title: New ferrocenic pyrrolo[1,2-a]quinoxaline derivatives: synthesis, and in vitro antimalarial activity.
abstract: Following our search for antimalarial compounds, novel series of ferrocenic pyrrolo[1,2-a]quinoxaline derivatives 1-2 were synthesized from various substituted nitroanilines and tested for in vitro activity upon the erythrocytic development of Plasmodiumfalciparum strains with different chloroquine-resistance status. The pyrrolo[1,2-a]quinoxalines 1 were prepared in 6-8 steps through a regioselective palladium-catalyzed monoamination by coupling 4-chloropyrrolo[1,2-a]quinoxalines with 1,3-bis(aminopropyl)piperazine or -methylamine using Xantphos as the ligand. The ferrocenic bispyrrolo[1,2-a]quinoxalines 2 were prepared by reductive amination of previously described bispyrrolo[1,2-a]quinoxalines 9 with ferrocene-carboxaldehyde, by treatment with NaHB(OAc)(3). The best results were observed with ferrocenic pyrrolo[1,2-a]quinoxalines linked by a bis(3-aminopropyl)piperazine. Moreover, it was observed that a methoxy group on the pyrrolo[1,2-a]quinoxaline nucleus and no substitution on the terminal N-ferrocenylmethylamine function enhanced the pharmacological activity. Selected compounds 1b, 1f-h, 1l and 2a were tested for their ability to inhibit beta-haematin formation, the synthetic equivalent of hemozoin, by using the HPIA (heme polymerization inhibitory activity) assay. Of the tested compounds, only 2a showed a beta-haematin formation inhibition, but no inhibition of haem polymerization was observed with the other selected ferrocenic monopyrrolo[1,2-a]quinoxaline derivatives 1b, 1f-h and 1l, as the IC(50) values were superior to 10 equivalents.
authors.affiliation: EA 4138-Pharmacochimie, UFR des Sciences Pharmaceutiques, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France. Jean.Guillon@chimphys.u-bordeaux2.fr
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.forename: Stéphane
authors.initials: S
authors.lastname: Moreau
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mouray
authors.forename: Véronique
authors.initials: V
authors.lastname: Sinou
authors.forename: Isabelle
authors.initials: I
authors.lastname: Forfar
authors.forename: Solene Belisle
authors.initials: SB
authors.lastname: Fabre
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.forename: Pascal
authors.initials: P
authors.lastname: Millet
authors.forename: Daniel
authors.initials: D
authors.lastname: Parzy
authors.forename: Christian
authors.initials: C
authors.lastname: Jarry
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005296:Ferrous Compounds / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D000075163:Metallocenes; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000962:Antimalarials; D005296:Ferrous Compounds; D000075163:Metallocenes; D011758:Pyrroles; D011810:Quinoxalines; C531444:pyrrolo(1,2-a)quinoxaline; C004998:ferrocene