Inorganic Chemistry; Organic Chemistry; Physical and Theoretical Chemistry; Computer Science Applications; Spectroscopy; Molecular Biology; General Medicine; Catalysis
Abstract :
[en] 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.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Bak, Andrzej ; Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland
Kos, Jiri ; Department of Biochemistry, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic ; Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia
Degotte, Gilles ; Université de Liège - ULiège > Université de Liège - ULiège ; I2BM, Department of Molecular Chemistry, University Grenoble-Alpes, Rue de la Chimie 570, 38610 Gieres, France
Swietlicka, Aleksandra; Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland
Strharsky, Tomas ; Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho 1946/1, 612 00 Brno, Czech Republic
Pindjakova, Dominika; Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia
Gonec, Tomas ; Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho 1946/1, 612 00 Brno, Czech Republic
Smolinski, Adam ; GiG Research Institute, Pl. Gwarkow 1, 40-166 Katowice, Poland
Francotte, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Frederich, Michel ; Université de Liège - ULiège > Département de pharmacie > Pharmacognosie
Kozik, Violetta; Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland
Jampilek, Josef ; Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia ; Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 845 10 Bratislava, Slovakia
Language :
English
Title :
Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides
Fondation Léon Fredericq [BE] Comenius University Bratislava [SK] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Funding text :
This work was supported by the Fondation Léon Frédéricq, FRS-FNRS (FC23283), and by the Operation Program of Integrated Infrastructure for the project, UpScale of Comenius University Capacities and Competence in Research, Development and Innovation, ITMS2014+: 313021BUZ3, co-financed by the European Regional Development Fund.
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