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.

Keywords: Alzheimer’s disease; biological activity; multitarget small molecules.

Scheme 1

Synthetic pathway of compounds 2a–2h and 3a–3h. Chemical reagents: (a) 3,5-dichlorobenzoic acid, CDMT, N-methylmorpholine, THF; (b) HCl/ether.

Figure 1

A Lineweaver-Burk plot presenting a mixed-type of AChE inhibition by 3f.

Figure 2

A Lineweaver-Burk plot presenting a mixed-type of BuChE inhibition by 3b.

Figure 3

The cartoon model of the superimposed AChE’s and BuChE’s pockets with the ball-and-stick representations of the key ligand-binding aromatic residues in the pockets of AChE (red) and BuChE (blue). Note that both enzymes share the position of one ligand-binding region, which correspond to the TRP 86 and TRP 82 residues in AChE and BuChE, respectively.

Figure 4

The thermally stable geometries of the smallest ligands in the studied series, calculated at the quantum-mechanical level of theory. Note that the bulky conformation of 3a is additionally stabilized by the intramolecular NH…O hydrogen bond. Both 3b and 3c exhibit hook-shaped structures.

Figure 5

The binding mode of the 3f ligand inside the pocket of AChE. The key ligand-binding aromatic residues in the pocket of AChE are marked in red.

Figure 6

The binding mode of the 3b ligand inside the pocket of BuChE. The key ligand-binding aromatic residues in the pocket of BuChE are marked in blue.