Jonet Alexia, Guillon Jean, Mullie Catherine, Cohen Anita, Bentzinger Guillaume, Schneider Jeremy, Taudon Nicolas, Hutter Sebastien, Azas Nadine, Moreau Stephane, Savrimoutou Solene, Agnamey Patrice, Dassonville-Klimpt Alexandra, Sonnet Pascal
Universite de Picardie Jules Verne, Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, UFR de Pharmacie, Amiens, France.
Universite de Bordeaux, Laboratoire ARNA, UFR des Sciences Pharmaceutiques, Bordeaux, France.
Med Chem. 2018;14(3):293-303. doi: 10.2174/1573406413666170726123938.
We prepared a novel series of enantiopure mefloquine analogues with pyrrolo[ 1,2-a]quinoxaline core in order to fight Plasmodium falciparum resistant strain.
To observe the influence of pyrrolo[1,2-a]quinoxaline core versus quinoline core on the antimalarial activity.
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.
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.
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.
我们制备了一系列以吡咯并[1,2-a]喹喔啉为核心的新型对映体纯甲氟喹类似物，以对抗恶性疟原虫耐药菌株。
观察吡咯并[1,2-a]喹喔啉核心与喹啉核心对抗疟活性的影响。
通过夏普莱斯不对称双羟基化反应，分八步合成了四种对映体纯氨基醇吡咯并[1,2-a]喹喔啉2。采用基于SYBR Green I荧光的方法，在两种恶性疟原虫菌株3D7和W2上评估了它们的抗疟活性，并在四种细胞系HepG2、THP-1、CHO和HFF上测定了它们的细胞毒性。
四种化合物2对两种恶性疟原虫菌株的IC50值接近微摩尔级。它们对恶性疟原虫W2菌株的活性比对恶性疟原虫3D7菌株的活性更高。无论哪种菌株，(R)-对映体总是比其(S)-对应体更具活性。化合物2的选择性指数低于100。
通过八步合成了一系列新型的以吡咯并[1,2-a]喹喔啉为核心的对映体纯氨基醇。它们对两种恶性疟原虫菌株3D7和W2的IC50值接近微摩尔级。尽管在该系列中，2,8-双三氟甲基喹啉对于最佳抗疟活性而言是比吡咯并[1,2-a]喹喔啉更好的核心，但吡咯并喹喔啉2b显示出有趣的抗疟活性。
