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Synthesis and Antimalarial Activity of New Enantiopure Aminoalcoholpyrrolo[ 1,2-a]quinoxalines

[ Vol. 14 , Issue. 3 ]

Author(s):

Alexia Jonet, Jean Guillon, Catherine Mullie, Anita Cohen, Guillaume Bentzinger, Jeremy Schneider, Nicolas Taudon, Sebastien Hutter, Nadine Azas, Stephane Moreau, Solene Savrimoutou, Patrice Agnamey, Alexandra Dassonville-Klimpt and Pascal Sonnet*   Pages 293 - 303 ( 11 )

Abstract:


Background: We prepared a novel series of enantiopure mefloquine analogues with pyrrolo[ 1,2-a]quinoxaline core in order to fight Plasmodium falciparum resistant strain.

Objectives: To observe the influence of pyrrolo[1,2-a]quinoxaline core versus quinoline core on the antimalarial activity.

Method: Four enantiopure aminoalcoholpyrrolo[1,2-a]quinoxalines 2 were synthetized via Sharpless asymmetric dihydroxylation reaction in eight steps. Their antimalarial activity was evaluated on two Plasmodium falciparum strains 3D7 and W2 with a SYBR Green I fluorescence-based method and their cytotoxicity was measured on four cell lines HepG2, THP-1, CHO and HFF.

Results: IC50 values of the four compounds 2 were close to the micromolar against the two P. falciparum strains. They were more active against P. falciparum strain W2 vs. P. falciparum strain 3D7. (R)- enantiomers were always more active than their (S)-counterpart whatever the strain. Selectivity indexes of compounds 2 were lower than 100.

Conclusion: A novel series of enantiopure aminoalcohols with pyrrolo[1,2-a]quinoxaline core were synthesized in eight steps. They displayed IC50 values close to the micromolar against two P. falciparum strains 3D7 and W2. Although, In this series, 2,8-bistrifluoromethylquinoline was a best core than pyrrolo[1,2-a]quinoxaline for an optimal antimalarial activity, the pyrroloquinoxaline 2b showed an interesting antimalarial activity.

Keywords:

Antimalarial activity, asymmetric synthesis, aminoalcoholquinoline derivatives, aminoalcoholpyrrolo[1, 2- a]quinoxaline derivatives, in vitro cytotoxicity, HepG2.

Affiliation:

Universite de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, UFR de Pharmacie, Amiens, Universite de Bordeaux, Laboratoire ARNA, UFR des Sciences Pharmaceutiques, Bordeaux, Universite de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, UFR de Pharmacie, Amiens, Universite Aix-Marseille, Laboratoire de Parasitologie et Mycologie, UMR-MD3, Faculte de Pharmacie, Marseille, Universite de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, UFR de Pharmacie, Amiens, Universite de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, UFR de Pharmacie, Amiens, Institut de Recherche Biomedicale des Armees, Unite de Toxicologie Analytique, Bretigny-sur-Orge, Universite Aix-Marseille, Laboratoire de Parasitologie et Mycologie, UMR-MD3, Faculte de Pharmacie, Marseille, Universite Aix-Marseille, Laboratoire de Parasitologie et Mycologie, UMR-MD3, Faculte de Pharmacie, Marseille, Universite de Bordeaux, Laboratoire ARNA, UFR des Sciences Pharmaceutiques, Bordeaux, Universite de Bordeaux, Laboratoire ARNA, UFR des Sciences Pharmaceutiques, Bordeaux, Universite de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, UFR de Pharmacie, Amiens, Universite de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, UFR de Pharmacie, Amiens, Universite de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, UFR de Pharmacie, Amiens

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