Muzychka_2026_RSC.Adv_16_2417

The development of acetylcholinesterase (AChE) inhibitors remains a promising research direction in drug discovery for Alzheimer's disease. A series of eighteen pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized as novel tacrine-like AChE inhibitors. Sixteen compounds inhibited AChE in the micromolar range. Among them, 4-(dimethylamino)-7,8-dimethylpyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6(7H)-one (22) exhibited the highest inhibitory activity against the enzyme with an IC(50) value of 0.22 +/- 0.02 microM, showing mixed-type inhibition. In silico studies showed that 22 occupies the catalytic anionic site of hAChE and forms strong Pi-Pi stacking interactions with Trp86, similar to those of tacrine. This study demonstrates the potential use of methyl-substituted pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidines in the development of potent AChE inhibitors.