New 1,2,3-triazole derivatives as acetylcholinesterase and carbonic anhydrase inhibitors: Synthesis, molecular docking, and solubility

Abstract

In this study, a series of new 1,2,3-triazole derivatives were synthesized in 84–93 % yield using copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry and characterized by ¹H/¹³C NMR, FT-IR, and HRMS analyses. The synthesized compounds (4a–h) were evaluated for their inhibitory activities against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE), which are clinically relevant targets in neurological and metabolic disorders. Among them, compounds 4f and 4g exhibited the most potent dual inhibitory activities. Compound 4f showed K_I values of 144.30 nM for hCA II and 205.10 nM for AChE, while compound 4g exhibited K_I values of 239.10 nM for hCA II and 125.90 nM for AChE. These values demonstrate that 4f and 4g are more effective than the reference drugs acetazolamide (hCA II, K_I = 381.44 nM) and tacrine (AChE, K_I = 255.44 nM). Structure-activity relationship (SAR) analysis revealed that hydrophobicity, steric bulk, and aromaticity significantly influenced enzyme affinity. In silico docking confirmed strong interactions with key active site residues. Furthermore, ethanol solubility profiling revealed that polar and hydrogen-bonding groups significantly improved solubility, while bulky or aromatic hydrophobic substituents reduced it. The combined biological activity and solubility data emphasize the potential of these triazole derivatives particularly 4f and 4g as promising candidates for multitarget drug design and further preclinical development.