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Due to the urgent need of innovation in the antimalarial therapeutic arsenal, a series of thirty-seven ring-substituted <i>N</i>-arylcinnamanilides prepared by microwave-assisted synthesis were subjected to primary screening against the chloroquine-sensitive strain of <i>P. falciparum</i> 3D7/MRA-102. The lipophilicity of all compounds was experimentally determined as the logarithm of the capacity factor <i>k</i>, and these data were subsequently used in the discussion of structure-activity relationships. Among the screened compounds, fourteen derivatives exhibited IC₅₀ from 0.58 to 31 µM, whereas (2<i>E</i>)-<i>N</i>-(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide (<b>24</b>) was the most effective agent (IC₅₀ = 0.58 µM). In addition, (2<i>E</i>)-<i>N</i>-[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide (<b>36</b>), (2<i>E</i>)-<i>N</i>-[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide (<b>18</b>), (2<i>E</i>)-<i>N</i>-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide (<b>23</b>), and (2<i>E</i>)-3-phenyl-<i>N</i>-(3,4,5-trichlorophenyl)prop-2-enamide (<b>33</b>) demonstrated efficacy in the IC₅₀ range from 2.0 to 4.3 µM, comparable to the clinically used standard chloroquine. The results of a cell viability screening performed using THP1-Blue™ NF-κB cells showed that none of these highly active compounds displayed any significant cytotoxic effect up to 20 μM, which makes them promising <i>Plasmodium</i> selective substances for further investigations.