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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Feb 25

PMID 36835023

Authors

Andrzej Bak

Jiri Kos

Gilles Degotte

Aleksandra Swietlicka

Tomas Strharsky

Dominika Pindjakova

Tomas Gonec

Adam Smolinski

Pierre Francotte

Michel Frederich

Violetta Kozik

Josef Jampilek

Affiliations

Soon will be listed here.

Abstract

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 3D7/MRA-102 highlighted that 23 compounds possessed IC < 30 µM. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2)--[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC = 1.6 µM was the most effective agent, while the other eight most active derivatives showed IC in the range from 1.8 to 4.6 µM. A good correlation between the experimental log 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 -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 -arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of -phenyl ring seems to play a key role in forming the halogen bonds.

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