Copper Nanoparticle‐Catalyzed Click Assembly of 1,2,3‐Triazolylphosphonates

The development of efficient and sustainable synthetic methodologies for accessing structurally complex molecules remains a key objective in organic chemistry. Herein, we report the design and synthesis of a library of 22 β ‐1,2,3‐triazolylphosphonate derivatives, 21 previously unreported, obtained through the integration of robust synthetic strategies under green conditions. The 1,2,3‐triazole scaffold was assembled via a Cu(I)‐catalyzed azide–alkyne cycloaddition click reaction using supported copper nanoparticles as an efficient and recyclable catalyst, while the phosphonate fragments were introduced through established organophosphorus methodologies. All compounds were fully characterized and evaluated for their in vitro acetyl‐ and butyrylcholinesterase (AChE and BChE) inhibitory activity. The majority of the derivatives exhibited pronounced selectivity toward BChE inhibition, with compounds 4aca and 4ack emerging as the most potent inhibitors (IC 50 = 2.7 and 2.9 µM, respectively). Notably, compound 4ack showed significantly lower neurotoxicity in N27 cells compared to 4aca , displaying a two‐order‐of‐magnitude separation between its BChE inhibitory potency and cytotoxic effects (IC 50 = 255.3 and 37.3 µM, respectively). In silico absorption, distribution, metabolism, and excretion predictions were performed for all derivatives. Collectively, these results highlight β ‐1,2,3‐triazolylphosphonates as a versatile chemical platform and underscore the effectiveness of combining click chemistry with organophosphorus approaches for the generation of structurally diverse bioactive candidates.