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A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of <i>Plasmodium falciparum</i> 3D7/MRA-102 highlighted that 23 compounds possessed IC₅₀ < 30 µM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2<i>E</i>)-<i>N</i>-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC₅₀ = 1.6 µM was the most effective agent, while the other eight most active derivatives showed IC₅₀ in the range from 1.8 to 4.6 µM. A good correlation between the experimental log<i>k</i> and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated <i>N</i>-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an ‘averaged’ selection-driven interaction pattern was produced based in namely ‘pseudo–consensus’ 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new <i>N</i>-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of <i>N</i>-phenyl ring seems to play a key role in forming the halogen bonds.