoxaline 1,4-di-N-oxide derivatives. Compounds 18 (3D7 IC50=1.40μM, FCR-3 IC50=2.56μM) and 19 (3D7 IC50=0.24μM, FCR-3 IC50=2.8μM) were identified as the most active against P. falciparum, and they were the least cytotoxic (CC50-values>241μM) and most selective (SI>86). None of the compounds tested against L. infantum were considered to be active. Additionally, the functional role of the hydrazine and hydrazide structures were studied in the quinoxaline 1,4-di-N-oxide system.
authors.affiliation: Universidad de Navarra, Institute of Tropical Health (ISTUN), Campus Universitario, 31008 Pamplona, Spain; Universidad de Navarra, Facultad de Farmacia y Nutrición, Department of Organic and Pharmaceutical Chemistry, Campus Universitario, 31008 Pamplona, Spain. Electronic address: mquiliano@alumni.unav.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quiliano
authors.affiliation: Malaria Group, Universidad de Antioquía, Medellín 1226, Colombia.
authors.forename: Adriana
authors.initials: A
authors.lastname: Pabón
authors.affiliation: Malaria Group, Universidad de Antioquía, Medellín 1226, Colombia.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ramirez-Calderon
authors.affiliation: Universidad de Navarra, Facultad de Farmacia y Nutrición, Department of Organic and Pharmaceutical Chemistry, Campus Universitario, 31008 Pamplona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Barea
authors.affiliation: Institut de Recherche pour le Développement (IRD), Université Paul Sabatier Toulouse III, UMR 152 PHARMA-DEV, 31059 Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deharo
authors.affiliation: Universidad de Navarra, Institute of Tropical Health (ISTUN), Campus Universitario, 31008 Pamplona, Spain; Universidad de Navarra, Facultad de Farmacia y Nutrición, Department of Organic and Pharmaceutical Chemistry, Campus Universitario, 31008 Pamplona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Galiano
authors.affiliation: Universidad de Navarra, Institute of Tropical Health (ISTUN), Campus Universitario, 31008 Pamplona, Spain; Universidad de Navarra, Facultad de Farmacia y Nutrición, Department of Organic and Pharmaceutical Chemistry, Campus Universitario, 31008 Pamplona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aldana
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D018314:Leishmania infantum / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D006834:Hydrazines; D011810:Quinoxalines; C003282:quindoxin
keywords: Hydrazide; Hydrazine; Leishmaniasis; Malaria; Quinoxaline 1,4-di-N-oxide