title: Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives.
abstract: Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC50in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.affiliation: c UMR-MD3, Faculty of Pharmacy , Aix-Marseille University, Laboratory of Parasitology , Marseille , France.
authors.forename: Anita
authors.initials: A
authors.lastname: Cohen
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Nassima Meriem
authors.initials: NM
authors.lastname: Gueddouda
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Rabindra Nath
authors.initials: RN
authors.lastname: Das
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Moreau
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ronga
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Solène
authors.initials: S
authors.lastname: Savrimoutou
authors.affiliation: c UMR-MD3, Faculty of Pharmacy , Aix-Marseille University, Laboratory of Parasitology , Marseille , France.
authors.forename: Louise
authors.initials: L
authors.lastname: Basmaciyan
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Alix
authors.initials: A
authors.lastname: Monnier
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Monget
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rubio
authors.affiliation: d Université de Picardie Jules Verne, Laboratoire de Glycochimie , des Antimicrobiens et des Agroressouces, UMR CNRS 7378, UFR de Pharmacie , Amiens , France.
authors.forename: Timothée
authors.initials: T
authors.lastname: Garnerin
authors.affiliation: c UMR-MD3, Faculty of Pharmacy , Aix-Marseille University, Laboratory of Parasitology , Marseille , France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Azas
authors.affiliation: a ARNA Laboratory , University Bordeaux, UFR des Sciences Pharmaceutiques , Bordeaux , France.|b INSERM U1212, UMR CNRS 5320, ARNA Laboratory , Bordeaux , France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.affiliation: d Université de Picardie Jules Verne, Laboratoire de Glycochimie , des Antimicrobiens et des Agroressouces, UMR CNRS 7378, UFR de Pharmacie , Amiens , France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mullié
authors.affiliation: d Université de Picardie Jules Verne, Laboratoire de Glycochimie , des Antimicrobiens et des Agroressouces, UMR CNRS 7378, UFR de Pharmacie , Amiens , France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D011437:Propylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D011437:Propylamines; D011810:Quinoxalines; C000614355:bis(N-((pyrrolo(1,2-a)quinoxalin-4-yl)benzyl)-3-aminopropyl)amine
keywords: Antimalarial activity; G-quadruplex; Plasmodium falciparum; antileishmanial activity; bis-pyrrolo[1,2-a]quinoxaline