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 IC50 from 0.58 to 31 µM, whereas (2E)-N-(4-bromo-2-chlorophenyl)-3-phenylprop-2-enamide (24) was the most effective agent (IC50 = 0.58 µM). In addition, (2E)-N-[2,6-dibromo-4-(trifluoromethyl)- phenyl]-3-phenylprop-2-enamide (36), (2E)-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-phenylprop- 2-enamide (18), (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide (23), and (2E)-3-phenyl-N-(3,4,5-trichlorophenyl)prop-2-enamide (33) 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 Plasmodium selective substances for further investigations.

Department of Analytical Chemistry Faculty of Natural Sciences Comenius University Ilkovicova 6 84215 Bratislava Slovakia

Department of Biochemistry Faculty of Medicine Masaryk University Kamenice 5 62500 Brno Czech Republic

Department of Chemical Biology Faculty of Science Palacky University Olomouc Slechtitelu 27 78371 Olomouc Czech Republic

Department of Chemical Drugs Faculty of Pharmacy Masaryk University Palackeho 1946 1 61200 Brno Czech Republic

I2BM Department of Molecular Chemistry University Grenoble Alpes Rue de la Chimie 570 38610 Gieres France

Laboratory of Medicinal Chemistry CIRM Department of Pharmacy University of Liege Avenue Hippocrate 15 4000 Liege Belgium

Laboratory of Pharmacognosy CIRM Department of Pharmacy University of Liege Avenue Hippocrate 15 4000 Liege Belgium

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Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides

Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections