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 Plasmodium falciparum 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. (2E)-N-[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 logk 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 N-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 N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.

Department of Analytical Chemistry Faculty of Natural Sciences Comenius University Ilkovicova 6 842 15 Bratislava Slovakia

Department of Biochemistry Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

Department of Chemical Drugs Faculty of Pharmacy Masaryk University Palackeho 1946 1 612 00 Brno Czech Republic

GiG Research Institute Pl Gwarkow 1 40 166 Katowice Poland

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

Institute of Chemistry University of Silesia Szkolna 9 40 007 Katowice Poland

Institute of Neuroimmunology Slovak Academy of Sciences Dubravska cesta 9 845 10 Bratislava Slovakia

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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