Dichamanetin attenuates hydrogen peroxide-induced cytotoxicity in retinoic acid (RA) -differentiated human neuroblastoma (SH-SY5Y) cells

Background Alzheimer’s disease (AD) is a leading neurodegenerative disorder that imposes a significant global socioeconomic burden. It is characterised as progressive cognitive decline and a complex multifactorial pathology. Despite extensive research, current therapeutic options are limited. Emerging evidence suggests that oxidative stress is critical in the early pathological event preceding the classical hallmarks of AD. Targeting oxidative stress is a promising strategy for treating AD. Flavonoids are attractive due to their antioxidant, anti-inflammatory, and neuroprotective effects in AD. Dichamanetin (C 29 H 24 O 6 ) is a rare C-benzylated flavanone that seldom occur in nature with reported antibacterial, and anti-malarial. Importantly, it has been suggested to possess anti-Alzheimer’s disease in-silico. However, neither its antioxidative nor neuroprotective potential has been explored in-vitro. Thus, this study aimed to address this gap by establishing an efficient method for the synthesis of dichamanetin and investigating its antioxidant properties and neuroprotective potential against hydrogen peroxide (H₂O₂)-induced cytotoxicity in-vitro. Methods In this study, we described the synthesis of dichamanetin using microwave irradiation and investigated its antioxidative activity using DPPPH and FRAP assay. Furthermore, we studied dichamanetin’s neuroprotective potential against hydrogen peroxide (H 2 O 2 )-insult as an in-vitro AD model using three treatment conditions include pre-treatment, co-treatment, and staggered co-treatment using CCK-8 cell viability assay. Results Dichamanetin was synthesised via microwave irradiation method, overcoming the limitations of isolation and purification from natural sources which often resulted in low yield. The improved synthesis method produced a good yield of 50% and purity of 95–97% determined via LC-MS and 1 H NMR analyses. It shows that dichamanetin has low antioxidative activity as shown by FRAP ability. Importantly, it was non-cytotoxic to cholinergic neurons at concentrations below 3.125 µg/mL. It is shown to be a potent neuroprotectant in protecting the cholinergic neurons against H 2 O 2 -insult at 0.781 µg/mL, eliciting the highest neuroprotective effect in 6-hour staggered co-treatment comparable to quercetin and donepezil. Conclusions Dichamanetin attenuated H₂O₂-induced cytotoxicity in RA-differentiated SH-SY5Y cells, supporting its potential as a neuroprotective candidate against oxidative stress. Further studies are warranted to elucidate the underlying mechanisms and validate its efficacy, pharmacokinetics, safety, and therapeutic potential in relevant in vivo models of Alzheimer’s disease.