| Autor: |
Vamvoukaki G; Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, GR-26504 Patras, Greece., Antoniou AI; Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, GR-26504 Patras, Greece., Baltas M; CNRS, LCC (Laboratoire de Chimie, de Coordination), Université de Toulouse, UPS, INPT, 205 Route de Narbonne, BP 44099, CEDEX 4, F-31077 Toulouse, France., Mouray E; MCAM, UMR 7245, Muséum National d'Histoire Naturelle, CNRS, CP52, 63 rue Buffon, F-75005 Paris, France., Charneau S; MCAM, UMR 7245, Muséum National d'Histoire Naturelle, CNRS, CP52, 63 rue Buffon, F-75005 Paris, France.; Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasilia 70910-900, Brazil., Grellier P; MCAM, UMR 7245, Muséum National d'Histoire Naturelle, CNRS, CP52, 63 rue Buffon, F-75005 Paris, France., Athanassopoulos CM; Synthetic Organic Chemistry Laboratory, Department of Chemistry, University of Patras, GR-26504 Patras, Greece. |
| Abstrakt: |
The synthesis and antiplasmodial evaluation of new hybrids combining the pharmacophore structures of artemisinin, ciprofloxacin or norfloxacin, and 7-chloroquinoline are reported in this study. The first step for all of the syntheses is the obtainment of key piperazine esters intermediates bearing the drugs ciprofloxacin and norfloxacin. Using these platforms, 18 final compounds were synthesized through a multistep procedure with overall yields ranging between 8 and 20%. All compounds were screened for their antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum FcB1 strain. Compounds 20 , 21 , 22 , and 28 , bearing an artesunate fragment with ciprofloxacin, exhibited IC 50 values in the range of 3.5-5.4 nM and excellent selectivity indices. Among the compounds bearing the artesunate moiety on the norfloxacin, two of them, 23 and 24 , afforded IC 50 values of 1.5 nM and 1.9 nM, respectively. They also showed excellent selectivity indices. The most potent compounds were also evaluated against the CQ-resistant Dd2 strain of Plasmodium falciparum , demonstrating that those compounds incorporating the artesunate fragment were the most potent. Finally, the combination of artesunate with either ciprofloxacin or norfloxacin moieties in a single molecular entity proved to substantially enhance the activity and selectivity when compared to the administration of the unconjugated counterparts artesunate/ciprofloxacin and artesunate/norfloxacin. |
