Publication details

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

Authors

BAK Andrzej KOS Jiří DEGOTTE Gilles SWIETLICKA Aleksandra STRHÁRSKY Tomáš PINDJAKOVA Dominika GONĚC Tomáš SMOLINSKI Adam FRANCOTTE Pierre FREDERICH Michel KOZIK Violetta JAMPÍLEK Josef

Year of publication 2023
Type Article in Periodical
Magazine / Source International Journal of Molecular Sciences
MU Faculty or unit

Faculty of Medicine

Citation
Web https://www.mdpi.com/1422-0067/24/4/3611
Doi http://dx.doi.org/10.3390/ijms24043611
Keywords arginase inhibition; arylcinnamamides; lipophilicity; CoMSA; molecular docking; similarity-activity landscape index
Description 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 mu M. 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 mu M was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 mu M. 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.

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