1,2,3‐Triazole Isonicotinate/Nicotinate Derivatives as Cholinesterase and α‐Amylase Inhibitors: Synthesis, Enzyme Inhibition, Antioxidant Activity, and Molecular Docking Studies

The 1,2,3-triazole and pyridine ester moieties represent key structural motifs in medicinal chemistry. 1,2,3-Triazoles serve as versatile pharmacophores due to their chemical stability, hydrogen-bonding potential, and strong interactions with biological targets, whereas pyridine esters enhance pharmacokinetic profiles by increasing lipophilicity and bioavailability. In this study, 1,2,3-triazole-based isonicotinate and nicotinate derivatives (3a-c and 4a-c) were synthesized via click chemistry followed by esterification, and were characterized using FT-IR, ¹H/¹³C NMR, and elemental analysis. The synthesized compounds were evaluated for their inhibitory activities against AChE, BChE, and α-amylase, as well as their antioxidant potential using DPPH and ABTS radical scavenging assays. Compound 3c showed the strongest AChE inhibition (IC₅₀ = 12.67±0.66 µM), while 3a exhibited the highest BChE inhibitory activity (IC₅₀ = 14.59±0.048 µM). Compound 4c, a 1,2,3-triazole nicotinate derivative, demonstrated good activity against AChE (IC₅₀ = 10.08±0.12 µM), BChE (IC₅₀ = 6.51±0.052 µM), and α-amylase (IC₅₀ = 7.76±0.09 µM), outperforming standard inhibitors. Compound 3c exhibited very good antioxidant activity using DPPH and ABTS radical scavenging tests. Molecular docking studies supported the experimental findings, demonstrating appropriate binding energies and essential hydrogen bonds and π-π interactions at the active sites of the target enzymes. Computerized ADME analysis showed promising pharmacokinetic properties, including high gastrointestinal absorption and blood-brain barrier permeability.