[(7-chloroquinolin-4-yl)amino]acetophenones and their copper(II) derivatives: Synthesis, characterization, computational studies and antimalarial activity

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Yonathan de Jesús Parra
Felix D Andueza L
Rosa E Ferrer M
Julia Bruno Colmenarez
María E Acosta
Jaime Charris
Philip J Rosenthal
Jiri Gut

Abstract

The synthesis of the compounds [(7-chloroquinolin-4-yl)amino]acetophenones (4, 5) and their copper(II) complexes (4a, 5a) is reported. The compounds were characterized using a wide range of spectroscopic and spectrometric techniques, such as FTIR, UV-vis, NMR, EPR, ESI-CID-MS2. The spectral results suggested that the ligand acted as chelating species coordinating the metal through the endocyclic nitrogen of the quinoline ring in both complexes, with general formulae expressed in two ways, according to the phase in which they are: [Cu(L)2Cl2] for solid phase and [Cu(L)2][2Cl] for liquid phase. The EPR study of the Cu (II) complexes indicated a probable distorted tetrahedral coordination geometry. This result was confirmed by the calculated optimized structures at the DFT/B3LYP method with the 6-31G (d,p) basis set. The characterization of the fragmentation pattern of protonated free ligands was extended here to fragments as low as m/z 43, while for coordination complexes it extends to fragments at m/z 80 and m/z 111. The antimalarial activity of the compounds was determined through three different tests: inhibitory activity against in vitro growth of Plasmodium falciparum (W2), inhibition of hemozoin formation (β-hematin) and in vitro inhibitory activity against recombinant falcipain-2, where compound 5 showed considerable activity. However, the activity of free ligands against P. falciparum was increased by complexing with the Cu (II) metal ion. The values of the HOMO-LUMO energy gap of 3.847 eV (4a) and 3.932 eV (5a) were interpreted with high chemical activity and thus, could influence on biological activity. In both compounds, the total electron density surface mapped with electrostatic potential clearly revealed the presence of high negative charge on the Cu atom. Also, this study reported the molecular docking of free ligands (4, 5) using software package ArgusLab 4.0.1. The results revealed the importance of water molecules as interaction bridges through hydrogen bonds between free ligands and β-hematin; at the same time, the hypothesis that π–π interaction between quinoline derivatives and the electronic system of hematin governs the formation of adducts was confirmed.

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How to Cite
Parra, Y., Andueza L, F., Ferrer M, R., Bruno Colmenarez, J., Acosta, M., Charris, J., Rosenthal, P., & Gut, J. (2019). [(7-chloroquinolin-4-yl)amino]acetophenones and their copper(II) derivatives: Synthesis, characterization, computational studies and antimalarial activity. EXCLI Journal, 18, 962-987. https://doi.org/10.17179/excli2019-1805
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Original articles