Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates
Autori
Jovanović, DunjaFilipović, Ana
Janjić, Goran
Lazarević-Pašti, Tamara
Džambaski, Zdravko
Bondžić, Bojan
Bondžić, Aleksandra
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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 pro...posed 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.
Ključne reči:
tetrahydroisoquinolines / acetylcholinesterase / butyrylcholinesterase / Alzheimer’s diseaseIzvor:
International Journal of Molecular Sciences, 2024, 25, 2, 1033-Izdavač:
- MDPI
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200017 (Univerzitet u Beogradu, Institut za nuklearne nauke Vinča, Beograd-Vinča) (RS-MESTD-inst-2020-200017)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200026 (Univerzitet u Beogradu, Institut za hemiju, tehnologiju i metalurgiju - IHTM) (RS-MESTD-inst-2020-200026)
Institucija/grupa
IHTMTY - JOUR AU - Jovanović, Dunja AU - Filipović, Ana AU - Janjić, Goran AU - Lazarević-Pašti, Tamara AU - Džambaski, Zdravko AU - Bondžić, Bojan AU - Bondžić, Aleksandra PY - 2024 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/7423 AB - 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. PB - MDPI T2 - International Journal of Molecular Sciences T1 - Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates VL - 25 IS - 2 SP - 1033 DO - 10.3390/ijms25021033 ER -
@article{ author = "Jovanović, Dunja and Filipović, Ana and Janjić, Goran and Lazarević-Pašti, Tamara and Džambaski, Zdravko and Bondžić, Bojan and Bondžić, Aleksandra", year = "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.", publisher = "MDPI", journal = "International Journal of Molecular Sciences", title = "Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates", volume = "25", number = "2", pages = "1033", doi = "10.3390/ijms25021033" }
Jovanović, D., Filipović, A., Janjić, G., Lazarević-Pašti, T., Džambaski, Z., Bondžić, B.,& Bondžić, A.. (2024). Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates. in International Journal of Molecular Sciences MDPI., 25(2), 1033. https://doi.org/10.3390/ijms25021033
Jovanović D, Filipović A, Janjić G, Lazarević-Pašti T, Džambaski Z, Bondžić B, Bondžić A. Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates. in International Journal of Molecular Sciences. 2024;25(2):1033. doi:10.3390/ijms25021033 .
Jovanović, Dunja, Filipović, Ana, Janjić, Goran, Lazarević-Pašti, Tamara, Džambaski, Zdravko, Bondžić, Bojan, Bondžić, Aleksandra, "Targeting Alzheimer’s Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates" in International Journal of Molecular Sciences, 25, no. 2 (2024):1033, https://doi.org/10.3390/ijms25021033 . .