Discovery of novel deoxyvasicinone derivatives with benzenesulfonamide substituents as multifunctional agents against Alzheimer's disease

A series of deoxyvasicinone derivatives with benzenesulfonamide substituents were designed and synthesized to find a multifunctional anti-Alzheimer's disease (AD) drug. The results of the biological activity evaluation indicated that most compounds demonstrated selective inhibition of acetylcholinesterase (AChE). Among them, g17 exhibited the most potent inhibitory effect on AChE (IC50 = 0.24 ± 0.04 μM). Additionally, g17 exhibited promising properties as a metal chelator and inhibitor of amyloid β peptides self-aggregation (68.34 % ± 1.16 %). Research on oxidative stress has shown that g17 displays neuroprotective effects and effectively suppresses the intracellular accumulation of reactive oxygen species. Besides, g17 demonstrated remarkable anti-neuroinflammatory effects by significantly reducing the production of pro-inflammatory cytokines (such as NO, IL-1β, and TNF-α) and inhibiting the expression of inflammatory mediators iNOS and COX-2. In vivo studies showed that g17 significantly improved AD model mice's cognitive and memory abilities. Histological examination of mouse hippocampal tissue sections using hematoxylin and eosin staining revealed that g17 effectively mitigates neuronal damage. Considering the multifunctional properties of g17, it is regarded as a promising lead compound for treating AD.