Studies of design, synthesis and biological properties, ADMET profiling, molecular docking, network pharmacology and molecular dynamics simulation of novel chalcone derivatives containing benzoyl-piperazin.

A close causal relationship exists between Alzheimer's disease (AD) and inflammation, where chronic inflammation serves as a critical driver in AD pathogenesis. To address this, a series of novel chalcone derivatives containing benzoyl-piperazin (2a-2v) were synthesized based on the multi-target drug synthesis strategy. All compounds were tested for their cholinesterase inhibitory activity and antioxidant activity, some compounds were further evaluated for their Aβ1-42 aggregation inhibitory ability, cytotoxicity, metal ion chelating ability, anti-inflammatory activity and in vivo mouse organ toxicity. On this basis, ADMET, molecular docking, network pharmacology analyses and molecular dynamics (MD) simulations were performed on the compounds with better activity. Among these, compound 2q emerged as the most promising candidate, exhibiting the strongest inhibitory activities against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and anti- inflammatory effects. The IC50 values were 73.65 ± 3.50 μM, 88.20 ± 9.56 μM and 31.42 ± 1.91 μM, respectively. Notably, compound 2q achieved a 35.30 ± 2.40% inhibition rate against Aβ1-42 aggregation. Importantly, 2q demonstrated no significant cytotoxicity within the 200 μM concentration range, with no adverse effects on hepatic or renal function, though it exhibited certain metal-ion chelating capabilities. Network pharmacology analysis further identified its interaction with inflammation and AD associated gene targets, including HSP90AA1 and GSK-3β. Furthermore, the stability of the binding of 2q to AChE and BChE was verified by MD simulations. Collectively, these findings suggest that compound 2q, as a multi-targeting agent, warrants further investigation for its therapeutic potential in AD.