Jovanovic_2024_Int.J.Mol.Sci_25_

Reference

Title : Targeting Alzheimer's Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates - Jovanovic_2024_Int.J.Mol.Sci_25_
Author(s) : Jovanovic D , Filipovic A , Janjic G , Lazarevic-Pasti T , Dzambaski Z , Bondzic BP , Bondzic AM
Ref : Int J Mol Sci , 25 : , 2024
Abstract :

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.

PubMedSearch : Jovanovic_2024_Int.J.Mol.Sci_25_
PubMedID: 38256107

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Citations formats

Jovanovic D, Filipovic A, Janjic G, Lazarevic-Pasti T, Dzambaski Z, Bondzic BP, Bondzic AM (2024)
Targeting Alzheimer's Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates
Int J Mol Sci 25 :

Jovanovic D, Filipovic A, Janjic G, Lazarevic-Pasti T, Dzambaski Z, Bondzic BP, Bondzic AM (2024)
Int J Mol Sci 25 :