Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease
Само за регистроване кориснике
2023
Аутори
Matošević, AnaOpsenica, Dejan
Spasić, Marta
Maraković, Nikola
Zandona, Antonio
Žunec, Suzana
Bartolić, Marija
Kovarik, Zrinka
Bosak, Anita
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 bl...ood-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.
Кључне речи:
Cholinesterase / Quinoline / MTDL / BBB penetration / BACE1 / Metal chelationИзвор:
Chemico-Biological Interactions, 2023, 382, 110620-Издавач:
- Elsevier
Финансирање / пројекти:
- Croatian Science Foundation (Grant no. IP-2020-02-9343)
- Croatian Science Foundation (Grant no. IP-2018-01-7683)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200026 (Универзитет у Београду, Институт за хемију, технологију и металургију - ИХТМ) (RS-MESTD-inst-2020-200026)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200168 (Универзитет у Београду, Хемијски факултет) (RS-MESTD-inst-2020-200168)
DOI: 10.1016/j.cbi.2023.110620
ISSN: 0009-2797
WoS: 001029901500001
Scopus: 2-s2.0-85164329702
Институција/група
IHTMTY - 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 . .