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

Abstract

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.

Discovery of a Novel Chemo-Type for TAAR1 Agonism via Molecular Modeling

“…Herein, ADMET properties explaining the drug-like profile of compounds 1a-6a and S186116 have been predicted, via the ACD/Lab Percepta platform [70] and SwissADME website [71]. Both of them are well-known tools applied in the prediction of pharmacokinetic properties [72][73][74][75][76][77][78].…”

Acridine–Isoxazole and Acridine–Azirine Hybrids: Synthesis, Photochemical Transformations in the UV/Visible Radiation Boundary Region, and Anticancer Activity

“…A stimulating strategy in drug discovery to maximize efficacy, minimize side effects, and combat drug resistance is the synthesis of hybrid molecules that include a combination of two biologically relevant heterocyclic moieties that act on different targets [6]. In particular, a number of molecular hybrids [7][8][9][10][11][12][13][14][15] containing an acridine moiety have been prepared because of efforts to develop new therapeutic agents. Thus, tacrine-acridine [8], cyclopentaquinoline-acridine [9], and acridine-flavone hybrids [10] are potentially useful for treating Alzheimer's disease, quinoline-acridine and pyrrolidine-acridine-artemisinin hybrids are antimalarials [11][12][13], neocryptolepine-acridine hybrids exhibit antiproliferative activity [6,14], and thiopheneacridine hybrids demonstrate antitumor activity [3,15].…”

“…In particular, a number of molecular hybrids [7][8][9][10][11][12][13][14][15] containing an acridine moiety have been prepared because of efforts to develop new therapeutic agents. Thus, tacrine-acridine [8], cyclopentaquinoline-acridine [9], and acridine-flavone hybrids [10] are potentially useful for treating Alzheimer's disease, quinoline-acridine and pyrrolidine-acridine-artemisinin hybrids are antimalarials [11][12][13], neocryptolepine-acridine hybrids exhibit antiproliferative activity [6,14], and thiopheneacridine hybrids demonstrate antitumor activity [3,15]. Another very important class of N-heterocyclic compound is isoxazoles because they have a wide spectrum of biological activity used as base for developing of several commercially available drugs [16][17][18][19][20][21][22][23][24][25][26].…”

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease

“…Tacrine, (9-amino-1,2,3,4-tetrahydroacridine), an especially well-known acridine-based cholinesterase inhibitor, was the first FDA-approved drug for the treatment of the cognitive symptoms of AD ( Crismon, 1994 ). Along with tacrine, the acridine template has been employed for the design and development of new multifunctional molecules as potential therapeutic agents for AD ( Makhaeva et al, 2017 ; Sharma and Piplani, 2017 ; Chufarova et al, 2018 ; Lotfi et al, 2020 ; Tseng et al, 2020 ; Maciejewska et al, 2022 ).…”