Design, synthesis and evaluation of new pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidines as tacrine-like acetylcholinesterase inhibitors

Abstract

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 IC₅₀ value of 0.22 ± 0.02 µM, showing mixed-type inhibition. In silico studies showed that 22 occupies the catalytic anionic site of hAChE and forms strong π–π 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.