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Article

Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer’s Disease

1
Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, 90-151 Lodz, Poland
2
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
3
Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, 20-090 Lublin, Poland
4
Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 01-163 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Academic Editor: José Luis Marco-Contelles
Int. J. Mol. Sci. 2022, 23(11), 5876; https://doi.org/10.3390/ijms23115876
Received: 1 May 2022 / Revised: 18 May 2022 / Accepted: 19 May 2022 / Published: 24 May 2022
(This article belongs to the Special Issue Advances in Alzheimer’s Disease Drug Research and Development)
A series of new cyclopentaquinoline derivatives with 9-acridinecarboxylic acid and a different alkyl chain length were synthesized, and their ability to inhibit cholinesterases was evaluated. All designed compounds, except derivative 3f, exhibited a selectivity for butyrylcholinesterase (BuChE) with IC50 values ranging from 103 to 539 nM. The 3b derivative revealed the highest inhibitory activity towards BuChE (IC50 = 103.73 nM) and a suitable activity against AChE (IC50 = 272.33 nM). The 3f derivative was the most active compound to AChE (IC50 = 113.34 nM) with satisfactory activity towards BuChE (IC50 = 203.52 nM). The potential hepatotoxic effect was evaluated for both 3b and 3f compounds. The 3b and 3f potential antioxidant activity was measured using the ORAC-FL method. The 3b and 3f derivatives revealed a significantly higher antioxidant potency, respectively 35 and 25 higher than tacrine. Theoretical, physicochemical, and pharmacokinetic properties were calculated using ACD Labs Percepta software. Molecular modeling and kinetic study were used to reveal the mechanism of cholinesterase inhibition in the most potent compounds: 3b and 3f. View Full-Text
Keywords: Alzheimer’s disease; multitarget small molecules; biological activity Alzheimer’s disease; multitarget small molecules; biological activity
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MDPI and ACS Style

Maciejewska, K.; Czarnecka, K.; Kręcisz, P.; Niedziałek, D.; Wieczorek, G.; Skibiński, R.; Szymański, P. Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 5876. https://doi.org/10.3390/ijms23115876

AMA Style

Maciejewska K, Czarnecka K, Kręcisz P, Niedziałek D, Wieczorek G, Skibiński R, Szymański P. Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer’s Disease. International Journal of Molecular Sciences. 2022; 23(11):5876. https://doi.org/10.3390/ijms23115876

Chicago/Turabian Style

Maciejewska, Karolina, Kamila Czarnecka, Paweł Kręcisz, Dorota Niedziałek, Grzegorz Wieczorek, Robert Skibiński, and Paweł Szymański. 2022. "Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer’s Disease" International Journal of Molecular Sciences 23, no. 11: 5876. https://doi.org/10.3390/ijms23115876

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