Structure-activity relationship of acetylcholinesterase inhibitory activity and neurite outgrowth promoting activity of homoisoflavans and related compounds

Inhibitors of acetylcholinesterase (AChE) and agents that enhance neurite outgrowth are regarded as promising therapeutic strategies for addressing neurodegenerative disease including Alzheimer's disease. In this study, a series of homoisoflavonoid derivatives was rationally designed and synthesised, drawing on the structure of (±)-3',4'-dihydroxyhomoisoflavan, a compound previously reported to exhibit both potent AChE inhibitory activity and neurite outgrowth-promoting effects. The structure-activity relationship (SAR) analysis on the synthesised compounds indicated that the presence of a catechol moiety on the B ring is essential for neurite outgrowth-promoting activity. Conversely, modifications to the C-ring had a minimal impact on this activity. Moreover, AChE inhibitory potency was enhanced in analogues with increased lipophilicity compared to the parent compound, 3',4'-dihydroxyhomoisoflavan. Among the seven analogues evaluated, those featuring both a catechol B ring and a C ring in which the oxygen atom was substituted with a carbon atom have emerged as promising lead compounds. These findings underscore the potential of this class of homoisoflavonoid derivatives as candidates for further development as therapeutic agents for dementia.