Synthesis and in vitro evaluation of 4-trichloromethylpyrrolo[1,2-a]quinoxalines as new antiplasmodial agents
Résumé
Thanks to a preliminary in vitro screening of several CCl 3-substituted-nitrogen containing heterocycles belonging to our chemical library, the 2-trichloromethylquinoxaline scaffold appeared to be of potential interest for developing new antiplasmodial agents. Then, combining these experimental results to the antimalarial properties reported for variouspyrrolo[1,2-a]quinoxaline derivatives, an original series of fifteen 7-substituted-4-trichoromethylpyrrolo[1,2-a]quinoxalines was synthesized in a 4 to 5 reaction steps pathway. All molecules were evaluated in vitro toward both their antiplasmodial activity on the K1 multi-resistant P. falciparum strain and their cytotoxicity on the HepG2 human cell line. Thus, 3 hit molecules were identified, displaying IC 50 values in the micromolar range and low cytotoxicity values, reaching good selectivity indexes, in comparison with the reference drugs chloroquine and doxycycline. Structure-activity relationship studies showed that the pyrrolo[1,2-a]quinoxaline scaffold can support selective antiplasmodial activity when substituted at position 4 by a CCl 3 group. However, substitution at position 7 of the same scaffold is neither beneficial for cytotoxicity nor favorable for the solubility in the biological media.
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