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

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, Pascal Sonnet*.

Journal Name: Medicinal Chemistry

Volume 14 , Issue 3 , 2018

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Graphical 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.

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Article Details

Year: 2018
Page: [293 - 303]
Pages: 11
DOI: 10.2174/1573406413666170726123938
Price: $65

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