Synthesis of C4-functionalized 1,2,3,4-tetrahydroacridine-based Pfitzinger acid derivatives in deep eutectic solvents and their biological evaluation as dual cholinesterase and α-glucosidase inhibitors

Abstract

Herein, we report an efficient strategy for the synthesis of C4-functionalized novel Pfitzinger acid derivatives via C(sp³)–H bond functionalization. This approach capitalizes on the use of a deep eutectic solvent (DES) comprising N,N′-dimethyl urea and L-(+)-tartaric acid (3 : 1 ratio) at 80 °C as the reaction medium. The 1,2,3,4-tetrahydroacridine-based Pfitzinger acid and its derivatives (methyl/benzyl esters, amides, and Weinreb amides) were used for C4 functionalization with aromatic aldehydes. All the synthesized compounds were evaluated for their dual cholinesterase and α-glucosidase inhibitory activity. Most of the evaluated products showed significant inhibitory activity against AChE, BChE and α-glucosidase enzymes in comparison with standard drug tacrine (AChE IC₅₀ = 201.05 nM; BChE IC₅₀ = 202.14 nM) and acarbose (IC₅₀ = 23 124 nM). Among the tested compounds, 6f showed inhibitory activity with IC₅₀ = 119.45 nM (for AChE) and IC₅₀ = 121.58 nM (for BChE), 6v showed inhibitory activity with IC₅₀ = 121.87 nM (for AChE) and IC₅₀ = 118.25 nM (for BChE) and 9g inhibitory activity against α-glucosidase with IC₅₀ = 21 442 nM. The docking and kinetic studies supported the experimental results obtained through in vitro experiments and predicted drug-like properties.