TY  - 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://vinar.vin.bg.ac.rs/handle/123456789/12450
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.
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.",
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, 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 . .

TY  - CONF
AU  - Bondžić, Aleksandra
AU  - Jovanović, Dunja
AU  - Džambaski, Zdravko
AU  - Filipović, Ana
AU  - Bondžić, Bojan
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/12366
AB  - The goal of this work was to investigate the inhibitory potency of three derivates of 2- phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ) with different substituents at C3 and C4 positions, namely 65P,71P and 66P, toward two cholinergic enzymes, acetyl and butyrylcholinesterase. The screening test showed that only compound 65P possesses inhibition activity higher than 50 % at 10 μM concentration toward both enzymes. The inhibition potency obtained at 10 μM of THIQ was correlated with differences in THIQ’s structures in order to predict the structure-activity relationship. It was found that the introduction of the methoxy group at positions C3 and C4 led to decreased inhibition potency, while the removing of fluorine atom from the benzene ring increases selectivity toward acetylcholinesterase. The IC50 value gained during the evaluation of inhibition activity of 65P indicated strong inhibition potency of this compound, while Hill’s coefficient ~ 1 indicated the non-existence of cooperativity and one binding site on both enzymes clearly indicating that THIQ could be promising therapeutic drugs in the treatment of Alzheimer’s disease.
PB  - Belgrade : Society of Physical Chemists of Serbia
C3  - PHYSICAL CHEMISTRY 2022 : 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry : Book of abstracts
T1  - New derivates of 2-phenyl-1,2,3,4-tetrahydroizoquinoline as dual inhibitors of cholinergic enzymes
SP  - 170
EP  - 170
UR  - https://hdl.handle.net/21.15107/rcub_vinar_12366
ER  - 

@conference{
author = "Bondžić, Aleksandra and Jovanović, Dunja and Džambaski, Zdravko and Filipović, Ana and Bondžić, Bojan",
year = "2022",
abstract = "The goal of this work was to investigate the inhibitory potency of three derivates of 2- phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ) with different substituents at C3 and C4 positions, namely 65P,71P and 66P, toward two cholinergic enzymes, acetyl and butyrylcholinesterase. The screening test showed that only compound 65P possesses inhibition activity higher than 50 % at 10 μM concentration toward both enzymes. The inhibition potency obtained at 10 μM of THIQ was correlated with differences in THIQ’s structures in order to predict the structure-activity relationship. It was found that the introduction of the methoxy group at positions C3 and C4 led to decreased inhibition potency, while the removing of fluorine atom from the benzene ring increases selectivity toward acetylcholinesterase. The IC50 value gained during the evaluation of inhibition activity of 65P indicated strong inhibition potency of this compound, while Hill’s coefficient ~ 1 indicated the non-existence of cooperativity and one binding site on both enzymes clearly indicating that THIQ could be promising therapeutic drugs in the treatment of Alzheimer’s disease.",
publisher = "Belgrade : Society of Physical Chemists of Serbia",
journal = "PHYSICAL CHEMISTRY 2022 : 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry : Book of abstracts",
title = "New derivates of 2-phenyl-1,2,3,4-tetrahydroizoquinoline as dual inhibitors of cholinergic enzymes",
pages = "170-170",
url = "https://hdl.handle.net/21.15107/rcub_vinar_12366"
}

Bondžić, A., Jovanović, D., Džambaski, Z., Filipović, A.,& Bondžić, B.. (2022). New derivates of 2-phenyl-1,2,3,4-tetrahydroizoquinoline as dual inhibitors of cholinergic enzymes. in PHYSICAL CHEMISTRY 2022 : 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry : Book of abstracts
Belgrade : Society of Physical Chemists of Serbia., 170-170.
https://hdl.handle.net/21.15107/rcub_vinar_12366

Bondžić A, Jovanović D, Džambaski Z, Filipović A, Bondžić B. New derivates of 2-phenyl-1,2,3,4-tetrahydroizoquinoline as dual inhibitors of cholinergic enzymes. in PHYSICAL CHEMISTRY 2022 : 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry : Book of abstracts. 2022;:170-170.
https://hdl.handle.net/21.15107/rcub_vinar_12366 .

Bondžić, Aleksandra, Jovanović, Dunja, Džambaski, Zdravko, Filipović, Ana, Bondžić, Bojan, "New derivates of 2-phenyl-1,2,3,4-tetrahydroizoquinoline as dual inhibitors of cholinergic enzymes" in PHYSICAL CHEMISTRY 2022 : 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry : Book of abstracts (2022):170-170,
https://hdl.handle.net/21.15107/rcub_vinar_12366 .