Abstract
A new class of compounds comprising two series of chalcones with 2,2,2-trifluoroethoxy group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay. Chalcones with 2,2,2-trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl ring showed weak antiplasmodial activity, while compounds substituted on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the 34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC50 values of 3.0 μg/mL and 2.2 μg/mL, respectively. Moreover, these compounds 3a and 3f showed profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules, 3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2-trifluoroethoxychalcones (Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future further development.
Highlights
Chalcones (1,3-diaryl-2-propen-1-ones), or α,β-unsaturated carbonyl compounds, the bioprecursors of flavonoids, are an interesting class of compounds that engross medicinal [1,2], synthetic [3], and material chemists [4,5,6] with their diverse applications
Our result reveals that 2-fluoroethoxy substitution in chalcone derivatives are more effective than 2,2,2-trifluoroethoxy substitution, irrespective of the position, in inhibition of plasmodial growth
We have reported the synthesis of a series of 2,2,2-trifluoroethoxy- and
Summary
Chalcones (1,3-diaryl-2-propen-1-ones), or α,β-unsaturated carbonyl compounds, the bioprecursors of flavonoids, are an interesting class of compounds that engross medicinal [1,2], synthetic [3], and material chemists [4,5,6] with their diverse applications. Radiolabeled chalcones have been used as PET imaging agents for in vivo imaging of the β-amyloid plaques of Alzheimer’s disease [17,18]. After the advent of licochalcone A with its antiplasmodial activity [19], a large number ofnovel synthetic chalcone derivatives and chalcone hybrids have been designed, synthesized and evaluated for their antiplasmodial activity [20,21,22,23,24]. Malaria is a parasitic disease caused by Plasmodium, which is transmitted to human by female anopheline mosquitoes and continues to be a major cause of the death, killing an estimated 1.5 to Several reports suggest that chalcones’ antiplasmodial potential is due the ability to inhibit both the plasmodial aspartate protease and cysteine protease targets [24,25].
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