| Autor: |
Jovanović D; Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia., Filipović A; Institute of Chemistry, Technology and Metallurgy, National Institute of the Republic of Serbia, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia., Janjić G; Institute of Chemistry, Technology and Metallurgy, National Institute of the Republic of Serbia, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia., Lazarević-Pašti T; Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia., Džambaski Z; Institute of Chemistry, Technology and Metallurgy, National Institute of the Republic of Serbia, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia., Bondžić BP; Institute of Chemistry, Technology and Metallurgy, National Institute of the Republic of Serbia, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia., Bondžić AM; Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia. |
| Abstrakt: |
We have synthesized 22 C-1 functionalized- N -aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. All synthesized derivates were divided into four groups based on the substituents in the C-1 position, and their inhibition potencies towards two cholinergic enzymes, acetyl- and butyrylcholinesterase were evaluated. Most potent derivatives were selected, and kinetic analysis was further carried out to obtain insights into the mechanisms of inhibition of these two enzymes. Further validation of the mode of inhibition of cholinergic enzymes by the two most potent THIQ compounds, 3c and 3i , was performed using fluorescence-quenching titration studies. Molecular docking studies further confirmed the proposed mechanism of enzymes' inhibition. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the selected most potent derivatives were performed using Swiss ADME tool. This was followed by UPLC-assisted log P determination and in vitro BBB permeability studies performed in order to assess the potential of the synthesized compounds to pass the BBB. |
