TY  - JOUR
AU  - Matošević, Ana
AU  - Opsenica, Dejan
AU  - Spasić, Marta
AU  - Maraković, Nikola
AU  - Zandona, Antonio
AU  - Žunec, Suzana
AU  - Bartolić, Marija
AU  - Kovarik, Zrinka
AU  - Bosak, Anita
PY  - 2023
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/7159
AB  - The most successful therapeutic strategy in the treatment of Alzheimer's disease (AD) is directed toward increasing levels of the neurotransmitter acetylcholine (ACh) by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes responsible for its hydrolysis. In this paper, we extended our study on 4-aminoquinolines as human cholinesterase inhibitors on twenty-six new 4-aminoquinolines containing an n-octylamino spacer on C(4) and different substituents on the terminal amino group. We evaluated the potency of new derivatives to act as multi-targeted ligands by determining their inhibition potency towards human AChE and BChE, ability to chelate biometals Fe, Cu and Zn, ability to inhibit the action of β-secretase 1 (BACE1) and their antioxidant capacity. All of the tested derivatives were very potent inhibitors of human AChE and BChE with inhibition constants (Ki) ranging from 0.0023 to 1.6 μM. Most of the compounds were estimated to be able to cross the blood-brain barrier (BBB) by passive transport and were nontoxic to human neuronal, kidney and liver cells in concentrations in which they inhibit cholinesterases. Generally, newly synthesised compounds were weak reductants compared to standard antioxidants, but all possessed a certain amount of antioxidant activity compared to tacrine. Of the eleven most potent cholinesterase inhibitors, eight compounds also inhibited BACE1 activity at 10–18%. Based on our overall results, compounds 8 with 3-fluorobenzyl, 11 with 3-chlorobenzyl and 17 with 3-metoxy benzyl substituents on the terminal amino group stood out as the most promising for the treatment of AD; they strongly inhibited AChE and BChE, were non-toxic on HepG2, HEK293 and SH-SY5Y cells, had the potential to cross the BBB and possessed the ability to chelate biometals and/or inhibit the activity of BACE1 within a range close to the therapeutically desired degree of inhibition.
PB  - Elsevier
T2  - Chemico-Biological Interactions
T1  - Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease
VL  - 382
SP  - 110620
DO  - 10.1016/j.cbi.2023.110620
ER  - 

@article{
author = "Matošević, Ana and Opsenica, Dejan and Spasić, Marta and Maraković, Nikola and Zandona, Antonio and Žunec, Suzana and Bartolić, Marija and Kovarik, Zrinka and Bosak, Anita",
year = "2023",
abstract = "The most successful therapeutic strategy in the treatment of Alzheimer's disease (AD) is directed toward increasing levels of the neurotransmitter acetylcholine (ACh) by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes responsible for its hydrolysis. In this paper, we extended our study on 4-aminoquinolines as human cholinesterase inhibitors on twenty-six new 4-aminoquinolines containing an n-octylamino spacer on C(4) and different substituents on the terminal amino group. We evaluated the potency of new derivatives to act as multi-targeted ligands by determining their inhibition potency towards human AChE and BChE, ability to chelate biometals Fe, Cu and Zn, ability to inhibit the action of β-secretase 1 (BACE1) and their antioxidant capacity. All of the tested derivatives were very potent inhibitors of human AChE and BChE with inhibition constants (Ki) ranging from 0.0023 to 1.6 μM. Most of the compounds were estimated to be able to cross the blood-brain barrier (BBB) by passive transport and were nontoxic to human neuronal, kidney and liver cells in concentrations in which they inhibit cholinesterases. Generally, newly synthesised compounds were weak reductants compared to standard antioxidants, but all possessed a certain amount of antioxidant activity compared to tacrine. Of the eleven most potent cholinesterase inhibitors, eight compounds also inhibited BACE1 activity at 10–18%. Based on our overall results, compounds 8 with 3-fluorobenzyl, 11 with 3-chlorobenzyl and 17 with 3-metoxy benzyl substituents on the terminal amino group stood out as the most promising for the treatment of AD; they strongly inhibited AChE and BChE, were non-toxic on HepG2, HEK293 and SH-SY5Y cells, had the potential to cross the BBB and possessed the ability to chelate biometals and/or inhibit the activity of BACE1 within a range close to the therapeutically desired degree of inhibition.",
publisher = "Elsevier",
journal = "Chemico-Biological Interactions",
title = "Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease",
volume = "382",
pages = "110620",
doi = "10.1016/j.cbi.2023.110620"
}

Matošević, A., Opsenica, D., Spasić, M., Maraković, N., Zandona, A., Žunec, S., Bartolić, M., Kovarik, Z.,& Bosak, A.. (2023). Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease. in Chemico-Biological Interactions
Elsevier., 382, 110620.
https://doi.org/10.1016/j.cbi.2023.110620

Matošević A, Opsenica D, Spasić M, Maraković N, Zandona A, Žunec S, Bartolić M, Kovarik Z, Bosak A. Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease. in Chemico-Biological Interactions. 2023;382:110620.
doi:10.1016/j.cbi.2023.110620 .

Matošević, Ana, Opsenica, Dejan, Spasić, Marta, Maraković, Nikola, Zandona, Antonio, Žunec, Suzana, Bartolić, Marija, Kovarik, Zrinka, Bosak, Anita, "Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease" in Chemico-Biological Interactions, 382 (2023):110620,
https://doi.org/10.1016/j.cbi.2023.110620 . .