Insights into Antimalarial Activity of N -Phenyl-Substituted Cinnamanilides.

Due to the urgent need of innovation in the antimalarial therapeutic arsenal, a series of thirty-seven ring-substituted N -arylcinnamanilides prepared by microwave-assisted synthesis were subjected to primary screening against the chloroquine-sensitive strain of P. falciparum 3D7/MRA-102. The lipophilicity of all compounds was experimentally determined as the logarithm of the capacity factor k , and these data were subsequently used in the discussion of structure-activity relationships. Among the screened compounds, fourteen derivatives exhibited IC 50 from 0.58 to 31 µM, whereas (2 E )- N -(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide ( 24 ) was the most effective agent (IC 50 = 0.58 µM). In addition, (2 E )- N -[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide ( 36 ), (2 E )- N -[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide ( 18 ), (2 E )- N -(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide ( 23 ), and (2 E )-3-phenyl- N -(3,4,5-trichlorophenyl)prop-2-enamide ( 33 ) demonstrated efficacy in the IC 50 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 Plasmodium selective substances for further investigations.