title: Trypanocidal properties, structure-activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives.
abstract: Pyrazole and propenone quinoxaline derivatives were tested against intracellular forms of Leishmania peruviana and Trypanosoma cruzi. Both series were tested for toxicity against proliferative and non-proliferative cells. The pyrazole quinoxaline series was quite inactive against T. cruzi; however, the compound 2,6-dimethyl-3-f-quinoxaline 1,4-dioxide was found to inhibit 50% of Leishmania growth at 8.9 μM, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T. cruzi. Among these compounds, two were particularly interesting, (2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages; the latter was active against Leishmania and inactive against the other tested cells. Furthermore, insilico studies showed that both series respected Lipinski's rules and that they confirmed a linear correlation between trypanocidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.
authors.affiliation: Université de Toulouse, UPS, UMR 152 (Laboratoire de pharmacochimie des substances naturelles et pharmacophores redox), 118, rte de Narbonne, F-31062 Toulouse cedex 9, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Estevez
authors.forename: Miguel
authors.initials: M
authors.lastname: Quiliano
authors.forename: Asunción
authors.initials: A
authors.lastname: Burguete
authors.forename: Billy
authors.initials: B
authors.lastname: Cabanillas
authors.forename: Mirko
authors.initials: M
authors.lastname: Zimic
authors.forename: Edith
authors.initials: E
authors.lastname: Málaga
authors.forename: Manuela
authors.initials: M
authors.lastname: Verástegui
authors.forename: Silvia
authors.initials: S
authors.lastname: Pérez-Silanes
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aldana
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Denis
authors.initials: D
authors.lastname: Castillo
authors.forename: Eric
authors.initials: E
authors.lastname: Deharo
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D005260:Female; D007891:Leishmania / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014709:Vero Cells / Q000469:parasitology
chemical_list: D011810:Quinoxalines; D014344:Trypanocidal Agents; C003282:quindoxin